Preoperative risk stratification based on PDE4D7 and DHX9 expression

Abstract

The present invention relates to a method for preoperative risk stratification of prostate cancer subjects, comprising determining the gene expression profile of phosphodiesterase 4D variant 7 (PDE4D7) in a biological sample obtained from the subject, determining the gene expression profile of DExH-box helicase 9 (DHX9) in the same or another biological sample obtained from the subject, and determining the preoperative prognostic risk score of the subject based on the gene expression profile of PDE4D7 and the gene expression profile of DHX9. This can improve the stratification of subjects in the preoperative setting and can obtain better primary treatment decisions. For example, for certain subgroups of prostate cancer patients, the preoperative prognostic risk score can provide better suggestions on whether to choose active monitoring or active intervention such as radical prostatectomy.

Description

Field of the Invention

[0001] The present invention relates to a method for preoperative risk stratification of prostate cancer subjects. Furthermore, the present invention relates to a diagnostic kit, the use of the diagnostic kit in a method for preoperative risk stratification of prostate cancer subjects, and the use of gene expression profiles of phosphodiesterase 4D variant 7 (PDE4D7) and DExH-box helicase 9 (DHX9) in preoperative risk stratification of prostate cancer subjects, as well as corresponding computer program products. Background of the Invention

[0003] Cancer is a class of diseases in which a group of cells exhibit uncontrolled growth, invasion, and sometimes metastasis. These three malignant properties of cancer distinguish it from benign tumors, which are self-limiting and do not invade or metastasize. Prostate cancer (PCa) is the most common non-skin malignancy in men, with approximately 1.1 million new cases diagnosed worldwide in 2012 (see Ferlay J. et al., GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet], Lyon, France, International Agency for Research on Cancer, 2013).

[0004] Due to the aging population, the incidence of PCa will further increase in the future (see Quon H. et al., "Dramatic increase in prostate cancer cases by 2021", BJU International, Vol. 108, No. 11, pages 1734 to 1738, 2011). Routine diagnosis by determining blood levels of prostate-specific antigen (PSA), digital rectal examination (DRE) and transrectal ultrasound analysis (TRUS) has led to significant first-line overdiagnosis of non-cancerous, benign prostate conditions (see Bangma CH et al., "Overdiagnosis and overtreatment of early detected prostate cancer", World Journal of Urology, Vol. 25, No. 1, pages 3 to 9, 2007, and FHet al., “Screening and Prostate-Cancer Mortality in a Randomized European Study”, The New England Journal of Medicine, Vol. 360, No. 13, pages 1320 to 1328, 2009): In the United States alone, approximately 250,000 new cases are found in the approximately 1 million prostate biopsies performed each year, and approximately 75% are unnecessary, resulting in many complications for patients (urosepsis, bleeding, and urinary retention) and a total cost of more than $2 billion (approximately $2,100 per biopsy procedure). At least 4 out of every 100 men with a negative biopsy are likely to be hospitalized due to side effects, and 9 out of every 10,000 biopsy patients are at risk of dying from currently used procedures (see Nam RK et al., "Increasing hospital admission rates for urological complications after transrectal ultrasound guided biopsy", Journal of Urology, Vol. 183, No. 3, pages 963 to 968, 2010).

[0005] Of the approximately 250,000 newly diagnosed PCa cases in the United States each year, approximately 200,000 are initially diagnosed as localized disease (see Snyder CF et al., “How does initial treatment choice affect short-term and long-term costs for clinically localized prostate cancer?”, Cancer, Vol. 116, No. 23, pages 5391 to 5399, 2010 and Cooperberg MR et al., “Contemporary trends in low-risk prostate cancer: risk assessment and treatment”, Journal of Urology, Vol. 173, No. 3, Pt. 2, pages 14 to 19, 2007), meaning the cancer is confined to the prostate gland. This condition can be cured to some extent by primary treatment, such as radiation therapy or, in particular, partial or complete removal of the prostate by surgery (prostatectomy). However, these interventions are often associated with serious side effects, particularly urinary incontinence and / or erectile dysfunction, which are very common consequences of prostatectomy. Up to 50% of men who undergo radical prostatectomy experience urinary incontinence. Studies show that 15% to 50% of men still report this problem one year after surgery. Erection problems are also a serious side effect of radical prostatectomy (RP). Only about half of men who undergo the surgery regain some ability to have an erection. Furthermore, all commonly used local PCa treatments are expensive (typically in the range of $20,000 to $30,000), resulting in a total direct cost of $5 billion annually in the United States.

[0006] Of the approximately 200,000 men diagnosed with clinically localized disease in the United States, up to 50% have very low-risk or low-risk cancer (see Bangma CHand Roobol MJ, "Defining and predicting indolent and low prostate cancer", Critical Reviews in Oncology / Hematology, Vol. 83, No. 2, pages 235 to 241, 2012). As a result, the NCCN (National Comprehensive Cancer Network) recently revised its PCa treatment guidelines, expanding active surveillance (AS) as a mild and convenient treatment option for patients with this low-risk disease (see www.nccn.org). By referring appropriate patients to AS, the quality of life of these patients is significantly improved compared to men who undergo primary treatment, and the 5-year cost of AS per patient is reported to be less than $10,000 (see Snyder CF et al.).

[0007] In addition, in the case of selecting surgery (relative to AS) as a treatment option for a given patient, stratifying the extent of surgery according to the potential progressiveness of the patient's tumor has significant advantages. For example, nerve-sparing surgical techniques can be more generally applied to men with predicted low-risk disease to minimize the sexual performance-related side effects of radical prostatectomy. Similarly, according to the latest prostate cancer guidelines of the European Association of Urology (EAU), although the extended lymph node dissection surgical procedure is complicated, time-consuming and associated with a higher complication rate compared to more limited methods, it is still recommended to implement (see Heidenreich A. et al., "Guidelines on Prostate Cancer", European Association of Urology, 2012) in the case of predicted high-risk cancer. Therefore, although less restricted lymph node dissection has been shown to miss approximately 50% of lymph node metastases (see Heidenreich A. et al., “Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis”, Journal of Urology, Vol. 167, No. 4, pages 1681 to 1686, 2002 and Bader P. et al, “Is a limited lymph node dissection and adequate staging procedure for prostate cancer?”, Journal of Urology, Vo. 168, No. 2, pages 514 to 518, 2002), treatment options for patients with localized prostate cancer require highly accurate preoperative prediction of the aggressive potential of individual tumors to provide optimal care for each patient.

[0008] WO 2014 / 028884 A2 discloses methods, systems, and kits for diagnosing, prognosing, and determining the progression of cancer in a subject. Further disclosed are methods, systems, and kits for determining a treatment modality for cancer in a subject. The methods, systems, and kits comprise expression-based biomarker analysis. Also disclosed are probe sets for assessing the cancer status of a subject. SUMMARY OF THE INVENTION

[0010] The present invention provides a method for preoperative risk stratification of prostate cancer subjects, which can improve preoperative prediction of the aggressive potential of individual tumors. Another object of the present invention is to provide a diagnostic kit, the use of the diagnostic kit in a method for preoperative risk stratification of prostate cancer subjects, the use of gene expression profiles of phosphodiesterase 4D variant 7 (PDE4D7) and DExH-box helicase 9 (DHX9) in preoperative risk stratification of prostate cancer subjects, and corresponding computer program products.

[0011] In a first aspect of the present invention, a method for preoperative risk stratification of a prostate cancer subject is provided, comprising:

[0012] - determining the gene expression profile of phosphodiesterase 4D variant 7 (PDE4D7) in a biological sample obtained from said subject,

[0013] - determining the gene expression profile of DExH-box helicase 9 (DHX9) in the same or another biological sample obtained from said subject, and

[0014] - determining a preoperative prognostic risk score for the subject based on the gene expression profile of PDE4D7 and the gene expression profile of DHX9.

[0015] The cAMP signaling pathway is known to play an important role in the development and progression of prostate cancer (see Merkle D. and Hoffmann R., "Roles of cAMP and cAMP-dependent protein kinase in the progression of prostate cancer: Cross-talk with the androgen receptor", Cellular Signaling, Vol. 23, No. 3, pages 507-515, 2011). Although the adenylate cyclase family is responsible for the synthesis of cAMP, cyclic nucleotide phosphodiesterases (PDEs) appear to represent the only cellular mechanism for its destruction. PDEs provide both signal termination and, more importantly, compartmentalization of cAMP signaling within the cellular 3D matrix. This is achieved by spatially discrete disruption of cAMP by subsets of different PDE isoforms sequestered by local anchor proteins / signalosomes (see, e.g., Conti M. and Beavo J., "Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling", Annual Review of Biochemistry, Vol. 76, pages 481-511, 2007). Thus, changes in the expression and / or activity of different PDE isoforms can alter downstream signaling pathways during disease onset and progression, providing potential targets for new biomarkers and targeted therapeutic interventions. Indeed, altered expression of members of the PDE4 family that degrade cAMP appears to be associated with a number of different diseases, including stroke, acrodysostosis, schizophrenia, and COPD. In recent years, it has been shown that downregulation of a specific PDE4 isoform (PDE4D7) may have an impact on prostate cancer (see, e.g., R. et al., "Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG-positive primary prostate cancer and independently increases the risk of post-surgical disease progression", British Journal of Cancer, Vol. 113, No. 10, pages 1502-1511, 2015). The PDE4D7 isoform is a so-called long isoform because it contains both the UCR1 and UCR2 regulatory domains. UCR1 is found in long, but not short, PDE4 isoforms and can be regulated by various protein kinases, including PKA and MK2, and can also determine the functional consequences of phosphorylation of the ERK catalytic unit. Functionally, it provides part of the cellular desensitization system for cAMP and enables crosstalk between signaling pathways that lead to, for example, activation of ERK and AMPK.

[0016] Emerging evidence suggests that human helicases such as DHX9 can act as hubs in cellular networks to coordinate cellular stress responses, maintain cell homeostasis to survive or trigger cell death. Interestingly, a series of human cancer cell lines have recently been shown to be susceptible to inhibition of DHX9 helicase activity both in vitro and in vivo. Gene expression profiling of tumor cells after DHX9 inhibition revealed deregulation of a series of pathways involved in tumorigenesis or development. In addition, DHX9 has recently been described as a major player in resolving R-loop-related DNA damage, which supports the maintenance of genomic stability. Due to rearrangements at the genomic level, the disruption of this process may lead to cancer occurrence and progression, a phenomenon that has been confirmed in many cancers. These recent findings are strongly supported by the data generated by the present inventors, showing that DHX9 gene expression is significantly correlated with prostate cancer recurrence time in a clinical prostate cancer patient cohort during longitudinal follow-up (unpublished data).

[0017] The present inventors have identified and confirmed the interaction between PDE4D7 and the helicase DHX9 in prostate cancer cells. Furthermore, it was shown that the N-terminal domain of DHX9 is phosphorylated in vitro by cAMP-dependent protein kinase A (PKA). This raises the question of whether this post-translational modification by PKA has any regulatory effect on the activity or cellular localization of DHX9, and whether the interaction with PDE4D7 influences phosphorylation in DHX9 microdomains by regulating cyclic AMP. In view of this, PDE4D7, as a newly identified interactor of DHX9, may play a key role in directly or indirectly controlling the function of DHX9 in prostate cancer development.

[0018] By determining a preoperative prognostic risk score for prostate cancer subjects based on the gene expression profiles of both PDE4D7 and DHX9, additional molecular information representing disease biology is obtained. By determining a preoperative prognostic risk score based on the gene expression profiles of both PDE4D7 and DHX9, the prognostic power of PDE4D7 and DHX9 can be used for preoperative patient risk assessment. This can improve subject stratification in the preoperative setting and lead to better primary treatment decisions. For example, for certain subpopulations of prostate cancer patients, a preoperative prognostic risk score can provide better advice on whether to choose active surveillance or active intervention, such as radical prostatectomy.

[0019] The term "phosphodiesterase 4D7" or "PDE4D7" refers to splice variant 7 of the human phosphodiesterase PDE4D, i.e., the human phosphodiesterase PDE4D7 gene, such as the sequence defined in NCBI Reference Sequence: NM_001165899.1, in particular the nucleotide sequence set forth in SEQ ID NO: 19, which corresponds to the sequence of the NCBI Reference Sequence for the PDE4D7 transcript, and also to the corresponding amino acid sequence, such as that set forth in SEQ ID NO: 20, which corresponds to the protein sequence defined in NCBI Protein Accession Reference Sequence NP_001159371.1 encoding the PDE4D7 polypeptide. The term "phosphodiesterase 4D7" or "PDE4D7" also refers to an amplicon that can be generated by the primer pair PDE4D7_Forward (SEQ ID NO: 21) and PDE4D7_Reverse (SEQ ID NO: 22) and detected by the probe SEQ ID NO: 23.

[0020] The PDE4D7 polypeptide can also be detected using the primer pair PDE4D7-2_Forward (SEQ ID NO: 24) and PDE4D7_Reverse (SEQ ID NO: 25) and can be detected using the probe SEQ ID NO: 26.

[0021] The term "PDE4D7" also encompasses nucleotide sequences having a high degree of homology to PDE4D7, such as nucleic acid sequences that are at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 19, or amino acid sequences that are at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 20, or nucleic acid sequences encoding amino acid sequences that are at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 20, or nucleic acid sequences encoding amino acid sequences that are at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: 20, or nucleic acid sequences encoding amino acid sequences that are at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO: The amino acid sequence encoded by the nucleic acid sequence shown in NO:19 has at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity.

[0022] The term "DExH-box helicase 9" or "DHX9" refers to the human DExH-box helicase 9 gene, such as the sequence defined in the NCBI reference sequence: NM_001357.4 (Ensembl: ENSG00000135829), in particular the nucleotide sequence shown in SEQ ID NO: 74, which corresponds to the sequence of the NCBI reference sequence of the above-mentioned DHX9 transcript, and also relates to the corresponding amino acid sequence shown in, for example, SEQ ID NO: 75, which corresponds to the protein sequence defined in the NCBI protein accession reference sequence NP_001348.2 encoding the DHX9 polypeptide.

[0023] The term "DHX9" also includes nucleotide sequences having a high degree of homology to DHX9, such as a nucleic acid sequence having at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the sequence of SEQ ID NO:74, or an amino acid sequence having at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the sequence of SEQ ID NO:75, or a nucleic acid sequence encoding an amino acid sequence having at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the sequence of SEQ ID NO:75, or a nucleic acid sequence encoding an amino acid sequence having at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the sequence of SEQ ID NO: The amino acid sequence encoded by the nucleic acid sequence shown in NO:74 has at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity.

[0024] The term "biological sample" or "sample obtained from a subject" refers to any biological material obtained from a subject, such as a prostate cancer patient, by a suitable method known to those skilled in the art. The biological sample used can be collected in a clinically acceptable manner, such as in a manner that preserves nucleic acids (particularly RNA) or proteins.

[0025] The biological sample may include body tissues and / or body fluids, such as, but not limited to, blood, sweat, and urine. In addition, the biological sample may include a cell extract derived from epithelial cells or a cell population comprising epithelial cells, such as cancerous epithelial cells or epithelial cells derived from suspected cancerous tissue. The biological sample may include a cell population derived from glandular tissue, for example, the sample may be derived from the prostate of a male subject. In addition, if necessary, cells can be purified from the obtained body tissues and body fluids and then used as a biological sample. In some instances, the sample may be a tissue sample, a urine sample, a urine sediment sample, a blood sample, a saliva sample, a semen sample, a sample comprising circulating tumor cells, an extracellular vesicle, a sample comprising exosomes secreted by the prostate, or a cell line or cancer cell line.

[0026] In a specific example, a biopsy or resection sample can be obtained and / or used. Such a sample can include cells or cell lysates.

[0027] It is also conceivable that the contents of the biological sample may be subjected to an enrichment step. For example, the sample may be contacted with a ligand specific for the cell membrane or organelles of certain cell types, such as prostate cells, which ligand is, for example, functionalized with magnetic particles. The material concentrated by the magnetic particles may then be used in the detection and analysis steps described above or below.

[0028] Furthermore, cells such as tumor cells can be enriched by filtration methods of fluid or liquid samples such as blood, urine, etc. Such filtration methods can also be combined with enrichment steps based on ligand-specific interactions as described above.

[0029] The term "prostate cancer" refers to a cancer of the prostate gland of the male reproductive system that occurs when prostate cells mutate and begin to proliferate uncontrollably. Typically, prostate cancer is associated with elevated levels of prostate-specific antigen (PSA). In one embodiment of the invention, the term "prostate cancer" relates to a cancer that shows a PSA level higher than 4.0. In another embodiment, the term relates to a cancer that shows a PSA level higher than 2.0. The term "PSA level" refers to the concentration of PSA in the blood in ng / ml.

[0030] The term "non-progressive prostate cancer status" refers to an individual sample that does not show parameter values ​​indicative of "biochemical recurrence" and / or "clinical recurrence".

[0031] The term "progressive prostate cancer status" refers to an individual sample showing parameter values ​​indicative of "biochemical recurrence" and / or "clinical recurrence".

[0032] The term "biochemical recurrence" generally refers to an increased PSA recurrence biological value, indicating the presence of prostate cancer cells in a sample. However, other markers that can be used to detect the presence or suspicion of such presence may also be used.

[0033] The term "clinical recurrence" refers to the presence of clinical signs indicating the presence of tumor cells, for example as measured using in vivo imaging.

[0034] As used herein, the term "prognosis of prostate cancer" refers to, for example, a period of time, during treatment or after treatment, a prediction of the course or outcome of the prostate cancer diagnosed or detected. The term also refers to determining that the subject will survive or recover from the disease, and predicts the expected survival time of the subject. Specifically, prognosis can include determining that the subject will survive for a period of time in the future, for example, 6 months, 1 year, 2 years, 3 years, 5 years, 10 years or any other time period.

[0035] Preferably, the gene expression profile of PDE4D7 and the gene expression profile of DHX9 are combined with a regression function obtained from a population of prostate cancer subjects.

[0036] Regression analysis helps people understand how the typical value of a dependent variable (or "standard variable") changes when any one of the independent variables changes while the other independent variables remain fixed. This relationship between the dependent and independent variables is recorded in a regression function, which can be used to predict the dependent variable given the values ​​of the independent variables. The dependent variable can be, for example, a binary variable, such as biochemical recurrence within 5 years after surgery. In this case, the regression is a logarithmic regression based on the logarithmic function of the independent variables (here, including or consisting of the gene expression profile of PDE4D7 and the gene expression profile of DHX9). With the help of the regression function, it is possible to improve the prediction of, for example, the risk of biochemical recurrence 5 years after surgery.

[0037] Preferably, the method further comprises:

[0038] - Based on the preoperative prognostic risk score, recommending a primary treatment for the subject, wherein the primary treatment is selected from: (i) at least partial prostatectomy; (ii) active treatment selected from radiation therapy, hormonal therapy, chemotherapy, and combinations thereof; and (iii) active surveillance.

[0039] Various national and international guidelines recommend different treatments for men with prostate cancer based on their risk of future disease progression and life expectancy. For example, active surveillance (AS) is often recommended for men with very-low- and low-risk prostate cancer, while radical prostatectomy may be indicated for high-risk cancer. However, known clinical risk descriptors do not effectively describe the extent of disease or its aggressiveness in all patients. For example, a distinct subgroup of patients within the National Comprehensive Cancer Network (NCCN) very-low- and low-risk groups has been identified who have a 10%-25% risk of cancer recurrence after primary treatment. Similarly, a subgroup within the intermediate-risk group is known to have a low risk of biochemical progression. By recommending primary treatment for men based on their preoperative prognostic risk score, better advice can be provided regarding whether to choose active surveillance or active intervention, such as radical prostatectomy, for certain subgroups of men with prostate cancer.

[0040] It is further preferred that the method comprises:

[0041] - normalizing the gene expression profile of PDE4D7 and / or the gene expression profile of DHX9 to one or more reference genes selected from the group consisting of: Homo sapiens hypoxanthine phosphoribosyltransferase 1 (HPRT1), tubulin-alpha-1b (TUBA1B), Homo sapiens pumilio RNA binding family member (PUM1) and Homo sapiens TATA box binding protein (TBP), wherein a preoperative prognostic risk score is determined based on the normalized gene expression profile.

[0042] By normalizing the gene expression profile against one or more reference genes and determining a preoperative prognostic risk score based on the normalized gene expression profile, the variability in determining the preoperative prognostic risk score can be reduced. This allows for differentiation between actual changes in the gene expression profile and changes due to the measurement method. In this regard, HPRT1, TUBA1B, PUM1, and TBP have been found to be particularly suitable reference genes for normalizing the PDE4D7 and / or DHX9 gene expression profiles.

[0043] Gene expression profiles can be determined by detecting mRNA expression using one or more primers and / or probes and / or one or more sets of primers and / or probes. In addition, gene expression profiles can be determined by amplification-based methods and / or microarray analysis and / or RNA sequencing. Determination of gene expression profiles can include performing real-time quantitative polymerase chain reaction (RT-qPCR) on RNA extracted from a biological sample. In other embodiments, gene expression profiles are determined by RNA sequencing, conventional PCR (using, for example, endpoint analysis by gel electrophoresis), or multiplex PCR. In the case of RT-qPCR, determination of gene expression profiles can include determining threshold cycle (Ct) values ​​for each of PDE4D7 and / or DHX9 and the one or more reference genes. PCR can be performed using at least one primer and / or probe to measure reference genes selected from HPRT1, TUBA1B, PUM1, and TBP.

[0044] Preferably, the one or more reference genes include at least two, or at least three, or all of HPRT1, TUBA1B, PUM1 and TBP.

[0045] Other reference genes that can be used additionally or alternatively to normalize PDE4D7 and / or DHX9 gene expression profiles include: Homo sapiens actin beta mRNA (ACTB); Homo sapiens 60S acidic ribosomal phosphoprotein P0 mRNA (RPLP0); polymerase (RNA) II (DNA-directed) polypeptide A, 220 kDa (POLR2A); beta-2-microglobulin (B2M); and aminolevulinic acid-delta-synthase (ALAS-1).

[0046] In some preferred embodiments, a standardized gene expression profile for PDE4D7 and / or DHX9 is converted to a predetermined range of values, such as a range of 1-5, using a suitable conversion function. The conversion function is preferably derived from the corresponding standardized gene expression profile, for example, the gene expression profiles for PDE4D7 and / or DHX9 standardized relative to HPRT1, TUBA1B, PUM1, and TBP for biological samples from a population of prostate cancer subjects (which can be the same population used to derive the regression function). In a preferred embodiment, the conversion function can be a linear conversion that converts the standardized gene expression profile to a predetermined range of values. This conversion can be determined by considering the frequency distribution of standardized gene expression profile values ​​for, for example, PDE4D7 (or DHX9) for biological samples from a population of prostate cancer subjects and determining a conversion that converts the frequency distribution to a desired range. By utilizing such a conversion function, the gene expression profile can be presented in a user-intuitive manner, such as a small positive range. This is similar to other classifications used in clinical practice, such as histopathological grading (Gleason) or multi-parameter MRI radiological scoring (PIRADS).

[0047] In a specific example, the transformed normalized gene expression profile is determined as follows:

[0048] TNGEP=(((GENE_norm+A)*B)+1), (1)

[0049] where "TNGEP" is the transformed normalized gene expression profile, "GENE_norm" is the normalized PDE4D7 or DHX9 gene expression profile value, A and B are variables and are appropriately selected to map "GENE_norm" to the desired value range.

[0050] Particularly preferably, determining the gene expression profile of PDE4D7 and / or the gene expression profile of DHX9 comprises performing RT-qPCR on RNA extracted from the biological sample, wherein the Cq value of PDE4D7 and / or DHX9 and / or each of the one or more reference genes is determined, wherein determining the preoperative risk score comprises normalizing the Cq value of PDE4D7 and / or DHX9 using the Cq value of each of the one or more reference genes and calculating the preoperative risk score based on the normalized Cq value.

[0051] For example, a normalized Cq value for PDE4D7 can be generated by applying the following formula:

[0052] N(Cq PDE4D7 )=Mean(Cq ref_genes )–(Cq PDE4D7 ), (2)

[0053] Where N(CqPDE4D7 ) is the normalized gene expression profile value (quantification cycle, Cq) of PDE4D7, Mean (Cq ref_genes ) is the arithmetic mean of the PCR Cq values ​​of the one or more reference genes, Cq PDE4D7 is the PCR Cq value of PDE4D7.

[0054] Likewise, the normalized Cq value for DHX9 can be generated by applying the following formula:

[0055] N(Cq DHX9 )=Mean(Cq ref_genes )–(Cq DHX9 ), (3)

[0056] Where N(Cq DHX9 ) is the normalized gene expression profile value (quantification cycle, Cq) of DHX9, Mean (Cq ref_genes ) is the arithmetic mean of the PCR Cq values ​​of the one or more reference genes, Cq DHX9 is the PCR Cq value of DHX9.

[0057] In another aspect of the present invention, a diagnostic kit is provided, comprising:

[0058] at least one primer and / or probe for determining the gene expression profile of phosphodiesterase 4D variant 7 (PDE4D7) in a biological sample obtained from a subject with prostate cancer;

[0059] at least one primer and / or probe for determining the gene expression profile of DExH-box helicase 9 (DHX9) in the same or another biological sample obtained from the subject; and

[0060] Optionally, at least one primer and / or probe for determining the gene expression profile of one or more reference genes selected from the group consisting of: Homo sapiens hypoxanthine phosphoribosyltransferase 1 (HPRT1), tubulin alpha-1b (TUBA1B), Homo sapiens pumilio RNA binding family member (PUM1), and Homo sapiens TATA box binding protein (TBP);

[0061] The diagnostic kit further comprises instructions for calculating a preoperative prognostic risk score based on the gene expression profile of PDE4D7 and the gene expression profile of DHX9, wherein the instructions are stored on a computer program product, and when executed by a computer, the computer performs a method comprising:

[0062] - determining a preoperative prognostic risk score for the subject based on the gene expression profile of PDE4D7 and the gene expression profile of DHX9, optionally wherein the method comprises:

[0063] - normalizing the gene expression profile of PDE4D7 and / or the gene expression profile of DHX9 relative to said one or more reference genes,

[0064] Among them, a preoperative prognostic risk score was determined based on standardized gene expression profiles.

[0065] Preferably, the instructions for calculating a preoperative prognostic risk score comprise instructions for combining the gene expression profile of PDE4D7 and the gene expression profile of DHX9 with a regression function derived from a population of prostate cancer subjects.

[0066] In another aspect of the present invention, there is provided a use of the diagnostic kit according to claim 7 or 8 in a method for preoperative risk stratification of prostate cancer subjects.

[0067] In another aspect of the present invention, there is provided a method for using a gene expression profile of phosphodiesterase 4D variant 7 (PDE4D7) and a gene expression profile of DExH-box helicase 9 (DHX9) in preoperative risk stratification of prostate cancer subjects, comprising:

[0068] - determining the gene expression profile of PDE4D7 in a biological sample obtained from said subject,

[0069] - determining the gene expression profile of DHX9 in the same or another biological sample obtained from said subject, and

[0070] - determining a preoperative prognostic risk score for the subject based on the gene expression profile of PDE4D7 and the gene expression profile of DHX9.

[0071] Preferably, the gene expression profile of PDE4D7 and the gene expression profile of DHX9 are combined with a regression function obtained from a population of prostate cancer subjects.

[0072] In another aspect of the present invention, there is provided a computer program product comprising instructions, which, when executed by a computer, cause the computer to perform a method comprising:

[0073] - determining a preoperative prognostic risk score for prostate cancer subjects based on the gene expression profile of phosphodiesterase 4D variant 7 (PDE4D7) and the gene expression profile of DExH-box helicase 9 (DHX9),

[0074] wherein the gene expression profile of PDE4D7 is determined in a biological sample obtained from the subject, and the gene expression profile of DHX9 is determined in the same or another biological sample obtained from the subject.

[0075] Preferably, the gene expression profile of PDE4D7 and the gene expression profile of DHX9 are combined with a regression function obtained from a population of prostate cancer subjects.

[0076] In a further preferred embodiment, the postoperative prognostic risk score of the subject is determined based on the preoperative prognostic risk score and the postoperative clinical risk score CAPRA-S.

[0077] Preferably, the preoperative prognostic risk score and the postoperative clinical risk score CAPRA-S are combined with a regression function derived from a population of prostate cancer subjects.

[0078] These further preferred embodiments can be realized by the method of claim 1 , the diagnostic kit of claim 7 , the use of the diagnostic kit of claim 9 , the use of the gene expression profile of claim 10 and the computer program of claim 12 .

[0079] It is to be understood that the method of claim 1 , the diagnostic kit of claim 7 , the use of the diagnostic kit of claim 9 , the use of the gene expression profile of claim 10 and the computer program of claim 12 have similar and / or identical preferred embodiments, in particular as defined in the accompanying claims.

[0080] It shall be understood that a preferred embodiment of the invention can also be any combination of the appended claims or the above embodiments and the respective independent claims.

[0081] These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter. Sequence Listing <110> Royal Philips Ltd. Glasgow University Council <120> Preoperative risk stratification based on PDE4D7 and DHX9 expression <130> 2018PF00399 <160> 75 <170> PatentIn version 3.5 <210> 1 <211> 7801 <212> DNA <213> Homo sapiens <400> 1 gtggtggccg cgcacccggc cgcggctgat tcattcactt caagtgccgt gcagaaggct 60 cggcaggcgg ggcgggcgtg gggccgcggc tccgggttgg ggaccgagga gatccggctg 120 tggaccagac gctcctctgc ggggcgggca cccaagcgcg ctcgccaccc cctcgccatc cgctagagcc gggctcctgg actgggactc gggcccgccg cacagttgaa aagtcgcata gtggtttttc cgctcgcgtc gctgtgtgaa agttggctcg ccgctctttg cacgccctcc 300 ctggaggccg acccgagacg ccaagctgga gagaccgtgc ctccccgagg ccggccgccc 360 cgcgagcaca gcctccgccc ccgttgcact gccgggctgg gcaatatgaa ggagcagccc 420 tcatgtgccg gcaccgggca tccgagcatg gcggggtatg gcaggatggc cccctttgaa 480 ctcgctagcg gacccgtgaa gcgcttgaga actgagtccc cctttccctg tctcttcgca 540 gaggaggcct accagaaact ggccagcgag accctggagg agctggactg gtgtctggac 600 cagctagaga ccctacagac caggcactcc gtcagtgaga tggcctccaa caagtttaaa aggatgctta atcgggagct cacccatctc tctgaaatga gtcggtctgg aaatcaagtg tcagagttta tatcaaacac attcttagat aagcaacatg aagtggaat tccttctcca actcagaagg aaaaggagaa aaaagaaaaga ccaatgtctc agatcagtgg agtcaagaaa ttgatgcaca gctctagtct gactaattca agtatcccaa ggtttggagt taaaactgaa 900 caagaagatg tccttgccaa ggaactagaa gatgtgaaca aatggggtct tcatgttttc 960 agaatagcag agttgtctgg taaccggccc ttgactgtta tcatgcacac catttttcag 1020 gaacgggatt tattaaaaac atttaaaatt ccagtagata ctttaattac atatcttatg 1080 actctcgaag accattacca tgctgatgtg gcctatcaca acaatatcca tgctgcagat 1140 gttgtccagt ctactcatgt gctattatct acacctgctt tggaggctgt gtttacagat 1200 ttggagattc ttgcagcaat ttttgccagt gcaatacatg atgtagatca tcctggtgtg 1260 tccaatcaat ttctgatcaa tacaaactct gaacttgcct tgatgtacaa tgattcctca 1320 gtcttagaga accatcattt ggctgtgggc tttaaattgc ttcaggaaga aaactgtgac 1380 attttccaga atttgaccaa aaaacaaaga caatctttaa ggaaaatggt cattgacatc 1440 gtacttgcaa cagatatgtc aaaacacatg aatctactgg ctgatttgaa gactatggtt 1500 gaaactaaga aagtgacaag ctctggagtt cttcttcttg ataattattc cgataggatt 1560 caggttcttc agaattggt gcactgtgca gatctgagca acccaacaaa gcctctccag ctgtaccgcc agtggacgga ccggataatg gaggagttct tccgccaagg agaccgagag agggaacgtg gcatggagat aagccccatg tgtgacaagc acaatgcttc cgtggaaaaa tcacaggtgg gcttcataga ctatattgtt catcccctct gggagacatg ggcagacctc gtccaccctg acgcccagga tattttggac actttggagg acaatcgtga atggtaccag agcacaatcc ctcagagccc ctctcctgca cctgatgacc cagaggaggg ccggcagggt 1980 - 1980 - 1980 - 1980 - 1980 - 1980 - 1980 - aaggacagtg gcagtcaagt ggaagaagac actagctgca gtgactccaa gactctttgt actcaagact cagagtctac tgaaattccc cttgatgac aggttgaga ggaggcagta ggggaagaag aggaaagcca gcctgaagcc tgtgtcatag atgatcgttc tcctgacacg taacagtgca aaaactttca tgcctttttt ttttttaagt agaaaaattg tttccaaagt gcatgtcaca tgccacaacc acggtcacac ctcactgtca tctgccagga cgtttgttga aaaaactga ccttgactac tcagtccagc gctcaggaat atcgtacca gttttcac 2340 ctccatgtca tccgagcaag gtggacatct tcacgacag cgtttttaac aagatttcag 2400 cttggtagag ctgacaaagc agataaaatc tactccaat tattttcaag agagtgtgac 2460 tcatcaggca gcccaaagt ttattggact tggttttct attccttttt atttgttgc 2520 atattttca gagaaaggc attgcacaga gtgaacttaa tggacgaagc aaaaatg 2580 tcagacag gattagcac gatctgtta ccagtaggg gaggatgagc cacagaatt 2640 gcataatttt ctaatttcaa gtcttcctga tacatgactg atagtgtgg ttcagtgagc 2700 tgcactgacc tctacatttt gtatgatatg taaaacagat tttgtaga gcttactttt 2760 attattaaat gtattgaggt attattatta aaaaaaacta tgttcagac ttcatctgcc 2820 actggttatt tttctaag gagtaacttg caagttttca gtacaatct gtgctacact 2880 ggataaaaat ctaatttatg atttactt gcaccttata gttcatagca atttactgat 2940 ttgtagtgat tcattgtttg ttttatatac caatgacttc catattttaa agagaaaaa 3000 caactttatg ttgcaggaaa ccctttttgt aagtctttat tatttacttt gcattttgtt 3060 tcactctttc cagataagca gagttgctct tcaccagtgt ttttcttcat gtgcaaagtg 3120 actatttgtt ctataatact tttatgtgtg ttatatcaaa tgtgtcttaa gcttcatgca 3180 aactcagtca tcagttcgtg ttgtctgaag caagtgggag atatataaat acccagtagc 3240 taaaatggtc agtctttttt agatgttttc ctacttagta tctcctaata acgttttgct 3300 gtgtcactag atgttcattt cacaagtgca tgtctttcta ataatccaca catttcatgc 3360 tctaataatc cacacatttc atgctcattt ttattgtttt tacagccagt tatagtaaga 3420 aaaaggtttt tccccttgtg ctgctttata atttagcgtg tgtctgaacc ttatccatgt 3480 ttgctagatg aggtcttgtc aaatatatca ctaccattgt caccggtgaa aagaaacagg 3540 tagttaagtt agggttaaca ttcatttcaa ccacgaggtt gtatatcatg actagctttt 3600 actcttggtt tacagagaaa agttaaacag ccaactaggc agtttttaag aatattaaca 3660 atatattaac aaacaccaat acaactaatc ctatttggtt ttaatgattt caccatggga 3720 ttaagaacta tatcaggaac atccctgaga aacggtttta agtgtagcaa ctactcttcc 3780 ttaatggaca gccacataac gtgtaggaag tcctttatca cttatcctcg atccataagc 3840 atacttgca gaggggaact acttctttaa acacatggag ggaaagaaga tgatgccact 3900 ggcaccagag ggttagtact gtgatgcatc ctaaaatatt tattatattg gtaaaaattc 3960 tggttaaata aaaattaga gatcactctt ggctgatttc agcaccagga actgtattac 4020 agttttagag attaattcct agtgtttacc tgattatagc agttggcatc atggggcatt 4080 taattctgac tttatcccca cgtcagcctt aataaagtct tctttacctt ctctatgaag 4140 actttaaagc ccaaataatc atttttcaca ttgatattca agaattgaga tagatagaag 4200 ccaaagtggg tatctgacaa gtggaaaatc aaacgtttaa gaagaattac aactctgaaa 4260 agcatttata tgtggaactt ctcaaggagc ctcctgggga ctggaaagta agtcatcagc 4320 caggcaaatg actcatgctg aagagagtcc ccatttcagt cccctgagat ctagctgatg 4380 cttagatcct ttgaaataaa aattatgtct ttataactct gatcttttac ataaagcaga 4440 agaggaatca actagttaat tgcaggttt ctactctgtt tcctctgtaa agatcagatg 4500 gtaatctttc aaataagaaaaataaga cgtatgtttg accaagtagt ttcacaagaa 4560 tatttgggaa cttgttctt ttaatttt ttgtccctga gtgaagtcta gaaagaaagg 4620 taaagagtct agagttt cctctttcca aaacattctc attcctcc tcctacact 4680 tagtatttcc cccacagagt gcctagaatc ttaataatga aaaaataa aagcagcaat 4740 atgtcattaa caatccaga cctgaaaggg taaagggtttt attackgcac taaaagg 4800 aggcttttt tttcttcc agtttgttgg ttttaatg taccgtgttg taagatacc 4860 cactaatgga caatcaatt gcagaaaagg ctcaatcc aagagacagg gactaatgca 4920 ctgtacaatc tgcttatcct tgccctc tcttgccaaa gtgtgctca gaaatatata 4980 ctgctttaaa aaagataaa agatatcct tttacaagtg gctttacatt tcctaaaatg 5040 ccataagaaa atgcaatc tgggtactgt atggggaaa aaatgtccaa gtttgtgtaa 5100 aaccagtgca ttcagcttg caagttactg aacacaataa tgctgtttta attttgtttt 5160 atacagtta aattcacaa tatgtagat agacaaatt acagacaagg aaaaaaaa 5220 cttgaatgaa atggatttta cagaaagctt tattgaatgca ttattattt 5280 ttgtgccat gcatttttt tctcaccaaa tgaccttacc tgtaatacag tcttgtttgt 5340 ctgtttacaa ccatgtattt attgcaatgt acatactgta atgttaattg taaattatct 5400 gttcttatta aaacatcatc ccatgatggg atggtgttga tatattgga aactcttggt 5460 gagagaatga atggtgtgta tacatactct gtacattttt cttttctccct gtaatatagt 5520 cttgtcacct tagacttgt ttatggaaga ttcaagaaa ctataaaata cttaaagata 5580 tataaattta aaaaaacata gctgcaggtc ttgtccca gggctgtgcc tttaactttaa 5640 ccaatatttt cttctgtttt gctgcattg aaggtaaca gtggagctag ggctgggcat 5700 tttacatcca ggctttaat tgattagaat tctgccaata ggtggatttt acaaaccac 5760 agacaacctc tgaaagattc tgagacctt tgagacaga agctcttaag tactctttgc 5820 cagggagcag cactgcatgt gtgatggttg ttgccatct gttgatcagg aactacttca 5880 5940 aatatattct ttcccagtga ttaaaacaa tctttttctt ttttttaagt ccttttggct 6000 tctagagctc ataggaaaat ggacttgatt tgaaattgga gccagagttt actcgtgttg 6060 gttatctatt catcagcttc ctgacatgtt aagagaatac attaagaga aaatactgtt 6120 ttttaatcct aaaatttttc ttccactaag ataaaccaaa tgtccttaca tatatgtaaa 6180 cccatctatt taaacgcaaa ggtgggttga tgtcagttta catagcagaa agcattcact 6240 atcctctaag atttgtttct gcaaaacttt cattgcttta gaattttaaa atttcacctt 6300 gtacaatggc cagcccctaa agcaggaaac atttataatg gattatatgg aaacatcctc 6360 ccagtacttg cccagccctt gaatcatgtg gcttttcagt gaaggaaag attctttttc 6420 taggaaaaat gagcctattt tattttatt tattttatt tttgacacaa actgtagatt 6480 ttagcagccc tggcccaaag gaatttgatt acttttgttt taaacagtac aaaggggaca 6540 ctataattac aaaaacatcc ttaactgatt tgagttgttt ttattcttt ggatatattt 6600 tcagagtggt aaattgtgtg tgagaattac aaatgattat tcttttagtg gtttcttagc 6660 ctctcttaca gcccacgggg atagtactgt acatcaatac cttcatatga aatttttata 6720 tgcaatgaaa ataaaagcat gggttgattc tgcctatta tgactcaatc tttaacaaat 6780 aaaagattat tcattttaaa ttatagttca atcagcatgt ctcttaggat actgaacgtg 6840 gttgaaatga agatagtg acatcataag ttagtactga tattcataac caataaagc 6900 caacttgagt aattttgcta cattaaaat taccaaaatt acttagatgg cctataagat 6960 taagcatggt gttttctaag caagctttga aaggggcctt ccatacttac ttaattgaat 7020 attctgggat attgaaaatt attcagatac ttgacaatta tttttggtta cctactccgc 7080 aaactacaaa gttttaagga ctcaacaata agttaatgag acacagtgtt tgctttcatg 7140 gagcttacag tctggagggg aaaaggctt aaacaatact catataatta tatatgtgat 7200 cattacaatg aaggagctca gtggggtaaa taagcaggaa cctgaacttg atctgttccg 7260 gagggccaca gaaggcttcc ttgaggcctt gagaaagtga tttgcatctg agttctgaag 7320 gattgtaaga ggtaactagg gaaaaagttg acaggaagag gaaggggatc cagacaagaa 7380 acatttgcaa agatcttgag gcataaatga gcttgagaca tctggagaaa ctgaggaaaa 7440 gtgagagagt aggcagggcc tggagccgca gagccattgc taaccatcct gtgtgagata 7500 tcccccattc tgtagcttta ttctcataac cctgctcaat tttctttata acacttctca 7560 cagatttata tacgtgtttg tttttgttat ctgtctctcc caccagacca cagctccatg 7620 agagcaaggt ctttgcttac caatatatca ctagcactta aaactatgcc tggtacacag 7680 taggttctta atatgtgttg aatatagcca tcaaattgat attggatata attcaatctg 7740 ataagatatt ttgagatatt aaagagtttt taacttgata ccataaaaaa aaaaaaaaaa 7800 a 7801 <210> 2 <211> 585 <212> PRT <213> Homo sapiens <400> 2 Met Lys Glu Gln Pro Ser Cys Ala Gly Thr Gly His Pro Ser Met Ala 1 5 10 15 Gly Tyr Gly Arg Met Ala Pro Phe Glu Leu Ala Ser Gly Pro Val Lys 20 25 30 Arg Leu Arg Thr Glu Ser Pro Phe Pro Cys Leu Phe Ala Glu Glu Ala 35 40 45 Tyr Gln Lys Leu Ala Ser Glu Thr Leu Glu Glu Leu Asp Trp Cys Leu 50 55 60 Asp Gln Leu Glu Thr Leu Gln Thr Arg His Ser Val Ser Glu Met Ala 65 70 75 80 Ser Asn Lys Phe Lys Arg Met Leu Asn Arg Glu Leu Thr His Leu Ser 85 90 95 Glu Met Ser Arg Ser Gly Asn Gln Val Ser Glu Phe Ile Ser Asn Thr 100 105 110 Phe Leu Asp Lys Gln His Glu Val Glu Ile Pro Ser Pro Thr Gln Lys 115 120 125 Glu Lys Glu Lys Lys Lys Arg Pro Met Ser Gln Ile Ser Gly Val Lys 130 135 140 Lys Leu Met His Ser Ser Ser Leu Thr Asn Ser Ser Ile Pro Arg Phe 145 150 155 160 Gly Val Lys Thr Glu Gln Glu Asp Val Leu Ala Lys Glu Leu Glu Asp 165 170 175 Val Asn Lys Trp Gly Leu His Val Phe Arg Ile Ala Glu Leu Ser Gly 180 185 190 Asn Arg Pro Leu Thr Val Ile Met His Thr Ile Phe Gln Glu Arg Asp 195 200 205 Leu Leu Lys Thr Phe Lys Ile Pro Val Asp Thr Leu Ile Thr Tyr Leu 210 215 220 Met Thr Leu Glu Asp His Tyr His Ala Asp Val Ala Tyr His Asn Asn 225 230 235 240 Ile His Ala Ala Asp Val Val Gln Ser Thr His Val Leu Leu Ser Thr 245 250 255 Pro Ala Leu Glu Ala Val Phe Thr Asp Leu Glu Ile Leu Ala Ala Ile 260 265 270 Phe Ala Ser Ala Ile His Asp Val Asp His Pro Gly Val Ser Asn Gln 275 280 285 Phe Leu Ile Asn Thr Asn Ser Glu Leu Ala Leu Met Tyr Asn Asp Ser 290 295 300 Ser Val Leu Glu Asn His His Leu Ala Val Gly Phe Lys Leu Leu Gln 305 310 315 320 Glu Glu Asn Cys Asp Ile Phe Gln Asn Leu Thr Lys Lys Gln Arg Gln 325 330 335 Ser Leu Arg Lys Met Val Ile Asp Ile Val Leu Ala Thr Asp Met Ser 340 345 350 Lys His Met Asn Leu Leu Ala Asp Leu Lys Thr Met Val Glu Thr Lys 355 360 365 Lys Val Thr Ser Ser Gly Val Leu Leu Leu Asp Asn Tyr Ser Asp Arg 370 375 380 Ile Gln Val Leu Gln Asn Met Val His Cys Ala Asp Leu Ser Asn Pro 385 390 395 400 Thr Lys Pro Leu Gln Leu Tyr Arg Gln Trp Thr Asp Arg Ile Met Glu 405 410 415 Glu Phe Phe Arg Gln Gly Asp Arg Glu Arg Glu Arg Gly Met Glu Ile 420 425 430 Ser Pro Met Cys Asp Lys His Asn Ala Ser Val Glu Lys Ser Gln Val 435 440 445 Gly Phe Ile Asp Tyr Ile Val His Pro Leu Trp Glu Thr Trp Ala Asp 450 455 460 Leu Val His Pro Asp Ala Gln Asp Ile Leu Asp Thr Leu Glu Asp Asn 465 470 475 480 Arg Glu Trp Tyr Gln Ser Thr Ile Pro Gln Ser Pro Ser Pro Ala Pro 485 490 495 Asp Asp Pro Glu Glu Gly Arg Gln Gly Gln Thr Glu Lys Phe Gln Phe 500 505 510 Glu Leu Thr Leu Glu Glu Asp Gly Glu Ser Asp Thr Glu Lys Asp Ser 515 520 525 Gly Ser Gln Val Glu Glu Asp Thr Ser Cys Ser Asp Ser Lys Thr Leu 530 535 540 Cys Thr Gln Asp Ser Glu Ser Thr Glu Ile Pro Leu Asp Glu Gln Val 545 550 555 560 Glu Glu Glu Ala Val Gly Glu Glu Glu Glu Ser Gln Pro Glu Ala Cys 565 570 575 Val Ile Asp Asp Arg Ser Pro Asp Thr 580 585 <210> 3 <211> twenty one <212> DNA <213> Artificial sequence <220> <223> PDE4D1D2_Forward Primer <400> 3 aatatgaagg agcagccctc a 21 <210> 4 <211> 18 <212> DNA <213> Artificial sequence <220> <223> PDE4D1D2_reverse primer <400> 4 gtctcgctgg ccagtttc 18 <210> 5 <211> 18 <212> DNA <213> Artificial sequence <220> <223> PDE4D1D2 probe <400> 5 catccgagca tggcggga 18 <210> 6 <211> 7715 <212> DNA <213> Homo sapiens <400> ) 6 gtggtggccg cgcacccggc cgcggctgat tcattcactt caagtgccgt gcagaaggct 60 cggcaggcgg ggcgggcgtg gggccgcggc tccgggttgg ggaccgagga gatccggctg 120 tggaccagac gctcctctgc ggggcgggca cccaagcgcg ctcgccaccc cctcgccatc 180 cgctagagcc gggctcctgg actgggactc gggcccgccg cacagttgaa aagtcgcata 240 gtggtttttc cgctcgcgtc gctgtgtgaa agttggctcg ccgctctttg cacgccctcc 300 ctggaggccg acccgagacg ccaagctgga gagaccgtgc ctccccgagg ccggccgccc 360 cgcgagcaca gcctccgccc ccgttgcact gccgggctgg gcaatatgaa ggagcagccc 420 tcatgtgccg gcaccgggca tccgagcatg gcgggaggag gcctaccaga aactggccag 480 cgagaccctg gaggagctgg actggtgtct ggaccagcta gagaccctac agaccaggca 540 ctccgtcagt gagatggcct ccaacaagtt taaaaggatg cttaatcggg agctcaccca 600 tctctctgaa atgagtcggt ctggaaatca agtgtcagag tttatatcaa acacattctt 660 agataagcaa catgaagtgg aaattccttc tccaactcag aaggaaaagg agaaaaagaa 720 aagaccaatg tctcagatca gtggagtcaa gaaattgatg cacagctcta gtctgactaa 780 ttcaagtatc ccaaggtttg gagttaaaac tgaacaagaa gatgtccttg ccaaggaact 840 agaagatgtg aacaaatggg gtcttcatgt tttcagaata gcagagttgt ctggtaaccg 900 gcccttgact gttatcatgc acaccatttt tcaggaacgg gatttattaa aaacatttaa 960 aattccagta gatactttaa ttacatatct tatgactctc gaagaccatt accatgctga 1020 tgtggcctat cacaacaata tccatgctgc agatgttgtc cagtctactc atgtgctatt 1080 atctacacct gctttggagg ctgtgtttac agatttggag attcttgcag caatttttgc 1140 cagtgcaata catgatgtag atcatcctgg tgtgtccaat caatttctga tcaatacaaa 1200 ctctgaactt gccttgatgt acaatgattc ctcagctta gagaaccatc atttggctgt 1260 gggctttaaa ttgcttcagg aagaaaactg tgacattttc cagaatttga ccaaaaaaca 1320 aagacaatct tggaaaaa tggtcattga catcgtactt gcacagata tgtcaaaca 1380 catgaatcta ctggctgat tgagactat ggttgaact aagaagtga caagctctgg 1440 agttctctt cttgataatt attccgatag gattcaggtt cttcagaata tggtgcactg 1500 tgcagatctg agcaccca CAAAGCCCT ccagctgtac cgccagtgga cggaccgat 1560 aatggaggag ttctccgcc aaggagaccg agagaggga cgtggcatgg agataagcccc 1620 catgtgtgac aagcacaatg cttccgtgga aaatcacag gtggggcttca tagactatat 1680 tgttcatccc ctctgggaga catgggcaga cctcgtccac cctgacgccc aggatatttt 1740 ggacactttg gaggacaatc gtgaatgta ccagagcaca atccctcaga gcccctcc 1800 tgcacctgat gacccagagg agggccggca gggtcaact gagaaatttcc agtttgaact 1860 aactttagag gagatggtg agtcagacac ggaaaggac agtggcagtc aagtgaaga 1920 agacactagc tgcagtgact ccagactct tgtactca gactcagagt ctactgaat 1980 tccccttgat gaacaggttg agaggaggc agtagggaa gagaggaaa gccagcctga 2040 agcctgtgtc atagatgatc gttctcctga cacgtaacag tgcaaaaact ttcatgcctt 2100 tttttttt aagtagaaaa attgtttcca aagtgcatgt cacatgccac aaccacggtc 2160 acacctcact gtcatctgcc aggacgtttg ttgaacaaaa ctgaccttga ctactcagtc 2220 cagcgctcag gaatatcgta accagttttt tcacctccat gtcatccgag caaggtggac 2280 atcttcacga acagcgtttt taacaagatt tcagcttggt agagctgaca aagcagataa 2340 aatctactcc aaattatttt caagagagtg tgactcatca ggcagcccaa aagtttattg 2400 gacttggggt ttctattcct ttttattgt ttgcaatatt ttcagaagaa aggcattgca 2460 cagagtgaac ttaatggacg aagcaacaaa tatgtcaaga acaggacata gcacgaatct 2520 gttaccagta ggaggaggat gagccacaga aattgcataa ttttctaatt tcaagtcttc 2580 ctgatacatg actgaatagt gtggttcagt gagctgcact gacctctaca ttttgtatga 2640 tatgtaaaac agattttttg tagagcttac ttttattatt aaatgtattg aggtattata 2700 tttaaaaaaa actatgttca gaacttcatc tgccactggt tatttttttc taaggagtaa 2760 cttgcaagtt ttcagtacaa atctgtgcta cactggataa aaatctaatt tatgaatttt 2820 acttgcacct tatagttcat agcaattaac tgatttgtag tgattcattg tttgttttat 2880 ataccaatga cttccatatt ttaaaagaga aaaacaactt tatgttgcag gaaacccttt 2940 ttgtaagtct ttattattta ctttgcattt tgtttcactc tttccagata agcagagttg 3000 ctcttcacca gtgtttttct tcatgtgcaa agtgactatt tgttctataa tacttttatg 3060 tgtgttatat caaatgtgtc ttaagcttca tgcaaactca gtcatcagtt cgtgttgtct 3120 gaagcaagtg ggagatatat aaatacccag tagctaaaat ggtcagtctt ttttagatgt 3180 tttcctactt agtatctcct aataacgttt tgctgtgtca ctagatgttc atttcacaag 3240 tgcatgtctt tctaataatc cacacatttc atgctctaat aatccacaca tttcatgctc 3300 atttttattg tttttacagc cagttatagt aagaaaaagg tttttcccct tgtgctgctt 3360 tataatttag cgtgtgtctg aaccttatcc atgtttgcta gatgaggtct tgtcaaatat 3420 atcactacca ttgtcaccgg tgaaaagaaa caggtagtta agttagggtt aacattcatt 3480 tcaccacga gttgtatat catgactagc ttttactt ggtttacaga gaaaagttaa 3540 spy aggcagttt windows aaxaatat window spy spy 3600 aatcctattt gttttaatg atttcaccat gggattaaga actatatcag gaacatccct 3660 gagaaacggt tttaagtgta gcaactactc ttccttaatg gatagccaca taacgtgtag 3720 gaagtccttt atcacttatc ctcgatccat aagcatatct tgcagagggg aactacttct 3780 ttaaacacat ggagggaag aagatgatgc cactggcacc agagggttag tactgtgatg 3840 catcctaaaa tattattat attggtaaaa attctggtta aaaaaaat tagagatcac 3900 tcttggctga ttcagcacc aggaactgta ttacagtttt agattaat tcctagtgtt 3960 tacctgatta tagcagttgg catcatgggg catttaattc tgacttatc cccacgtcag 4020 ccttataaa gtctcttta ccttcttat gagacttta aagcccaaat atcattttt 4080 cacattgata ttcaagaatt gagatagata gaagccaag tggtactctg acagtggaa 4140 aatcaaacgt ttagagaa ttacaactct gaaagcatt ttatgtgga acttctcaag 4200 gagcctcctg gggactggaa agtaagtcat cagccaggca aatgactcat gctgaagaga 4260 gtccccattt cagtcccctg agatctagct gatgcttaga tcctttgaaa taaaaattat 4320 gtctttataa ctctgatctt ttacataaag cagaagagga atcaactagt taattgcaag 4380 gtttctactc tgtttcctct gtaaagatca gatggtaatc tttcaaataa gaaaaaaaata 4440 aagacgtatg tttgaccaag tagtttcaca agaatatttg ggaacttgtt tcttttaatt 4500 ttatttgtcc ctgagtgaag tctagaaaga aaggtaaaga gtctagagtt tattcctctt 4560 tccaaaacat tctcattcct ctcctcccta cacttagtat ttcccccaca gagtgcctag 4620 aatcttaata atgaataaaa taaaaagcag caatatgtca ttaacaaatc cagacctgaa 4680 agggtaaagg gtttataact gcactataata agagaggctc tttttttttc ttccagtttg 4740 ttggttttta atggtaccgt gttgtaaaga taccactaa tggacaatca aattgcagaa 4800 aaggctcaat atccaagaga cagggactaa tgcactgtac aatctgctta tccttgccct 4860 tctctcttgc caaagtgtgc ttcagaaata tatactgctt taaaaaagaa taaaaagaata 4920 tccttttaca agtggcttta cattcctaa atgccataa gaaatgcaa tatctgggta 4980 ctgtatgggg aaaaaaatgt ccaagttgt gtaaaaccag tgcattcag ctgcaagtt 5040 actgaacaca ataatgctgt tttaatttg ttttatatca gttaaaattc acaataatgt 5100 agatagaca attacagac aaaga aaaacttgaa tgaatggat tttacagaaa 5160 gctttatgat aatttttgaa tgcattattt atttttgtg ccatgcattt tttctcac 5220 caaatgacct tacctgtaat acagcttgt tgtctgttt acaaccatgt atttattgca 5280 atgtacatac tgtaatgtta attgtaaatt atctgttctt attaaaacat catcccatga 5340 tgggatggtg tgatatatt tggaaactct tggtgagaga atgaatggtg tgtatacata 5400 ctctgtacat tttctttc tcctgtaata tagtcttgtc accttagagc ttgtttatgg 5460 aagattcaag aaactataa atacttaaa gatatataa ttaaaaaa catagctgca 5520 ggtctttgt cccaggggctg tgccttaact ttaccata ttttctctg tttgctgca 5580 ttgaaggt aacagtggag ctaggggctgg gcattttaca tccaggcttt taattgatta 5640 gattctgcc ataggtgga ttttacaaa ccacagacaa cctctgaaag attctgagac 5700 ccttttgaga cagaagctct taagtacttc ttgccaggga gcagcactgc atgtgtgatg 5760 gttgtttgcc atctgttgat caggaactac ttcagctact tgcattgat tattccttt 5820 tttttttt ttactcgga aacacaactg gggaaatata ttcttttt gtgattataa 5880 acaatcttt tcttttttt aagtcctttt gggctctaga gctcatagga aaatggactt 5940 gatttgaaat tggagccaga gtttactcgt gttggttatc tattcatcag cttcctgaca 6000 tgttaagaga atacattaaa gagaaaatac tgttttttaa tcctaaaattt ttctctccac 6060 tattataac aaggtggg tacatatatg taaacccatc tatttaacg haaggtggg 6120 ttgatgtcag tttacatagc agaaagcatt cactatccctc taagattgt ttctgcaaaa 6180 ctttcattgc tttagaattt taaaatttca ccttgtacaa tggccagccc ctaaagcagg 6240 aaacatttat atggattat atggaacat cctcccagta cttgccagc ccttgaatca 6300 tgtggctttt cagtgaaagg aagattcttt tttctaggaa aaatgagcct attttattt 6360 attttattt attttttgac acaactgta gattttagca gccctggccc aaggaattt 6420 gattactttt gttttaaca gtacaagggg vakactaa ttacaaaac atccttaact 6480 gatttgagtt gttttattt ctttggatat attttcagag tggtaattg tgtgtgagaa 6540 ttacaaatga ttattcttt agtggttct tagcctct tacagcccac ggggatagta 6600 ctgtacatca ataccttcat atgaatttt tatatgcaat gaaaataaa gcatggggttg 6660 attctgccta tttatgactc aatctttac aaaaaga ttattcattt taaattatag 6720 ttcaatcagc atgtctctta ggatactgaa cgtggttgaa atgaaaggat agtgacatca 6780 taagttagta ctgatattca taaccaata aagccaactt gagtatttt gctacattaa 6840 aaattaccaa attackattag atggcctata agattaagca tggtgttttc taagcaagct 6900 ttgaaagggg ccttccatac ttacttatt gatatttctg ggatattgaa attattcag 6960 atacttgaca attatttttg gttacctact ccgcaacta CAagtttta aggactcac 7020 aaagttaa tgagacacag tgtttgcttt catggagctt acagtctgga ggggacaaag 7080 gcttaaacaa tactcatata attatatatg tgatcagtac aatgaaggag ctcagtgggg 7140 taaataagca ggaacctgaa cttgatctgt tccggagggc cacagaaggc ttccttgagg 7200 ccttgagaaa gtgatttgca tctgagttct gaaggattgt aagaggtaac tagggaaaaa 7260 gttgacagga agaggaaggg gatccagaca agaaacattt gcaaagatct tgaggcataa 7320 atgagcttga gacatctgga gaaactgagg aaaagtgaga gagtaggcag ggcctggagc 7380 cgcagagcca ttgctaacca tcctgtgtga gatatccccc attctgtagc tttattctca 7440 taaccctgct caattttctt tataacactt ctcacagatt tatatacgtg tttgtttttg 7500 ttatctgtct ctcccaccag accacagctc catgagagca aggtctttgc ttaccaatat 7560 atcactagca cttaaaacta tgcctggtac acagtaggtt cttaatatgt gttgaatata 7620 gccatcaaat tgatattgga tataattcaa tctgataaga tattttgaga tattaaagag 7680 tttttaactt gataccataa aaaaaaaaaa aaaaa 7715 <210> 7 <211> 507 <212> PRT <213> Homo sapiens <400> 7 Met Ala Ser Asn Lys Phe Lys Arg Met Leu Asn Arg Glu Leu Thr His 1 5 10 15 Leu Ser Glu Met Ser Arg Ser Gly Asn Gln Val Ser Glu Phe Ile Ser 20 25 30 Asn Thr Phe Leu Asp Lys Gln His Glu Val Glu Ile Pro Ser Pro Thr 35 40 45 Gln Lys Glu Lys Glu Lys Lys Lys Arg Pro Met Ser Gln Ile Ser Gly 50 55 60 Val Lys Lys Leu Met His Ser Ser Ser Leu Thr Asn Ser Ser Ile Pro 65 70 75 80 Arg Phe Gly Val Lys Thr Glu Gln Glu Asp Val Leu Ala Lys Glu Leu 85 90 95 Glu Asp Val Asn Lys Trp Gly Leu His Val Phe Arg Ile Ala Glu Leu 100 105 110 Ser Gly Asn Arg Pro Leu Thr Val Ile Met His Thr Ile Phe Gln Glu 115 120 125 Arg Asp Leu Leu Lys Thr Phe Lys Ile Pro Val Asp Thr Leu Ile Thr 130 135 140 Tyr Leu Met Thr Leu Glu Asp His Tyr His Ala Asp Val Ala Tyr His 145 150 155 160 Asn Asn Ile His Ala Ala Asp Val Val Gln Ser Thr His Val Leu Leu 165 170 175 Ser Thr Pro Ala Leu Glu Ala Val Phe Thr Asp Leu Glu Ile Leu Ala 180 185 190 Ala Ile Phe Ala Ser Ala Ile His Asp Val Asp His Pro Gly Val Ser 195 200 205 Asn Gln Phe Leu Ile Asn Thr Asn Ser Glu Leu Ala Leu Met Tyr Asn 210 215 220 Asp Ser Ser Val Leu Glu Asn His His Leu Ala Val Gly Phe Lys Leu 225 230 235 240 Leu Gln Glu Glu Asn Cys Asp Ile Phe Gln Asn Leu Thr Lys Lys Gln 245 250 255 Arg Gln Ser Leu Arg Lys Met Val Ile Asp Ile Val Leu Ala Thr Asp 260 265 270 Met Ser Lys His Met Asn Leu Leu Ala Asp Leu Lys Thr Met Val Glu 275 280 285 Thr Lys Lys Val Thr Ser Ser Gly Val Leu Leu Leu Asp Asn Tyr Ser 290 295 300 Asp Arg Ile Gln Val Leu Gln Asn Met Val His Cys Ala Asp Leu Ser 305 310 315 320 Asn Pro Thr Lys Pro Leu Gln Leu Tyr Arg Gln Trp Thr Asp Arg Ile 325 330 335 Met Glu Glu Phe Phe Arg Gln Gly Asp Arg Glu Arg Glu Arg Gly Met 340 345 350 Glu Ile Ser Pro Met Cys Asp Lys His Asn Ala Ser Val Glu Lys Ser 355 360 365 Gln Val Gly Phe Ile Asp Tyr Ile Val His Pro Leu Trp Glu Thr Trp 370 375 380 Ala Asp Leu Val His Pro Asp Ala Gln Asp Ile Leu Asp Thr Leu Glu 385 390 395 400 Asp Asn Arg Glu Trp Tyr Gln Ser Thr Ile Pro Gln Ser Pro Ser Pro 405 410 415 Ala Pro Asp Asp Pro Glu Glu Gly Arg Gln Gly Gln Thr Glu Lys Phe 420 425 430 Gln Phe Glu Leu Thr Leu Glu Glu Asp Gly Glu Ser Asp Thr Glu Lys 435 440 445 Asp Ser Gly Ser Gln Val Glu Glu Asp Thr Ser Cys Ser Asp Ser Lys 450 455 460 Thr Leu Cys Thr Gln Asp Ser Glu Ser Thr Glu Ile Pro Leu Asp Glu 465 470 475 480 Gln Val Glu Glu Glu Ala Val Gly Glu Glu Glu Glu Ser Gln Pro Glu 485 490 495 Ala Cys Val Ile Asp Asp Arg Ser Pro Asp Thr 500 505 <210> 8 <211> 7783 <212> DNA <213> Homo sapiens <400> 8 aatacttgtt gcaataattg cccacgatag ctgctcaaac aagagagttg gaattcatct 60 gtaaaaatca ctacatgtaa cgtaggagac aagaaaaata ttaatgacag aagatctgcg 120 aacatgatgc acgtgaataa ttttcccttt agaaggcatt cctggatatg ttttgatgtg 180 gacaatggca catctgcggg acggagtccc ttggatccca tgaccagccc aggatccggg 240 ctaattctcc aagcaaattt tgtccacagt caacgacggg agtccttcct gtatcgatcc 300 gacagcgatt atgacctctc tccaaagtct atgtcccgga actcctccat tgccagtgat 360 atacacggag atgacttgat tgtgactcca tttgctcagg tcttggccag tctgcgaact 420 gtacgaaaca actttgctgc attaactaat ttgcaagatc gagcacctag caaaagatca 480 cccatgtgca accaaccatc catcaacaaa gccaccataa cagaggaggc ctaccagaaa 540 ctggccagcg agaccctgga ggagctggac tggtgtctgg accagctaga gaccctacag 600 accaggcact ccgtcagtga gatggcctcc aacaagttta aaaggatgct taatcgggag 660 ctcacccatc tctctgaaat gagtcggtct ggaaatcaag tgtcagagtt tatatcaaac 720 acattcttag ataagcaaca tgaagtggaa attccttctc caactcagaa ggaaaaggag 780 aaaaagaaaa gaccaatgtc tcagatcagt ggagtcaaga aattgatgca cagctctagt 840 ctgactaatt caagtatccc aaggtttgga gttaaaactg aacaagaaga tgtccttgcc 900 aaggaactag aagatgtgaa caaatggggt cttcatgttt tcagaatagc agagttgtct 960 ggtaaccggc ccttgactgt tatcatgcac accatttttc aggaacgggga tttattaaaa 1020 acatttaaaa ttccagtaga tactttaatt acatatctta tgactctcga agaccattac 1080 catgctgatg tggcctatca caacaatatc catgctgcag atgttgtcca gtctactcat 1140 gtgctattat ctacacctgc tttggaggct gtgtttacag atttggagat tcttgcagca 1200 atttttgcca gtgcaataca tgatgtagat catcctggtg tgtccaatca atttctgatc 1260 aatacaaact ctgaacttgc cttgatgtac aatgattcct cagtcttaga gaaccatcat 1320 ttggctgtgg gctttaaatt gcttcaggaa gaaaactgtg acattttcca gaatttgacc 1380 aaaaaaaaa gacaatcttt areaaaatg gtcattgaca tcgtacttgc aacagatatg 1440 1500 agctctggag ttcttcttct tgataattat tccgatagga ttcaggttct tcagaatatg 1560 gtgcactgtg cagatctgag caacccaaca aagcctctcc agctgtaccg ccagtggacg 1620 1680 ataagcccca tgtgtgacaa gcacaatgct tccgtggaaa aatcacaggt gggcttcata 1740 gactatattg ttcatcccct ctgggagaca tgggcagacc tcgtccaccc tgacgcccag 1800 gaattttgg acacttttgga ggacaatcgt gaatggtacc agagcacaat ccctcagagc 1860 ccctctcctg cacctgatga cccagaggag ggccggcagg gtcaaactga gaaattccag 1920 tttgaactaa ctttagagga agatggtgag tcagacacgg aaaggacag tggcagtca 1980 gtggaagaag acactagctg cagtgactcc aagactctt gtactcaaga ctcagagtct 2040 actgaaatttc cccttgatga acaggttgaa gaggaggcag tagggaga agaggaagc 2100 cagcctgaag cctgtgtcat agatgatcgt tctcctgaca cgtaacagtg caaaacttt 2160 catgcctttt ttttttaa gtagaaaaat tgtttccaaa gtgcatgtca catgccacaa 2220 ccacggtcac acctcactgt catctgccag gacgttgtt gaacaaact gaccttgact 2280 actcagtcca gcgctcagga atatcgtaac cagttttc acctccatgt catccgagca 2340 aggtggacat cttcacgaac agcgtttta acaagatttc agcttggtag agctgacaaa 2400 gcagataaaa tctactccaa attattca agagagtgtg actcatcagg cagcccaaaa 2460 gtttattgga cttggggttt ctattcctttt ttatttgttt gcaatatttt cagaagaaag 2520 gcattgcaca gagtgaactt aatggacgaa gcaaaata tgtcagaac aggacatagc 2580 acgaatctgt taccagtagg aggaggatga gccacagaaa ttgcatatt ttctaatttc 2640 aagtcttcct gatacatgac tgaatagtgt ggttcagtga gctgcactga cctctacatt 2700 ttgtatgata tgtaaaacag attttttgta gagcttactt ttattattaa atgtattgag 2760 gtattatatt taaaaaaaac tatgttcaga acttcatctg ccactggtta ttttttcta 2820 aggagtaact tgcaagtttt cagtacaaat ctgtgctaca ctggataaaa atctaattta 2880 tgaatttac ttgcacctta tagttcatag caattaactg atttgtagtg attcattgtt 2940 tgttttatat accaatgact tccatatttt aaaagagaaa aacaacttta tgttgcagga 3000 aacccttttt gtaagtcttt attatttact ttgcattttg tttcactctt tccagataag 3060 cagagttgct cttcaccagt gttttctttc atgtgcaaag tgactatttg ttctataata 3120 ctttatgtg tgttatatca aatgtgtctt aagcttcatg caaactcagt catcagttcg 3180 tgttgtctga agcaagtggg agatatataa atacccagta gctaaaatgg tcagtcttttt 3240 ttagatgttt tcctacttag tatctcctaa taacgttttg ctgtgtcact agatgttcat 3300 ttcacaagtg catgtctttc tataatcca cacatttcat gctctaataa tccacacatt 3360 tcatgctcat ttttattgtt tttacagcca gttatagtaa gaaaaaggtt tttccccttg 3420 tgctgcttta taatttagcg tgtgtctgaa ccttatccat gtttgctaga tgaggtcttg 3480 tcaaatatat cactaccatt gtcaccggtg aaaagaaaca ggtagttaag ttagggttaa 3540 cattcatttc aaccacgagg ttgtatatca tgactagctt ttactcttgg tttacagaga 3600 aaagttaaac agccaactag gcagttttta agaatattaa caatatatta acaaacacca 3660 atacaactaa tcctatttgg ttttaatgat ttcaccatgg gattaagaac tatatcagga 3720 acatccctga gaaacggttt taagtgtagc aactactctt ccttaatgga cagccacata 3780 acgtgtagga agtcctttat cacttatcct cgatccataa gcatatcttg cagaggggaa 3840 ctacttcttt aaacacatgg agggaaagaa gatgatgcca ctggcaccag agggttagta 3900 ctgtgatgca tcctaaaata tttattatat tggtaaaaat tctggttaaa taaaaatta 3960 gagatcactc ttggctgatt tcagcaccag gaactgtatt acagttttag agattaattc 4020 ctagtgttta cctgattata gcagttggca tcatggggca tttaattctg actttatccc 4080 cacgtcagcc tttaaagt cttctttacc ttctctatga agactttaaa gccaaataa 4140 tcattttca cattgatatt cagaattga gatagataga agccaaagtg ggtatctgac 4200 aagtggaaaa tcaacgtttt aagagaatt acaacctga aaagcattta tatgtggaac 4260 ttctcagga gcctcctggg gactggaag tagtcatca gccaggcaa tgactcatgc 4320 tgaagagagt ccccattca gtcccctgag atcttagctga tgctgatc ctttgaaata 4380 aaaatttagt ctttatact ctgatctttt acataagca gagaggaat caactagtta 4440 attgcaagt ttctactctg tttcctctgt aagatcaga tggtaatctt tcaataga 4500 aaaaaaayaa gacgtatgtt tgaccagta gtttcacaag atattggg aacttgtttc 4560 ttttaattt atttgtccct gagtgaagtc tagaagaaa ggtaaaggt ctagagttta 4620 ttcctctttc caaacattc tcattcctct cctccctaca cttagtattt cccccacaga 4680 gtgcctagaa tcttaataat gataaaata aaagcagca attgtcatt aacaaatcca 4740 gacctgaaag ggtaaagggt ttataactgc actaataag agaggctctt tttttctt 4800 ccagtttgtt ggttttaat ggtaccgtgt tgtaagata cccactaatg gatacaaa 4860 ttgcagaaaa ggctcaat ccagagaca gggactaatg cactgtacaa tctgcttatc 4920 cttgcccttc tctcttgcca aagtgtgctt cagaaatata tactgcttta aaaaagaata 4980 aaagaatatc cttttacaag tggctttaca ttcctaaaa tgccataaga aaatgcaata 5040 tctgggtact gtatgggaa aaaatgtcc aagtttgtgt aaaaccagtg cattcagct 5100 tgcaagttac tgaacacaat aatgctgttt taatttgtt ttatatcagt taaaattcac 5160 aaatgtag atagaaaaaa ttacagaaaaaacttgaatg aaatggattt 5220 tacagaaagc tttatgataa ttttgaatg cattatttat ttttgtgcc atgcattttt 5280 tttctcacca aatgacctta cctgtaatac agtcttgttt gtctgtttac aaccatgtat 5340 ttattgcaat gtacatactg taatgttaat tgtaattat ctgttcttat taaaacatca 5400 tcccatgatg ggatggtgtt gatattttg gaaactcttg gtgagagaat gatggtgtg 5460 tatacatact ctgtacattt ttcttctc ctgtatata gtcttgtcac cttagagctt 5520 gttttaggaa gattcaagaaacttaaaaacttaaatt taaaaaaaaca 5580 tagctgcagg tctttggtcc tagggctgtg ccttaacttt aaccaatatt ttctctgtt 5640 ttgctgcatt tgaaggta cagtggagct agggctgggc atttacatc caggcttta 5700 attgattaga attctgccaa taggtggatt ttacaaacc acagacaacc tctgaagat 5760 tctgagaccc ttttgagaca gaagctctta agtactctt gccagggagc agcactgcat 5820 gtgtgatggt tgtttgccat ctgttgatca ggaactactt cagctacttg catttgatta 5880 tttcctttttt tttttttt aactcggaaa cacaacggg gaaatatatt ctttcccagt 5940 gattataaac aatctttc ttttttaa gtccttttgg cttctagagc tcataggaaa 6000 atggacttga ttgaaattg gagccagagt ttactcgtgt tggttatcta ttcatcagct 6060 tcctgacatg ttaagaat acattaaaga gaaatactg tttttaatc ctaaaatttt 6120 tcttccacta agataaacca atgtcctta catatatgta aacccatcta tttaaacgca 6180 aaggtgggtt gatgtcagtt tacatagcag aaagcattca ctatcctcta agatttgttt 6240 ctgcaaaact ttcattgctt tagaatttta aaatttcacc ttgtacaatg gccagcccct 6300 aaagcaggaa acatttataa tggattatat ggaaacatcc tcccagtact tgcccagccc 6360 ttgaatcatg tggcttttca gtgaaaggaa agattctttt tctaggaaaa atgagcctat 6420 tttattttat tttattttat tttttgacac aaactgtaga ttttagcagc cctggcccaa 6480 aggaatttga ttacttttgt tttaaacagt acaaagggga cactataatt acaaaaacat 6540 ccttaactga tttgagttgt ttttatttct ttggatatat tttcagagtg gtaaattgtg 6600 tgtgagaatt acaaatgatt attcttttag tggtttctta gcctctctta cagcccacgg 6660 ggatagtact gtacatcaat accttcatat gaaattttta tatgcaatga aaataaaagc 6720 atgggttgat tctgcctatt tatgactcaa tcttttacaa ataaaagatt attcatttta 6780 aattatagtt caatcagcat gtctcttagg atactgaacg tggttgaaat gaaaggatag 6840 tgacatcata agttagtact gatattcata accaaataaa gccaacttga gtaattttgc 6900 tacattaaaa attackaaa ttacttagat ggcctataag attaagcatg gtgttttcta 6960 agcaagcttt gaaaggggcc ttccatactt acttaattga atattctggg atattgaaaa 7020 ttattcagat acttgacaat tatttttggt tacctactcc gcaaactaca aagttttaag 7080 gactcaacaa taagttaatg agacacagtg tttgctttca tggagcttac agtctggagg 7140 ggacaaaggc ttaaacaata ctcatataat tatatatgtg atcagtacaa tgaaggagct 7200 cagtggggta aataagcagg aacctgaact tgatctgttc cggagggcca cagaaggctt 7260 ccttgaggcc ttgagaaagt gatttgcatc tgagttctga aggattgtaa gaggtaacta 7320 gggaaaagt tgacaggaag aggaagggga tccagacaag aaacatttgc aaagatcttg 7380 aggcataaat gagcttgaga catctggaga aactgaggaa aagtgagaga gtaggcaggg 7440 cctggagccg cagagccatt gctaaccatc ctgtgtgaga tatcccccat tctgtagctt 7500 tattctcata accctgctca attttcttta taacacttct cacagattta tatacgtgtt 7560 tgttttgtt atctgtctct cccaccagac cacagctcca tgagagcaag gtctttgctt 7620 accaatatat cactagcact taaaactatg cctggtacac agtaggttct taatatgtgt 7680 tgaatatagc catcaaattg atattggata taattcaatc tgataagata ttttgagata 7740 ttaaagagtt tttaacttga taccataaaa aaaaaaaaaa aaa 7783 <210> 9 <211> 673 <212> PRT <213> Homo sapiens <400> 9 Met Met His Val Asn Asn Phe Pro Phe Arg Arg His Ser Trp Ile Cys 1 5 10 15 Phe Asp Val Asp Asn Gly Thr Ser Ala Gly Arg Ser Pro Leu Asp Pro 20 25 30 Met Thr Ser Pro Gly Ser Gly Leu Ile Leu Gln Ala Asn Phe Val His 35 40 45 Ser Gln Arg Arg Glu Ser Phe Leu Tyr Arg Ser Asp Ser Asp Tyr Asp 50 55 60 Leu Ser Pro Lys Ser Met Ser Arg Asn Ser Ser Ile Ala Ser Asp Ile 65 70 75 80 His Gly Asp Asp Leu Ile Val Thr Pro Phe Ala Gln Val Leu Ala Ser 85 90 95 Leu Arg Thr Val Arg Asn Asn Phe Ala Ala Leu Thr Asn Leu Gln Asp 100 105 110 Arg Ala Pro Ser Lys Arg Ser Pro Met Cys Asn Gln Pro Ser Ile Asn 115 120 125 Lys Ala Thr Ile Thr Glu Glu Ala Tyr Gln Lys Leu Ala Ser Glu Thr 130 135 140 Leu Glu Glu Leu Asp Trp Cys Leu Asp Gln Leu Glu Thr Leu Gln Thr 145 150 155 160 Arg His Ser Val Ser Glu Met Ala Ser Asn Lys Phe Lys Arg Met Leu 165 170 175 Asn Arg Glu Leu Thr His Leu Ser Glu Met Ser Arg Ser Gly Asn Gln 180 185 190 Val Ser Glu Phe Ile Ser Asn Thr Phe Leu Asp Lys Gln His Glu Val 195 200 205 Glu Ile Pro Ser Pro Thr Gln Lys Glu Lys Glu Lys Lys Lys Arg Pro 210 215 220 Met Ser Gln Ile Ser Gly Val Lys Lys Leu Met His Ser Ser Ser Leu 225 230 235 240 Thr Asn Ser Ser Ile Pro Arg Phe Gly Val Lys Thr Glu Gln Glu Asp 245 250 255 Val Leu Ala Lys Glu Leu Glu Asp Val Asn Lys Trp Gly Leu His Val 260 265 270 Phe Arg Ile Ala Glu Leu Ser Gly Asn Arg Pro Leu Thr Val Ile Met 275 280 285 His Thr Ile Phe Gln Glu Arg Asp Leu Leu Lys Thr Phe Lys Ile Pro 290 295 300 Val Asp Thr Leu Ile Thr Tyr Leu Met Thr Leu Glu Asp His Tyr His 305 310 315 320 Ala Asp Val Ala Tyr His Asn Asn Ile His Ala Ala Asp Val Val Gln 325 330 335 Ser Thr His Val Leu Leu Ser Thr Pro Ala Leu Glu Ala Val Phe Thr 340 345 350 Asp Leu Glu Ile Leu Ala Ala Ile Phe Ala Ser Ala Ile His Asp Val 355 360 365 Asp His Pro Gly Val Ser Asn Gln Phe Leu Ile Asn Thr Asn Ser Glu 370 375 380 Leu Ala Leu Met Tyr Asn Asp Ser Ser Val Leu Glu Asn His His Leu 385 390 395 400 Ala Val Gly Phe Lys Leu Leu Gln Glu Glu Asn Cys Asp Ile Phe Gln 405 410 415 Asn Leu Thr Lys Lys Gln Arg Gln Ser Leu Arg Lys Met Val Ile Asp 420 425 430 Ile Val Leu Ala Thr Asp Met Ser Lys His Met Asn Leu Leu Ala Asp 435 440 445 Leu Lys Thr Met Val Glu Thr Lys Lys Val Thr Ser Ser Gly Val Leu 450 455 460 Leu Leu Asp Asn Tyr Ser Asp Arg Ile Gln Val Leu Gln Asn Met Val 465 470 475 480 His Cys Ala Asp Leu Ser Asn Pro Thr Lys Pro Leu Gln Leu Tyr Arg 485 490 495 Gln Trp Thr Asp Arg Ile Met Glu Glu Phe Phe Arg Gln Gly Asp Arg 500 505 510 Glu Arg Glu Arg Gly Met Glu Ile Ser Pro Met Cys Asp Lys His Asn 515 520 525 Ala Ser Val Glu Lys Ser Gln Val Gly Phe Ile Asp Tyr Ile Val His 530 535 540 Pro Leu Trp Glu Thr Trp Ala Asp Leu Val His Pro Asp Ala Gln Asp 545 550 555 560 Ile Leu Asp Thr Leu Glu Asp Asn Arg Glu Trp Tyr Gln Ser Thr Ile 565 570 575 Pro Gln Ser Pro Ser Pro Ala Pro Asp Asp Pro Glu Glu Gly Arg Gln 580 585 590 Gly Gln Thr Glu Lys Phe Gln Phe Glu Leu Thr Leu Glu Glu Asp Gly 595 600 605 Glu Ser Asp Thr Glu Lys Asp Ser Gly Ser Gln Val Glu Glu Asp Thr 610 615 620 Ser Cys Ser Asp Ser Lys Thr Leu Cys Thr Gln Asp Ser Glu Ser Thr 625 630 635 640 Glu Ile Pro Leu Asp Glu Gln Val Glu Glu Glu Ala Val Gly Glu Glu 645 650 655 Glu Glu Ser Gln Pro Glu Ala Cys Val Ile Asp Asp Arg Ser Pro Asp 660 665 670 Thr <210> 10 <211> 8240 <212> DNA <213> Homo sapiens <400> 10 cccctctcgg tagccctgag gctctggcgc cttcaagtga gaagctaagc accagcctct 60 gctgggctgc agaagcggcg gcggcggcag cagcagcagc agcatcagga aggcgctcgg 120 gccagcgcgg tgaacccggg ctgggcagca ggtcgcggag ccgcgagcca ggatggaggc 180 agagggcagc agcgcgccgg cccgggcggg cagcggagag ggcagcgaca gcgccggcgg 240 ggccacgctc aaagccccca agcatctctg gaggcacgag cagcaccacc agtacccgct 300 ccggcagccc cagttccgcc tcctgcatcc ccatcaccac ctgcccccgc cgccgccacc 360 ctcgccccag ccccagcccc agtgtccgct acagccgccg ccgccgcccc ccctgccgcc 420 gcccccgccg ccgcccgggg ctgcccgcgg ccgctacgcc tcgagcgggg ccaccggccg 480 cgtccggcat cgcggctact cggacaccga gcgctacctg tactgtcgcg ccatggaccg 540 cacctcctac gcggtggaga ccggccaccg gcccggcctg aagaaatcca ggatgtcctg 600 gccctcctcg ttccagggac tcaggcgttt tgatgtggac aatggcacat ctgcgggacg 660 gagtcccttg gatcccatga ccagcccagg atccgggcta attctccaag caaattttgt 720 ccacagtcaa cgacgggagt ccttcctgta tcgatccgac agcgattatg acctctctcc 780 aaagtctatg tcccggaact cctccattgc cagtgatata cacggagatg acttgattgt 840 gactccattt gctcaggtct tggccagtct gcgaactgta cgaaacaact ttgctgcatt 900 aactaatttg caagatcgag cacctagcaa aagatcaccc atgtgcaacc aaccatccat 960 caacaagcc accatacag aggaggccta ccagaactg gccagcgaga ccctggagga 1020 gctggactgg tgtctggacc agctagagac cctacagacc agcactccg tcagtgagat 1080 ggcctccaac aagtttaaa ggatgcttaa tcgggagctc acccatctct ctgaatgag 1140 tcggtctgga atcaagtgt cagagtttat atcaacaca ttcttagata agcacatga 1200 agtggaaattt ccttctccaa ctcagaagga aaggaaaaagaaagac caatgtctca 1260 gatcagtgga gtcaagaat tgatgcacag ctctagtctg actaattcaa gtatcccaag 1320 gtttggagtt aaaactgaac aagagatgt ccttgccaag gaactagaag atgtgacaa 1380 atggggtctt catgttttca gatagcaga gttgtctggt aaccggccct tgactgttat 1440 catgcacacc attttcagg aacgggatt attaaaaaca tttaaaattc cagtagatac 1500 ttatattaca tatcttatga ctctcgaaga ccattaccat gctgatgtgg cctatcacaa 1560 caatatccat gctgcagatg ttgtccagtc tactcatgtg ctattatcta cacctgcttt 1620 ggaggctgtg tttacagatt tggagcatt ttgccagtg tttacatga 1680 tgtagatcat cctggtgtgt ccaatcaatt tctgatcaat acaaactctg aacttgcctt 1740 gatgtacaat gattcctcag tcttagagaa ccatcatttg gctgtgggct ttaaattgct 1800 tcaggaagaa aactgtgaca ttttccagaa tttgaccaaa aaacaaagac aatctttaag 1860 gaaaatggtc attgacatcg tacttgcaac agatatgtca aaacacatga atctactggc 1920 tgatttgaag actatggttg aaactaagaa agtgacaagc tctggagttc ttcttcttga 1980 taattattcc gataggattc aggttcttca gaatatggtg cactgtgcag atctgagcaa 2040 ccaacaaag cctctccagc tgtaccgcca gtggacggac cggataatgg aggagttctt 2100 ccgccaagga gaccgagaga gggaacgtgg catggagata agccccatgt gtgacaagca 2160 caatgcttcc gtggaaaaat cacaggtggg cttcatagac tatattgttc atcccctctg 2220 ggagacatgg gcagacctcg tccaccctga cgcccaggat atttggaca cttttggagga 2280 caatcgtgaa tggtaccaga gcacaatccc tcagagcccc tctcctgcac ctgatgaccc 2340 agaggagggc cggcagggtc aaactgagaa attccagttt gaactaactt tagaggaaga 2400 tggtgagtca ghacacgaaa aggacagtgg cagtcaagtg gagagaca ctagctgcag 2460 tgactccaag actcttgta ctcagactc agagtctact gaattcccc ttgatgacaca 2520 ggttgaagag gaggcagtag gggaagaga ggaagccag cctgaagcct gtgtcataga 2580 tgatcgttct cctgacacgt aacagtgcaa aacttcat gcctttttt ttttaagta 2640 gaaaaattgt ttccaaagtg catgtcacat gccacaacca cggtcacacc tcactgtcat 2700 ctgccaggac gttgttgaa caaactgac ctgactact cagtccagcg ctcaggaata 2760 tcgtaaccag ttttcacc tccatgtcat ccgagcagg tggacatct cacgacacagc 2820 gttttacaa agatttcagc ttggtagagc tgacaagca gataaaatct actccaaatt 2880 atttcaaga gagtgtgact catcaggcag cccaaagtt tattggactt ggggtttcta 2940 ttcctttttta ttgtttgca atattttcag agaaaggca ttgcacag tgaaaggcag 3000 ggaagaagca acaatatgt haaaaagg acatagcacg aatctgttac cagtaggagg 3060 aggatgagcc acagaaattg cataatttc taatttcaag tctcctgat acatgactga 3120 atagtgtggt tcagtgagct gcactgacct ctacattttg tatgatatgt aaaacagatt 3180 ttttgtagag cttactttta ttattaaatg tattgaggta ttatatttaa aaaaaactat 3240 gttcagaact tcatctgcca ctggttattt tttctaagg agtaacttgc aagttttcag 3300 tacaaatctg tgctacactg gataaaaatc taatttatga attttacttg caccttatag 3360 ttcatagcaa ttaactgatt tgtagtgatt cattgtttgt tttatatacc aatgacttcc 3420 atattttaaa agagaaaac aactttatgt tgcaggaaac cctttttgta agtctttatt 3480 atttactttg cattttgttt cactctttcc agataagcag agttgctctt caccagtgtt 3540 tttcttcatg tgcaaagtga ctatttgttc tataatactt ttatgtgtgt tatatcaaat 3600 gtgtcttaag cttcatgcaa actcagtcat cagttcgtgt tgtctgaagc aagtgggaga 3660 tatataaata cccagtagct aaaatggtca gtctttttta gatgttttcc tacttagtat 3720 ctcctaataa cgttttgctg tgtcactaga tgttcatttc acaagtgcat gtctttctaa 3780 taatccacac atttcatgct ctaataatcc acacatttca tgctcatttt tattgtttt 3840 acagccagtt atagtaagaa aaagtttt ccccttgtgc tgctttataa tttagcgtgt 3900 gtctgaacct tatccatgtt tgctagatga ggtcttgtca atatatcac taccattgtc 3960 accggtgaaa agaaacaggt agttaagtta gggttaacat tcattcac cacgaggttg 4020 tatatcatga ctagcttta ctcttggtttt acagagaaaa gttaaacagc caactaggca 4080 gtttttaaga atattacaa atattaca aacaccata caactaatcc tattttggtttt 4140 taatgatttc accatgggat tagaactat atcaggaaca tccctgagaa acggttttaa 4200 gtgtagcaac tactctcct taatggacag ccacataacg tgtaggagt cctttatcac 4260 ttatcctcga tccataagca tatcttgcag agggaacta cttctttaaa cacatggagg 4320 gaaagaagat gatgccactg gcaccagagg gttagtactg tgatgcatcc taaaatattt 4380 attatattgg taaaaatttct gggttaataa aaaattagag atcacttg gctgatttca 4440 gcaccaggaa ctgtattaca gttttagaga ttattccta gtgttttacct gattatagca 4500 gttggcatca tggggcattt aattctgact ttacccac gtcagcctta ataaagtctt 4560 ctttaccttc tctatgaaga ctttaaagcc caaataatca tttttcacat tgatattcaa 4620 gaattgagat agatagaagc caaagtgggt atctgacaag tggaaaatca aacgtttaag 4680 aagaattaca actctgaaaa gcatttatat gtggaacttc tcaaggagcc tcctggggac 4740 tggaaagtaa gtcatcagcc aggcaaatga ctcatgctga agagagtccc catttcagtc 4800 ccctgagatc tagctgatgc ttagatcctt tgaaataaa attatgtctt tataactctg 4860 atcttttaca taaagcagaa gaggaatcaa ctagttaatt gcaaggtttc tactctgttt 4920 cctctgtaaa gatcagatgg taatctttca aataagaaaa aaataaaagac gtatgtttga 4980 ccaagtagtt tcacaagaat atttgggaac ttgtttcttt taattttatt tgtccctgag 5040 tgaagtctag aaagaaaggt aaagagtcta gagtttattc ctctttccaa aacattctca 5100 ttcctctcct ccctacactt agtatttccc ccacagagtg cctagaatct taataatgaa 5160 taaataaaaa agcagcaata tgtcattaac aaatccagac ctgaaagggt aaagggttta 5220 5280 accgtgttgt aaagataccc actaatggac aatcaaattg cagaaaaggc tcaatatcca 5340 agagacaggg actaatgcac tgtacaatct gcttatcctt gcccttctct cttgccaaag 5400 tgtgcttcag aaatatatac tgctttaaaa aagaataaaa gaatatcctt ttacaagtgg 5460 ctttacattt cctaaaatgc cataagaaaa tgcaatatct gggtactgta tggggaaaaaa 5520 aatgtccaag tttgtgtaaa accagtgcat ttcagcttgc aagttactga acacaataat 5580 gctgttttaa ttttgtttta tatcagttaa aattcacaat aatgttagata gaacaaatta 5640 cagacaagga aagaaaaaac ttgaatgaaa tggattttac agaaagcttt atgataattt 5700 ttgaatgcat tatttatttt ttgtgccatg catttttttt ctcaccaaat gaccttacct 5760 gtaatacagt cttgtttgtc tgtttacaac catgtatta ttgcaatgta catactgtaa 5820 tgttaattgt aaattatctg ttcttattaa aacatcatcc catgatggga tggtgttgat 5880 atatttggaa actcttggtg agagaatgaa tggtgtgtat acatactctg tacatttttc 5940 ttttctcctg taatatagtc ttgtcacctt agagcttgtt tatggaagat tcaagaaaac 6000 tataaaatac ttaaaagatat ataaatttaa aaaaacatag ctgcaggtct ttggtcccag 6060 ggctgtgcct taactttaac caatattttc ttctgttttg ctgcatttga aaggtaacag 6120 tggagctagg gctgggcatt ttacatccag gcttttaatt gattagaatt ctgccaatag 6180 gtggatttta caaaaccaca gacaacctct gaagattct gagaccttt tgagacagaa 6240 gctcttaagt acttcttgcc agggagcagc actgcatgtg tgatggttgt ttgccatctg 6300 ttgatcagga actacttcag ctacttgcat ttgattattt cctttttttt tttttttaac 6360 tcggaaacac aactggggaa atatattctt tcccagtgat tataaacaat ctttttcttt 6420 tttttaagtc ctttggctt ctagagctca taggaaaatg gacttgattt gaaattggag 6480 ccagagttta ctcgtgttgg ttatctattc atcagcttcc tgacatgtta agagaataca 6540 ttaaaagaa aatactgttt tttaatccta aaatttttct tccactaaga taaaccaaat 6600 gtccttacat atatgttaac ccatctattt aaacgcaaag gtgggttgat gtcagtttac 6660 atagcagaaa gcattcacta tcctctaaga tttgtttctg caaaactttc attgctttag 6720 aattttaaaa tttcaccttg tacaatggcc agcccctaaa gcaggaaaca tttataatgg attatatgga aacatcctcc cagtacttgc ccagcccttg aatcatgtgg cttttcagtg aaaggaaga ttctttttct aggaaaaatg agcctatttt attttatttt attttatttt ttgacacaaa ctgtagattt tagcagccct ggcccaaagg aatttgatta cttttgtttt 7020. aaacagtaca aaggggacac father aaaacatcct taactgattt gagttgtttt tatttctttg gatatatttt cagagtggta aattgtgtgt gagaattaca aatgattatt cttttagtgg tttcttagcc tctcttacag cccacgggga tagtactgta catcaatacc ttcatatgaa atttttatat gcaatgaaaa taaaagcatg ggttgattct gcctatttat gactcaatct tttacaata aaagattatt cattttaat tatagttcaa tcagcatgtc tcttaggata ctgaacgtgg ttgaaatgaa aggatagtga catcataagt tagtactgat attcataacc aaataagcc aacttgagta attttgctac attaaaatt accaaaatta cttagatggc ctaaagatt aagcatggtg ttttctaagc aagctttgaa aggggccttc catacttact taattgaata ttctgggata ttgaaaatta ttcagatact tgacaattat 7500 ttttggttac ctactccgca aactacaaag ttttaaggac tcaacaataa gttaatgaga 7560 cacagtgttt gctttcatgg agcttacagt ctggagggga caaaggctta aacaatactc 7620 atataattat atatgtgatc agtacaatga aggagctcag tggggtaaat aagcaggaac 7680 ctgaacttga tctgttccgg agggccacag aaggcttcct tgaggccttg agaaagtgat 7740 ttgcatctga gttctgaagg attgtaagag gtaactaggg aaaaagttga caggaagagg 7800 aaggggatcc agacaagaaa catttgcaaa gatcttgagg cataaatgag cttgagacat 7860 ctggagaaac tgaggaaaag tgagagagta ggcagggcct ggagccgcag agccattgct 7920 aaccatcctg tgtgagatat cccccattct gtagctttat tctcataacc ctgctcaatt 7980 ttctttataa cacttctcac agatttatat acgtgtttgt ttttgttatc tgtctctccc 8040 accagaccac agctccatga gagcaaggtc tttgcttacc aatatatcac tagcacttaa 8100 aactatgcct ggtacacagt aggttcttaa tatgtgttga atatagccat caaattgata 8160 ttggatataa ttcaatctga taagatattt tgagatatta aagagttttt aacttgatac 8220 cataaaaaaa aaaaaaaaaa 8240 <210> 11 <211> 809 <212> PRT <213> Homo sapiens <400> 11 Met Glu Ala Glu Gly Ser Ser Ala Pro Ala Arg Ala Gly Ser Gly Glu 1 5 10 15 Gly Ser Asp Ser Ala Gly Gly Ala Thr Leu Lys Ala Pro Lys His Leu<00�1054>20 25 30 Trp Arg His Glu Gln His His Gln Tyr Pro Leu Arg Gln Pro Gln Phe 35 40 45 Arg Leu Leu His Pro His His His Leu Pro Pro Pro Pro Pro Pro Ser 50 55 60 Pro Gln Pro Gln Pro Gln Cys Pro Leu Gln Pro Pro Pro Pro Pro Pro 65 70 75 80 Leu Pro Pro Pro Pro Pro Pro Pro Gly Ala Ala Arg Gly Arg Tyr Ala 85 90 95 Ser Ser Gly Ala Thr Gly Arg Val Arg His Arg Gly Tyr Ser Asp Thr 100 105 110 Glu Arg Tyr Leu Tyr Cys Arg Ala Met Asp Arg Thr Ser Tyr Ala Val It should be noted that there may be an error in the "00�1054" in the original text, which is likely "0001054". This has been translated as best as possible while maintaining the integrity of the original content.115 120 125 Glu Thr Gly His Arg Pro Gly Leu Lys Lys Ser Arg Met Ser Trp Pro 130 135 140 Ser Ser Phe Gln Gly Leu Arg Arg Phe Asp Val Asp Asn Gly Thr Ser 145 150 155 160 Ala Gly Arg Ser Pro Leu Asp Pro Met Thr Ser Pro Gly Ser Gly Leu 165 170 175 Ile Leu Gln Ala Asn Phe Val His Ser Gln Arg Arg Glu Ser Phe Leu 180 185 190 Tyr Arg Ser Asp Ser Asp Tyr Asp Leu Ser Pro Lys Ser Met Ser Arg 195 200 205 Asn Ser Ser Ile Ala Ser Asp Ile His Gly Asp Asp Leu Ile Val Thr 210 215 220 Pro Phe Ala Gln Val Leu Ala Ser Leu Arg Thr Val Arg Asn Asn Phe 225 230 235 240 Ala Ala Leu Thr Asn Leu Gln Asp Arg Ala Pro Ser Lys Arg Ser Pro 245 250 255 Met Cys Asn Gln Pro Ser Ile Asn Lys Ala Thr Ile Thr Glu Glu Ala 260 265 270 Tyr Gln Lys Leu Ala Ser Glu Thr Leu Glu Glu Leu Asp Trp Cys Leu 275 280 285 Asp Gln Leu Glu Thr Leu Gln Thr Arg His Ser Val Ser Glu Met Ala 290 295 300 Ser Asn Lys Phe Lys Arg Met Leu Asn Arg Glu Leu Thr His Leu Ser 305 310 315 320 Glu Met Ser Arg Ser Gly Asn Gln Val Ser Glu Phe Ile Ser Asn Thr 325 330 335 Phe Leu Asp Lys Gln His Glu Val Glu Ile Pro Ser Pro Thr Gln Lys 340 345 350 Glu Lys Glu Lys Lys Lys Arg Pro Met Ser Gln Ile Ser Gly Val Lys 355 360 365 Lys Leu Met His Ser Ser Ser Leu Thr Asn Ser Ser Ile Pro Arg Phe 370 375 380 Gly Val Lys Thr Glu Gln Glu Asp Val Leu Ala Lys Glu Leu Glu Asp 385 390 395 400 Val Asn Lys Trp Gly Leu His Val Phe Arg Ile Ala Glu Leu Ser Gly 405 410 415 Asn Arg Pro Leu Thr Val Ile Met His Thr Ile Phe Gln Glu Arg Asp 420 425 430 Leu Leu Lys Thr Phe Lys Ile Pro Val Asp Thr Leu Ile Thr Tyr Leu 435 440 445 Met Thr Leu Glu Asp His Tyr His Ala Asp Val Ala Tyr His Asn Asn 450 455 460 Ile His Ala Ala Asp Val Val Gln Ser Thr His Val Leu Leu Ser Thr 465 470 475 480 Pro Ala Leu Glu Ala Val Phe Thr Asp Leu Glu Ile Leu Ala Ala Ile 485 490 495 Phe Ala Ser Ala Ile His Asp Val Asp His Pro Gly Val Ser Asn Gln 500 505 510 Phe Leu Ile Asn Thr Asn Ser Glu Leu Ala Leu Met Tyr Asn Asp Ser 515 520 525 Ser Val Leu Glu Asn His His Leu Ala Val Gly Phe Lys Leu Leu Gln 530 535 540 Glu Glu Asn Cys Asp Ile Phe Gln Asn Leu Thr Lys Lys Gln Arg Gln 545 550 555 560 Ser Leu Arg Lys Met Val Ile Asp Ile Val Leu Ala Thr Asp Met Ser 565 570 575 Lys His Met Asn Leu Leu Ala Asp Leu Lys Thr Met Val Glu Thr Lys 580 585 590 Lys Val Thr Ser Ser Gly Val Leu Leu Leu Asp Asn Tyr Ser Asp Arg 595 600 605 Ile Gln Val Leu Gln Asn Met Val His Cys Ala Asp Leu Ser Asn Pro 610 615 620 Thr Lys Pro Leu Gln Leu Tyr Arg Gln Trp Thr Asp Arg Ile Met Glu 625 630 635 640 Glu Phe Phe Arg Gln Gly Asp Arg Glu Arg Glu Arg Gly Met Glu Ile 645 650 655 Ser Pro Met Cys Asp Lys His Asn Ala Ser Val Glu Lys Ser Gln Val 660 665 670 Gly Phe Ile Asp Tyr Ile Val His Pro Leu Trp Glu Thr Trp Ala Asp 675 680 685 Leu Val His Pro Asp Ala Gln Asp Ile Leu Asp Thr Leu Glu Asp Asn 690 695 700 Arg Glu Trp Tyr Gln Ser Thr Ile Pro Gln Ser Pro Ser Pro Ala Pro 705 710 715 720 Asp Asp Pro Glu Glu Gly Arg Gln Gly Gln Thr Glu Lys Phe Gln Phe 725 730 735 Glu Leu Thr Leu Glu Glu Asp Gly Glu Ser Asp Thr Glu Lys Asp Ser 740 745 750 Gly Ser Gln Val Glu Glu Asp Thr Ser Cys Ser Asp Ser Lys Thr Leu 755 760 765 Cys Thr Gln Asp Ser Glu Ser Thr Glu Ile Pro Leu Asp Glu Gln Val 770 775 780 Glu Glu Glu Ala Val Gly Glu Glu Glu Glu Ser Gln Pro Glu Ala Cys 785 790 795 800 Val Ile Asp Asp Arg Ser Pro Asp Thr 805 s<210> 12 <211> 7979 <212> DNA <213> Homo sapiens <400> 12 cagcagcagg ctcagacctg cttccctgga catttccggg accgtgagcg agggaaccac 60 gttgccctgg attcttgcca gctgtacaaa gttgaccagg aaaatggctc agcagacaag 120 cccggacact ttaacagtac ctgaagtgga taatccgcat tgtccaaacc cgtggctgaa 180 cgaagacctt gtgaaatcct tgcgagaaaa cctgttgcag catgagaagt ccaagacagc 240 gaggaaatcg gtttctccca agctctctcc agtgatctct ccgagaaatt cccccaggct 300 tctgcgcaga atgcttctca gcagcaacat ccccaaacag cggcgtttca cggtggcaca 360 tacatgtttt gatgtggaca atggcacatc tgcgggacgg agtcccttgg atcccatgac 420 cagcccagga tccgggctaa ttctccaagc aaattttgtc caagtcaac gacgggagtc 480 cttcctgtat cgatccgaca gcgattatga cctctctcca aagtctatgt cccggaactc 540 ctccattgcc agtgatatac acggagatga cttgattgtg actccatttg ctcaggtctt 600 ggccagtctg cgaactgtac gaaaactt tgctgcatta actaatttgc aagatcgagc 660 acctagcaaa agatcaccca tgtgcaacca accatccatc aacaaagcca ccataacaga 720 ggaggcctac cagaaactgg ccagcgagac cctgggagg ctggactggt gtctggacca 780 gctagagacc ctacagacca ggcactccgt cagtgagatg gcctccaaca agtttaaaag 840 gatgcttaat cgggagctca cccatctctc tgaaatgagt cggtctggaa atcaagtgtc 900 agagtttata tcaaacacat tcttagataa gcaacatgaa gtggaaattc cttctccaac 960 tcagaaggaa aagagaaaa agaaaagacc aatgtctcag atcagtggag tcaagaaatt 1020 gatgcacagc tctagtctga ctaattcaag tatcccaagg tttggagtta aaactgaaca 1080 agaagatgtc cttgccaagg aactagaaga tgtgaacaaa tggggtcttc atgttttcag 1140 atagcagag ttgtctggta accggccctt gactgttatc atgcacacca ttttcagga 1200 acgggattta ttaaaaacat ttaaaattcc agtagatact ttaattacat atcttatgac 1260 tctcgaagac cattaccatg ctgatgtggc ctatcacaac aatatccatg ctgcagatgt 1320 tgtccagtct actcatgtgc tattatctac acctgctttg gaggctgtgt ttacagattt 1380 ggagattctt gcagcaattt ttgccagtgc aatacatgat gtagatcatc ctggtgtgtc 1440 caatcaattt ctgatcaata caaactctga acttgccttg atgtacaatg attcctcagt 1500 cttagagaac catcatttgg ctgtgggctt taaattgctt caggaagaaa actgtgacat 1560 tttccagaat ttgaccaaaa aaaagaca atctttaagg aaaatggtca ttgacatcgt 1620 acttgcaaca gatatgtcaa aacacatgaa tctactggct gatttgaaga ctatggttga 1680 aactaagaaa gtgacaagct ctggagttct tcttcttgat aattattccg ataggattca 1740 ggttcttcag aatatggtgc actgtgcaga tctgagcaac ccaacaaagc ctctccagct 1800 gtaccgccag tggacggacc ggataatgga ggagttctc cgccaaggag accgagagag 1860 ggaacgtggc atggataa gcccatgtg tgacaagcac aatgctccg tggaaaaatc 1920 acaggtgggc ttcatagact atattgttca tccctctgg gagacatggg cagacctcgt 1980 ccaccctgac gcccaggata tttggacac tttggaggac atcgtgaat ggtaccagag 2040 cacaatccct cagagcccct ctcctgcacc tgatgaccca gaggaggggcc ggcagggtca 2100 aactgagaaa ttccagttg acactacttt agaggagat ggtgagtcag acacggaaaa 2160 ggacagtggc agtcaagtgg aagagacac tagctcagt gactccaga ctctttgtac 2220 tcaagactca gagtctactg aaattcccct tgatgacag gttgaagagg aggcagtagg 2280 ggaagaagg gaaagccagc ctgaagcctg tgtcatagat gatcgttctc ctgacacgta 2340 acagtgcaaa aactttcatg cctttttt ttttaagtag aaaaattgtt tccaagtgc 2400 atgtcacatg ccacaccac ggtcacacct cactgtcatc tgccaggacg ttgttgac 2460 aaaactgacc ttgactactc agtccagcgc tcaggaat cgtaccagt ttttcacct 2520 2580. ccatgtcatc cgagcaaggt ggacatcttc acgaacagcg tttttaacaa gatttcagct tggtaggct gacaaagcag ataaaatcta ctccaaatta ttttcaagag agtgtgactc atcaggcagc ccaaaagttt attggacttg gggtttctat tcctttttt ttgtttgcaa tattttcaga agaaaggcat tgcacagagt gaacttaatg gacgaagcaa caaatatgtc aagaacagga catagcacga atctgttacc to be rich ggatgagcca cagaaattgc ataattttct aatttcaagt cttcctgata catgactgaa tagtgtggtt cagtgagctg cactgacctc tacattttgt atgatatgta aaacagattt tttgtagc ttacttttat father attgaggtat father aaaaactatg ttcagaactt catctgccac tggttatttt tttctaagga gtaacttgca agttttcagt acaaatctgt gctacactgg ataaaatct aatttatgaa ttttacttgc accttatagt tcatagcaat taactgattt gtagtgattc attgtttgtt ttatatacca atgacttcca tattttaaaa gagaaaaaca actttatgtt gcaggaaacc ctttttgtaa gtctttatta tttactttgc attttgtttc actctttcca gataagcaga gttgctcttc accagtgttt ttcttcatgt gcaaagtgac 3300 tatttgttct ataatacttt tatgtgtgtt atatcaaatg tgtcttaagc ttcatgcaaa 3360 ctcagtcatc agttcgtgtt gtctgaagca agtgggagat atataaatac ccagtagcta 3420 aaatggtcag tcttttttag atgttttcct acttagtatc tcctaataac gttttgctgt 3480 gtcactagat gttcatttca caagtgcatg tctttctaat aatccacaca tttcatgctc 3540 tataatcca cacatttcat gctcattttt attgttttta cagccagtta tagtaagaaa 3600 aaggtttttc cccttgtgct gctttataat ttagcgtgtg tctgaacctt atccatgttt 3660 gctagatgag gtcttgtcaa atatatcact accattgtca ccggtgaaaa gaaacaggta 3720 gttaagttag ggttaacatt catttcaacc acgaggttgt atatcatgac tagcttttac 3780 tcttggttta cagagaaaag ttaaacagcc aactaggcag ttttaagaa tattaacaat 3840 atattaacaa acaccaatac aactaatcct atttggtttt aatgatttca ccatgggatt 3900 aagaactata tcaggaacat ccctgagaaa cggttttaag tgtagcaact actcttcctt 3960 aatggacagc cacataacgt gtaggaagtc ctttatcact tatcctcgat ccataagcat 4020 atcttgcaga ggggaactac ttctttaac acatggaggg aaagagatg atgccactgg 4080 caccagagggg ttagtactgt gatgcatcct aaatattta ttatattgt aaaaattctg 4140 gttaaataaa aattagaga tgtattacag 4200 ttttagagat taattcctag tgtttacctg attatagcag ttggcatcat ggggcattta 4260 attctgactt tatccccacg tcagccttaa taaagtctc tttaccttct cttagaagac 4320 tttaaagcccc aaataatcat ttttcacatt gatattcaag aattgagata gatagaagcc 4380 aaagtgggta tctgacaagt ggaaatca acgtttaaga agaattacaa ctctgaaag 4440 catttatatg tggaacttct caggagcct cctggggact ggaagtaag tcatcagcca 4500 ggcaaatgac tcatgctgaa gagagtcccc atttcagtcc cctgagatct agctgatgct 4560 tagatcctttt gaataaaaa ttatgcttt attackactctga tctttacat aaagcagaag 4620 aggaatcaac tagttaattg caagttct actctgttc ctctgtaaag atcagatggt 4680 aatctttcaa ataagaaaaa aataaagacg tatgtttgac caagtagttt cacaagaata 4740 tttgggaact tgtttctttt aattttattt gtccctgagt gaagtctaga aagaaaggta 4800 aagagtctag agtttattcc tctttccaaa acattctcat tcctctcctc cctacactta 4860 gtatttcccc cacagagtgc ctagaatctt aataatgaat aaaataaaaa gcagcaatat 4920 gtcattaaca aatccagacc tgaaagggta aagggtttat aactgcacta ataaagagag 4980 gctctttttt tttcttccag tttgttggt tttaatggta ccgtgttgta aagataccca 5040 ctaatggaca atcaaattgc agaaaaggct caatatccaa gagacaggga ctaatgcact 5100 gtacaatctg cttatccttg cccttctctc ttgccaaagt gtgcttcaga aatatatact 5160 gctttaaaaa agaataaaag aatatccttt tacaagtggc tttacatttc ctaaaatgcc 5220 ataagaaaat gcaatatctg ggtactgtat ggggaaaaaa atgtccaagt ttgtgtaaaa 5280 ccagtgcatt tcagcttgca agttactgaa cacaataatg ctgttttaat tttgttttat 5340 atcagttaaa attcacaata atgtatag aacaaattac agacaaggaa agaaaaaact 5400 tgaatgaaat ggattttaca gaaagcttta tgataatttt tgaatgcatt atttatttt 5460 tgtgccatgc attttttttc tcaccaaatg accttacctg taatacagtc ttgtttgtct 5520 gtttacaacc atgtatttat tgcaatgtac atactgtaat gttaattgta aattatctgt 5580 tcttattaaa acatcatccc atgatgggat ggtgttgata tatttggaaa ctcttggtga 5640 gagaatgaat ggtgtgtata catactctgt acatttttct tttctcctgt aatatagtct 5700 tgtcacctta gagcttgttt atggagaatt caagaaaaact ataaaatact taaagatata 5760 taaatttaaa aaaacatagc tgcaggtctt tggtcccagg gctgtgcctt aactttaacc 5820 aatattttct tctgttttgc tgcatttgaa aggtaacagt ggagctaggg ctgggcattt 5880 tacatccagg cttttaattg attagaattc tgccaatagg tggatttac aaaaccacag 5940 acaacctctg aaagattctg agaccctttt gagacagaag ctcttaagta cttcttgcca 6000 gggagcagca ctgcatgtgt gatggttgtt tgccatctgt tgatcaggaa ctacttcagc 6060 tacttgcatt tgattatttc cttttttttt ttttttaact cggaaacaca actgggggaaa 6120 tatattcttt cccagtgatt ataaacaatc ttttcttttt ttttaagtcc ttttggcttc 6180 tagagctcat aggaaaatgg acttgatttg aaattggagc cagagtttac tcgtgttggt 6240 tatctattca tcagcttcct gacatgttaa gagaatacat taaagagaaa atactgtttt 6300 ttaatcctaa aatttttctt ccactaagat aaaccaaatg tccttacata tatgtaaacc 6360 catctattta aacgcaaagg tgggttgatg tcagtttaca tagcagaaag cattcactat 6420 cctctaagat ttgtttctgc aaaactttca ttgctttaga atttaaaat ttcaccttgt 6480 acaatggcca gcccctaaag caggaaacat ttatatgga ttatatggaa acatcctccc 6540 agtacttgcc cagcccttga atcatgtggc ttttcagtga aaggaaagat tctttttcta 6600 ggaaaaatga gcctatttta ttttatttta ttttatttt tgacacaaac tgtagattttt 6660 agcagccctg gcccaaagga atttgattac ttttgtttta aacagtacaa aggggacact 6720 ataattacaa aaacatcctt aactgatttg agttgttttt atttctttgg atatattttc 6780 agagtggtaa attgtgtgtg agaattacaa atgattattc ttttagtggt ttcttagcct 6840 ctcttacagc ccacggggat agtactgtac atcaatacct tcatatgaaa tttttatatg 6900 caatgaaaat aaaagcatgg gttgattctg cctatttatg actcaatctt ttacaaataa 6960 aagattattc attttaaatt atagttcaat cagcatgtct cttaggatac tgaacgtggt 7020 tgaaatgaaa ggatagtgac atcataagtt agtactgata ttcataacca aataaagcca 7080 acttgagtaa ttttgctaca ttaaaaatta ccaaaattac ttagatggcc tataagatta 7140 agcatggtgt tttctaagca agctttgaaa ggggccttcc atacttactt aattgaatat 7200 tctgggatat tgaaaattat tcagatactt gacaattatt tttggttacc tactccgcaa 7260 actacaaagt tttaaggact caacaataag ttaatgagac acagtgtttg ctttcatgga 7320 gcttacagtc tggaggggac aaaggcttaa acaatactca tataattata tatgtgatca 7380 gtacaatgaa ggagctcagt ggggtaaata agcaggaacc tgaacttgat ctgttccgga 7440 gggccacaga aggcttcctt gaggccttga gaaagtgatt tgcatctgag ttctgaagga 7500 ttgtaagagg taactaggga aaaagttgac aggaagagga aggggatcca gacaagaaac 7560 atttgcaaag atcttgaggc ataaatgagc ttgagacatc tggagaaact gaggaaaagt 7620 gagagagtag gcagggcctg gagccgcaga gccattgcta accatcctgt gtgagatatc 7680 ccccattctg tagctttatt ctcataaccc tgctcaattt tctttataac acttctcaca 7740 gatttatata cgtgtttgtt tttgttatct gtctctccca ccagaccaca gctccatgag 7800 agcaaggtct ttgcttacca atatatcact agcacttaaa actatgcctg gtacacagta 7860 ggttcttaat atgtgttgaa tatagccatc aaattgatat tggatataat tcaatctgat 7920 aagatatttt gagatattaa agagttttta acttgatacc ataaaaaaaa aaaaaaaaa 7979 <२१०> १३ <२११> ७४५ <२१२> PRT <२१३> Homo sapiens <४००> १३ Met Ala Gln Gln Thr Ser Pro Asp Thr Leu Thr Val Pro Glu Val Asp १ ५ १० १५ Asn Pro His Cys Pro Asn Pro Trp Leu Asn Glu Asp Leu Val Lys Ser २० २५ ३० Leu Arg Glu Asn Leu Leu Gln His Glu Lys Ser Lys Thr Ala Arg Lys ३५ ४० ४५ Ser Val Ser Pro Lys Leu Ser Pro Val Ile Ser Pro Arg Asn Ser Pro 50 55 60 Arg Leu Leu Arg Arg Met Leu Leu Ser Ser Asn Ile Pro Lys Gln Arg 65 70 75 80 Arg Phe Thr Val Ala His Thr Cys Phe Asp Val Asp Asn Gly Thr Ser 85 90 95 Ala Gly Arg Ser Pro Leu Asp Pro Met Thr Ser Pro Gly Ser Gly Leu 100 105 110 Ile Leu Gln Ala Asn Phe Val His Ser Gln Arg Arg Glu Ser Phe Leu 115 120 125 Tyr Arg Ser Asp Ser Asp Tyr Asp Leu Ser Pro Lys Ser Met Ser Arg 130 135 140 Asn Ser Ser Ile Ala Ser Asp Ile His Gly Asp Asp Leu Ile Val Thr 145 150 155 160 Pro Phe Ala Gln Val Leu Ala Ser Leu Arg Thr Val Arg Asn Asn Phe 165 170 175 Ala Ala Leu Thr Asn Leu Gln Asp Arg Ala Pro Ser Lys Arg Ser Pro 180 185 190 Met Cys Asn Gln Pro Ser Ile Asn Lys Ala Thr Ile Thr Glu Glu Ala 195 200 205 Tyr Gln Lys Leu Ala Ser Glu Thr Leu Glu Glu Leu Asp Trp Cys Leu 210 215 220 Asp Gln Leu Glu Thr Leu Gln Thr Arg His Ser Val Ser Glu Met Ala 225 230 235 240 Ser Asn Lys Phe Lys Arg Met Leu Asn Arg Glu Leu Thr His Leu Ser 245 250 255 Glu Met Ser Arg Ser Gly Asn Gln Val Ser Glu Phe Ile Ser Asn Thr 260 265 270 Phe Leu Asp Lys Gln His Glu Val Glu Ile Pro Ser Pro Thr Gln Lys 275 280 285 Glu Lys Glu Lys Lys Lys Arg Pro Met Ser Gln Ile Ser Gly Val Lys 290 295 300 Lys Leu Met His Ser Ser Ser Leu Thr Asn Ser Ser Ile Pro Arg Phe 305 310 315 320 Gly Val Lys Thr Glu Gln Glu Asp Val Leu Ala Lys Glu Leu Glu Asp 325 330 335 Val Asn Lys Trp Gly Leu His Val Phe Arg Ile Ala Glu Leu Ser Gly 340 345 350 Asn Arg Pro Leu Thr Val Ile Met His Thr Ile Phe Gln Glu Arg Asp 355 360 365 Leu Leu Lys Thr Phe Lys Ile Pro Val Asp Thr Leu Ile Thr Tyr Leu 370 375 380 Met Thr Leu Glu Asp His Tyr His Ala Asp Val Ala Tyr His Asn Asn 385 390 395 400 Ile His Ala Ala Asp Val Val Gln Ser Thr His Val Leu Leu Ser Thr 405 410 415 Pro Ala Leu Glu Ala Val Phe Thr Asp Leu Glu Ile Leu Ala Ala Ile 420 425 430 Phe Ala Ser Ala Ile His Asp Val Asp His Pro Gly Val Ser Asn Gln 435 440 445 Phe Leu Ile Asn Thr Asn Ser Glu Leu Ala Leu Met Tyr Asn Asp Ser 450 455 460 Ser Val Leu Glu Asn His His Leu Ala Val Gly Phe Lys Leu Leu Gln 465 470 475 480 Glu Glu Asn Cys Asp Ile Phe Gln Asn Leu Thr Lys Lys Gln Arg Gln 485 490 495 Ser Leu Arg Lys Met Val Ile Asp Ile Val Leu Ala Thr Asp Met Ser 500 505 510 Lys His Met Asn Leu Leu Ala Asp Leu Lys Thr Met Val Glu Thr Lys 515 520 525 Lys Val Thr Ser Ser Gly Val Leu Leu Leu Asp Asn Tyr Ser Asp Arg 530 535 540 Ile Gln Val Leu Gln Asn Met Val His Cys Ala Asp Leu Ser Asn Pro 545 550 555 560 Thr Lys Pro Leu Gln Leu Tyr Arg Gln Trp Thr Asp Arg Ile Met Glu 565 570 575 Glu Phe Phe Arg Gln Gly Asp Arg Glu Arg Glu Arg Gly Met Glu Ile 580 585 590 Ser Pro Met Cys Asp Lys His Asn Ala Ser Val Glu Lys Ser Gln Val 595 600 605 Gly Phe Ile Asp Tyr Ile Val His Pro Leu Trp Glu Thr Trp Ala Asp 610 615 620 Leu Val His Pro Asp Ala Gln Asp Ile Leu Asp Thr Leu Glu Asp Asn 625 630 635 640 Arg Glu Trp Tyr Gln Ser Thr Ile Pro Gln Ser Pro Ser Pro Ala Pro 645 650 655 Asp Asp Pro Glu Glu Gly Arg Gln Gly Gln Thr Glu Lys Phe Gln Phe 660 665 670 Glu Leu Thr Leu Glu Glu Asp Gly Glu Ser Asp Thr Glu Lys Asp Ser 675 680 685 Gly Ser Gln Val Glu Glu Asp Thr Ser Cys Ser Asp Ser Lys Thr Leu 690 695 700 Cys Thr Gln Asp Ser Glu Ser Thr Glu Ile Pro Leu Asp Glu Gln Val 705 710 715 720 Glu Glu Glu Ala Val Gly Glu Glu Glu Glu Ser Gln Pro Glu Ala Cys 725 730 735 Val Ile Asp Asp Arg Ser Pro Asp Thr 740 745 <210> 14 <211> 19 <212> DNA <213> Artificial sequence <220> <223> PDE4D5_Forward Primer <400> 14 gcttctcagc agcaacatc 19 <210> 15 <211> 20 <212> DNA <213> Artificial sequence <220> <223> PDE4D5_Reverse Primer <400> 15 tgccattgtc cacatcaaaa 20 <210> 16 <211> twenty four <212> DNA <213> Artificial sequence <220> <223> PDE4D5 probe <400> 16 acagcggcgt ttcacggtgg caca 24 <210> 17 <211> 7591 <212> DNA <213> Homo sapiens <400> 17 agttccttat ttggtagctt ttgacaggac tagcctttct tgcaactaag catcttgaca 60 tacattattc attaagccct ggagctcggg agagaaagat gcagaccctt agatctttag 120 atattccttt atcacgtgga ttttctttat tcagaatagt tgctgaattt tgtgccattc 180 tggagtctta caaatggcat gtattcgatg ggaagacggc tggatgggat ttaatgcgag 240 gctttcttat gtatacttaa ttaccaaaaa tctttaaaaa ctcatactct gcgtggcttg 300 tggaggttgt taaagtgtcg agattttgaa gctaaataca ttttagagct tactatatat 360 atacatatat atatatatac atataatcaa tcaaaaatgc ctgaagcaaa ctatttactg 420 tcagtgtctt ggggctacat aaagtttaaa aggatgctta atcgggagct cacccatctc 480 tctgaaatga gtcggtctgg aaatcaagtg tcagagttta tatcaaacac attcttagat 540 aagcaacatg aagtggaaat tccttctcca actcagaagg aaaaggagaa aaagaaaaga 600 ccaatgtctc agatcagtgg agtcaagaaa ttgatgcaca gctctagtct gactaattca 660 agtatcccaa ggtttggagt taaaactgaa caagaagatg tccttgccaa ggaactagaa 720 gatgtgaaca aatggggtct tcatgttttc agaatagcag agttgtctgg taaccggccc 780 ttgactgtta tcatgcacac catttttcag gaacgggatt tattaaaaac atttaaaatt 840 ccagtagata ctttaattac atatcttatg actctcgaag accattacca tgctgatgtg 900 gcctatcaca acaatatcca tgctgcagat gttgtccagt ctactcatgt gctattatct 960 acacctgctt tggaggctgt gtttacagat ttggagattc ttgcagcaat ttttgccagt 1020 gcaatacatg atgtagatca tcctggtgtg tccaatcaat ttctgatcaa tacaaactct 1080 gaacttgcct tgatgtacaa tgattcctca gtcttagaga accatcattt ggctgtgggc 1140 tttaaattgc ttcaggaaga aaactgtgac attttccaga atttgaccaa aaaacaaaga 1200 caatctttaa ggaaaatggt cattgacatc gtacttgcaa cagatatgtc aaaacacatg 1260 aatctactgg ctgatttgaa gactatggtt gaaactaaga aagtgacaag ctctggagtt 1320 cttcttcttg ataattattc cgataggatt caggttcttc agaatatggt gcactgtgca 1380 gatctgagca accccaacaaa gcctctccag ctgtaccgcc agtggacgga ccggataatg gaggagttct tccgccaagg agaccgagag agggacgtg gcatggagat aagccccatg 1560. tgtgacaagc acaatgcttc cgtggaaaaa tcacaggtgg gcttcataga ctatattgtt catcccctct gggagacatg ggcagacctc gtccaccctg acgcccagga tattttggac 1620 actttggagg acaatcgtga atggtaccag agcacaatcc ctcagagccc ctctcctgca 1680. cctgatgacc cagaggaggg ccggcagggt caaactgaga aattccagtt tgaactaact ttagaggaag atggtgagtc agacacggaa aaggacagtg gcagtcaagt ggaagaagac actagctgca gtgactccaa actctttgt actcaagact cagagtctac tgaaattccc cttgatgaac aggttgaaga ggaggcagta ggggaagaag aggaaagcca gcctgaagcc tgtgtcatag atgatcgttc tcctgacacg taacagtgca aaaactttca tgcctttttt ttttttaagt agaaaaattg tttccaaagt gcatgtcaca tgccacaacc acggtcacac ctcactgtca tctgccagga cgtttgttga acaaaactga ccttgactac tcagtccagc gctcaggaat atcgtaacca gttttcac ctccatgtca tccgagcaag gtggacatct 2160 tcacgaacag cgttttaac aagatttcag cttggtagag ctgacaagc agataaaatc 2220 tactccaaat tatttcaag agagtgtgac tcatcaggca gcccaaagt tattggact 2280 tggggttctt atttcctttt atttgtttgc atattttca gagaaaggc attgcacaga 2340 gtgaacttaa tggacgaagc aaaataatg tcahacag gatagcac gatctgtta 2400 ccagtaggag gaggatgagc cacagaaatt gcatatttt ctaatttca gtcttcctga 2460 tacatgactg atagtgtgg ttcagtgagc tgcactgacc tctacatttt gtatgatatg 2520 taaaacagat ttttgtaga gcttactttt attattaat gtattgaggt attattatta 2580 aaaaaaacta tgttcagaac ttcatctgcc actggttatt tttctaag gagtacttg 2640 caagttttca gtacaaatct gtgctacact ggataaaaat ctaatttatg aattttact 2700 gcaccttata gttcatagca atttaacgat tgtagtgat tcattgttg ttttatatac 2760 caatgacttc catattttaa agagaaaa caatttatg ttgcaggaaa cccttttgt 2820 aagtctttat tatttacttt gcattttgtt tcactctttc cagataagca gagttgctct 2880 tcaccagtgt ttttcttcat gtgcaaagtg actatttgtt ctataatact tttatgtgtg 2940 ttatatcaaa tgtgtcttaa gcttcatgca aactcagtca tcagttcgtg ttgtctgaag 3000 caagtgggag atatataaat acccagtagc taaaatggtc agtctttttt agatgttttc 3060 ctacttagta tctcctaata acgttttgct gtgtcactag atgttcattt cacaagtgca 3120 tgtctttcta ataatccaca catttcatgc tctaataatc cacacatttc atgctcattt 3180 ttattgtttt tacagccagt tatagtaaga aaaaggtttt tccccttgtg ctgctttata 3240 atttagcgtg tgtctgaacc ttatccatgt ttgctagatg aggtcttgtc aaatatatca 3300 ctaccattgt caccggtgaa aagaaacagg tagttaagtt agggttaaca ttcatttcaa 3360 ccacgaggtt gtatatcatg actagctttt actcttggtt tacagagaaa agttaaacag 3420 ccaactaggc agtttttaag aatattaaca atatattaac aaacaccaat acaactaatc 3480 ctatttggtt ttaatgattt caccatggga ttaagaacta tatcaggaac atccctgaga 3540 aacggtttta agtgtagcaa ctactcttcc ttaatggaca gccacataac gtgtaggaag 3600 tcctttatca cttatcctcg atccataagc atatcttgca gagggaact acttctttaa 3660 acacatggag ggaaagaga tgatgccact ggcaccagag ggttagtact gtgatgcatc 3720 ctaaaatatt tattatattg gtaaaaatttc tggttaaata aaaaattaga gatcactct 3780 ggctgatttc agcaccagga actgtattac agttttagag atttattcct agtgttttacc 3840 tgattatagc agttggcatc atggggcatt taattctgac ttatcccca cgtcagcctt 3900 aaaagtct tctttacctt ctctatgaag actttaaagc ccaataatc atttttcaca 3960 ttgatattca agaattgaga tagatagag ccaagtggg tatctgacaa gtggaaaatc 4020 aaacgtttaa gagaattac aactctgaaa agcattatta tgtggaactt ctcaggagc 4080 ctcctgggga ctggaagta agtcatcagc caggcaatg actcatgctg aagagtcc 4140 ccattcagt cccctgagat ctagctgatg cttagatcct ttgaataaa aattatgtct 4200 ttataactct gatctttac aaagcaga agaggaatca actaagttaat tgcaggtttt 4260 ctactctgtt tcctctgtaa agatcagatg gtaatctttc aaataagaaaaataaga 4320 cgtatgtttg accaagtagt ttcacaagaa tatttgggaa cttgttttctt ttaattttat 4380 ttgtccctga gtgaagtcta gaagaaagg taaagagtct agagtttt cctctttcca 4440 aaacattctc attcctcc tccctacact tagtatttcc cccacagagt gcctagaatc 4500 ttaataatga aaaataa aaagcagcaat atgtcattaa aaatccaga cctgaaaggg 4560 taaagggttt atactgcac taataagag aggctcttt ttttctttcc agttttgttgg 4620 ttttaatgg taccgtgttg taagatacc cactaatgga caatcaatt gcagaaaagg 4680 ctcaatcc agagacagg gactaatgca ctgtacaatc tgcttacct tgccctctc 4740 tcttgccaaa gtgtgcttca gaaatatata ctgctttaaa aaagataaa agaataatcct 4800 tttacaagtg gctttacatt tcctaaaatg ccataagaaa atgcaatc tggtactgt 4860 atggggaaaa aaatgtccaa gtttgtgtaa aaccagtgca ttcagcttg caagttactg 4920 aacacataa tgctgtttta atttgtttt atatcagtta aattcacaa taatgtagat 4980 agaaaaaatt acagaaaaaaaaaaaa cttgaatgaa atggatttta cagaaagctt 5040 tatgataatt ttgaatgca tatttattt ttgtgccat gcatttttt tctcaccaaa 5100 tgaccttacc tgtaatacag tcttgtttgt ctgtttacaa ccatgtattt attgcaatgt 5160 acatactgta atgttaattg taaattatct gttcttatta aaacatcatc ccatgatggg 5220 atggtgttga tatatttgga aactctttggt gagagaatga atggtgtgta tacatactct 5280 gtacattttt cttttctcct gtaatatagt cttgtcacct tagagctgt ttatggaaga 5340 ttcaagaaaa ctataaaata cttaaagata tataaattta aaaaaacata gctgcaggtc 5400 ttggtccca gggctgtgcc ttactttaa ccaatatttt cttctgtttt gctgcatttg 5460 aaagtaaca gtggagctag ggctgggcat tttacatcca ggcttttaat tgattagaat 5520 tctgccaata ggtggatttt acaaaccac agacaacctc tgaagattc tgagaccct 5580 ttgagacaga agctcttaag tactcttgc cagggagcag cactgcatgt gtgatggttg 5640 ttgccatct gttgatcagg aactacttca gctacttgca tttgattat tcctttttt 5700 ttttttttaa ctcggaaaca caactggga aatatattct ttcccagtga ttataaacaa 5760 tctttttctt ttttttaagt ccttttggct tctagagctc ataggaaaat ggacttgatt 5820 tgaaattgga gccagagttt actcgtgttg gttatctatt catcagcttc ctgacatgtt 5880 aagagaatac attaagaga aaatactgtt ttttaatcct aaaatttttc ttccactaag 5940 ataaaccaaa tgtccttaca tatatgtaaa cccatctatt taaacgcaaa ggtgggttga 6000 tgtcagttta catagcagaa agcattcact atcctctaag atttgtttct gcaaaacttt 6060 cattgcttta gaattttaaa atttcacctt gtacaatggc cagcccctaa agcaggaaac 6120 atttataatg gattatatgg aaacatcctc ccagtacttg cccagccctt gaatcatgtg 6180 gcttttcagt gaaggaaag attcttttc taggaaaaat gagcctattt tattttattt 6240 tattttattt tttgacacaa actgtagatt ttagcagccc tggcccaaag gaatttgatt 6300 acttttgttt taaacagtac aaaggggaca ctataattac aaaaacatcc ttaactgatt 6360 tgagttgttt ttattcttt ggatatattt tcagagtggt aaattgtgtg tgagaattac 6420 aaatgattat tcttttagtg gtttcttagc ctctcttaca gcccacgggg atagtactgt 6480 acatcaatac cttcatatga aatttttata tgcaatgaaa ataaagcat gggttgattc 6540 tgcctatta tgactcaatc ttttacaaat aaaagattat tcattttaaa ttatagttca 6600 atcagcatgt ctcttaggat actgaacgtg gttgaatga areatagtg acatcataag 6660 6720 taccaaaatt acttagatgg cctataagat taagcatggt gttttctaag caagctttga 6780 aaggggcctt ccatacttac ttaattgaat attctgggat attgaaaatt attcagatac 6840 ttgacaatta tttttggtta cctactccgc aaactacaaa gttttaaagga ctcaacaata 6900 agttaatgag acacagtgtt tgctttcatg gagcttacag tctggagggg acaaaggctt 6960 aaacaatact catataatta tatatgtgat cagtacaatg aaggagctca gtggggtaaa 7020 taggagaa cctgaacttg atctgttccg gagggccaca gaaggcttcc ttgaggcctt 7080 7140 acaggaagag gaaggggatc cagacaagaa acatttgcaa agatcttgag gcataaatga 7200 gcttgagaca tctggagaaa ctgaggaaaa gtgagagagt aggcagggcc tggagccgca 7260 gagccattgc taaccatcct gtgtgagata tcccccattc tgtagcttta ttctcataac 7320 cctgctcaat tttctttata acacttctca cagatttata tacgtgtttg tttttgttat 7380 ctgtctctcc caccagacca cagctccatg agagcaaggt ctttgcttac caatatatca 7440 ctagcactta aaactatgcc tggtacacag taggttctta atatgtgttg aatatagcca 7500 tcaaattgat attggatata attcaatctg ataagatatt ttgagatatt aaagagtttt 7560 taacttgata ccataaaaaa aaaaaaaaaa a 7591 <210> 18 <211> 518 <212> PRT <213> Homo sapiens <400> 18 Met Pro Glu Ala Asn Tyr Leu Leu Ser Val Ser Trp Gly Tyr Ile Lys 1 5 10 15 Phe Lys Arg Met Leu Asn Arg Glu Leu Thr His Leu Ser Glu Met Ser 20 25 30 Arg Ser Gly Asn Gln Val Ser Glu Phe Ile Ser Asn Thr Phe Leu Asp 35 40 45 Lys Gln His Glu Val Glu Ile Pro Ser Pro Thr Gln Lys Glu Lys Glu 50 55 60 Lys Lys Lys Arg Pro Met Ser Gln Ile Ser Gly Val Lys Lys Leu Met 65 70 75 80 His Ser Ser Ser Leu Thr Asn Ser Ser Ile Pro Arg Phe Gly Val Lys 85 90 95 Thr Glu Gln Glu Asp Val Leu Ala Lys Glu Leu Glu Asp Val Asn Lys 100 105 110 Trp Gly Leu His Val Phe Arg Ile Ala Glu Leu Ser Gly Asn Arg Pro 115 120 125 Leu Thr Val Ile Met His Thr Ile Phe Gln Glu Arg Asp Leu Leu Lys 130 135 140 Thr Phe Lys Ile Pro Val Asp Thr Leu Ile Thr Tyr Leu Met Thr Leu 145 150 155 160 Glu Asp His Tyr His Ala Asp Val Ala Tyr His Asn Asn Ile His Ala 165 170 175 Ala Asp Val Val Gln Ser Thr His Val Leu Leu Ser Thr Pro Ala Leu 180 185 190 Glu Ala Val Phe Thr Asp Leu Glu Ile Leu Ala Ala Ile Phe Ala Ser 195 200 205 Ala Ile His Asp Val Asp His Pro Gly Val Ser Asn Gln Phe Leu Ile 210 215 220 Asn Thr Asn Ser Glu Leu Ala Leu Met Tyr Asn Asp Ser Ser Val Leu 225 230 235 240 Glu Asn His His Leu Ala Val Gly Phe Lys Leu Leu Gln Glu Glu Asn 245 250 255 Cys Asp Ile Phe Gln Asn Leu Thr Lys Lys Gln Arg Gln Ser Leu Arg 260 265 270 Lys Met Val Ile Asp Ile Val Leu Ala Thr Asp Met Ser Lys His Met 275 280 285 Asn Leu Leu Ala Asp Leu Lys Thr Met Val Glu Thr Lys Lys Val Thr 290 295 300 Ser Ser Gly Val Leu Leu Leu Asp Asn Tyr Ser Asp Arg Ile Gln Val 305 310 315 320 Leu Gln Asn Met Val His Cys Ala Asp Leu Ser Asn Pro Thr Lys Pro 325 330 335 Leu Gln Leu Tyr Arg Gln Trp Thr Asp Arg Ile Met Glu Glu Phe Phe 340 345 350 Arg Gln Gly Asp Arg Glu Arg Glu Arg Gly Met Glu Ile Ser Pro Met 355 360 365 Cys Asp Lys His Asn Ala Ser Val Glu Lys Ser Gln Val Gly Phe Ile 370 375 380 Asp Tyr Ile Val His Pro Leu Trp Glu Thr Trp Ala Asp Leu Val His 385 390 395 400 Pro Asp Ala Gln Asp Ile Leu Asp Thr Leu Glu Asp Asn Arg Glu Trp 405 410 415 Tyr Gln Ser Thr Ile Pro Gln Ser Pro Ser Pro Ala Pro Asp Asp Pro 420 425 430 Glu Glu Gly Arg Gln Gly Gln Thr Glu Lys Phe Gln Phe Glu Leu Thr 435 440 445 Leu Glu Glu Asp Gly Glu Ser Asp Thr Glu Lys Asp Ser Gly Ser Gln 450 455 460 Val Glu Glu Asp Thr Ser Cys Ser Asp Ser Lys Thr Leu Cys Thr Gln 465 470 475 480 Asp Ser Glu Ser Thr Glu Ile Pro Leu Asp Glu Gln Val Glu Glu Glu 485 490 495 Ala Val Gly Glu Glu Glu Glu Ser Gln Pro Glu Ala Cys Val Ile Asp 500 505 510 Asp Arg Ser Pro Asp Thr 515 <210> 19 <211> 8130 <212> DNA <213> Homo sapiens <400> 19 agattatagc ccagcgtacg agaagcacga gtcctatagt tggcgtaccc tgaggcctgc 60 cagttcctgc cttaatgcat atgtagtcgt aattgagttc tgacacggcc ttggatgttt 120 ctgtcctaaa tagctgacat tgcatcttca agactgtcat tccagttggc ttttgagtgg 180 atacgtgcag tgagatcatt gacactggaa acactagttc ccattttaat tacttaaaac 240 accacgatga aaagaaatac ctgtgatttg ctttctcgga gcaaaagtgc ctctgaggaa 300 acactacatt ccagtaatga agaggaagac cctttccgcg gaatggaacc ctatcttgtc 360 cggagacttt catgtcgcaa tattcagctt ccccctctcg ccttcagaca gttggaacaa 420 gctgacttga aaagtgaatc agagaacatt caacgaccaa ccagcctccc cctgaagatt 480 ctgccgctga ttgctatcac ttctgcagaa tccagtggtt ttgatgtgga caatggcaca 540 tctgcgggac ggagtccctt ggatcccatg accagcccag gatccgggct aattctccaa 600 gcaaatttg tccacagtca acgacgggag tccttcctgt atcgatccga cagcgattat 660 gacctctctc caaagtctat gtcccggac tcctccattg ccagtgatat acacggagat 720 gacttgattg tgactccatt tgctcaggtc ttggccagtc tgcgaactgt acgaaacaac 780 tttgctgcat tactaattt gcaagatcga gcacctagca aaagatcacc catgtgcaac caccatcca tcacaaagc caccataca gaggaggcct accagaact ggccagcgag accctggagg agctggactg gtgtctggac cagctagaga ccctacagac caggcactcc 960 gtcagtgaga tggcctccaa caagtttaaa aggatgctta atcgggagct cacccatctc tctgaatga gtcggtctgg aaatcaagtg tcagagttta tatcaaacac attcttagat aagcaacatg aagtggaaat tccttctcca actcagaagg aaaaggagaa aaagaaaga ccaatgtctc agatcagtgg agtcaagaaa ttgatgcaca gctctagtct gactaattca agtatcccaa ggtttggagt taaaactgaa caagaagatg tccttgccaa ggaactagaa gatgtgaaca aatggggtct tcatgttttc agaatagcag agttgtctgg taaccggccc ttgactgtta tcatgcacac catttttcag gaacgggatt tattaaaaac atttaaaatt 1380 ccagtagata ctttaattac atatcttatg actctcgaag accattacca tgctgatgtg 1440 gcctatcaca acaatatcca tgctgcagat gttgtccagt ctactcatgt gctattatct 1500 acacctgctt tggaggctgt gtttacagat ttggagattc ttgcagcaat ttttgccagt 1560 gcaatacatg atgtagatca tcctggtgtg tccaatcaat ttctgatcaa tacaaactct 1620 gaacttgcct tgatgtacaa tgattcctca gtcttagaga accatcattt ggctgtgggc 1680 tttaaattgc ttcaggaaga aaactgtgac attttccaga atttgaccaa aaaacaaaga 1740 caatctttaa ggaaaatggt cattgacatc gtacttgcaa cagatatgtc aaaacacatg 1800 aatctactgg ctgatttgaa gactatggtt gaaactaaga aagtgacaag ctctggagtt 1860 cttcttcttg ataattattc cgataggatt caggttcttc agaatatggt gcactgtgca 1920 gatctgagca acccaacaaa gcctctccag ctgtaccgcc agtggacgga ccggataatg 1980 gaggagttct tccgccaagg agaccgagag agggaacgtg gcatggagat aagccccatg 2040 2100. tgtgacaagc acaatgcttc cgtggaaaaa tcacaggtgg gcttcataga ctatattgtt catcccctct gggagacatg ggcagacctc gtccaccctg acgcccagga tattttggac 2160 actttggagg acaatcgtga atggtaccag agcacaatcc ctcagagccc ctctcctgca cctgatgacc cagaggaggg ccggcagggt caaactgaga aattccagtt tgaactaact ttagaggaag atggtgagtc agacacggaa aaggacagtg gcagtcaagt ggaagaagac actagctgca gtgactccaa actctctgt actcaagact cagagtctac tgaaattccc cttgatgaac aggttgaaga ggaggcagta ggggaagaag aggaaagcca gcctgaagcc tgtgtcatag atgatcgttc tcctgacacg taacagtgca aaaactttca tgcctttttt ttttttaagt agaaaaattg tttccaaagt gcatgtcaca tgccacaacc acggtcacac ctcactgtca tctgccagga cgtttgttga acaaaactga ccttgactac tcagtccagc gctcaggaat atcgtaacca gttttttcac ctccatgtca tccgagcaag gtggacatct tcacgaacag cgtttttaac aagatttcag cttggtagag ctgacaaagc agataaaatc tactccaaat tatttcaag agagtgtgac tcatcaggca gcccaaagt tattggact 2820 tggggttctt atttccttttttgtttgc atattttca gagaaaggc attgcacaga 2880 gtgaacttaa tggacgaagc aaaaatg tcagacag gatagcac gatctgtta 2940 ccagtaggag gaggatgagc cacagaaatt gcatatttt ctaatttca gtcttcctga 3000 tacatgactg atagtgtgg ttcagtgagc tgcactgacc tctacatttt gtatgatatg 3060 taaaacagat ttttgtaga gcttacttt attattaat gtattgaggt attattatta 3120 aaaaaaacta tgttcagaac ttcatctgcc actggttatt ttttctaag gagtacttg 3180 caagttttca gtacaaatct gtgctacact ggataaaaat ctaatttatg aattttact 3240 gcaccttata gttcatagca atttaacgat tgtagtgat tcattgttg ttttatatac 3300 caatgacttc catattttaa agagaaaa caatttatg ttgcaggaaa ccctttttgt 3360 aagtctttat tattacttt gcattttgtt tcactcttc cagataagca gagttgctct 3420 tcaccagtgt tttcttcat gtgcaaagtg actatttgtt ctataatact tttatgtgtg 3480 ttatatcaaa tgtgtcttaa gcttcatgca aactcagtca tcagttcgtg ttgtctgaag 3540 caagtgggag atatataaat acccagtagc taaaatggtc agtctttttt agatgttttc 3600 ctacttagta tctcctaata acgttttgct gtgtcactag atgttcattt cacaagtgca 3660 tgtctttcta ataatccaca catttcatgc tctaataatc cacacatttc atgctcattt 3720 ttattgtttt tacagccagt tatagtaaga aaaaggtttt tccccttgtg ctgctttata 3780 atttagcgtg tgtctgaacc ttatccatgt ttgctagatg aggtcttgtc aaatatatca 3840 ctaccattgt caccggtgaa aagaaacagg tagttaagtt agggttaaca ttcatttcaa 3900 ccacgaggtt gtatatcatg actagctttt actcttggtt tacagagaaa agttaaacag 3960 ccaactaggc agtttttaag aatattaaca atatattaac aaacaccaat acaactaatc 4020 ctatttggtt ttaatgattt caccatggga ttaagaacta tatcaggaac atccctgaga 4080 aacggtttta agtgtagcaa ctactcttcc ttaatggaca gccacataac gtgtaggaag 4140 tcctttatca cttatcctcg atccataagc atatcttgca gaggggaact acttctttaa 4200 acacatggag ggaaagaga tgatgccact ggcaccagag ggttagtact gtgatgcatc 4260 ctaaaatatt tattatattg gtaaaaatttc tggttaaata aaaaattaga gatcactct 4320 ggctgatttc agcaccagga actgtattac agttttagag atttattcct agtgttttacc 4380 tgattatagc agttggcatc atggggcatt taattctgac ttatcccca cgtcagcctt 4440 aaaagtct tctttacctt ctctatgaag actttaaagc ccaataatc atttttcaca 4500 ttgatattca agaattgaga tagatagaag ccaagtggg tatctgacaa gtggaaaatc 4560 aaacgtttaa gagaattac aactctgaaa agcattatta tgtggaactt ctcaggagc 4620 ctcctgggga ctggaagta agtcatcagc caggcaatg actcatgctg aagagagtcc 4680 ccatttcagt cccctgagat ctagctgatg cttagatcct ttgaataaa aattatgtct 4740 ttataactct gatctttac attaagcaga agaggaatca actaagttaat tgcaggtttt 4800 ctactctgtt tcctctgtaa agatcagatg gtaatctttc aaataagaaaaataaga 4860 cgtatgtttg accaagtagt ttcacaagaa tatttgggaa cttgttttctt ttaattttat 4920 ttgtccctga gtgaagtcta gaagaaagg taaagagtct agagtttt cctctttcca 4980 aaacattctc attcctcc tccctacact tagtatttcc cccacagagt gcctagaatc 5040 ttaataatga aaaataa aaagcagcaat atgtcattaa aaatccaga cctgaaaggg 5100 taaagggttt atactgcac taataagag aggcttttt ttttctttcc agttttgttgg 5160 ttttaatgg taccgtgttg taagatacc cactaatgga caatcaatt gcagaaaagg 5220 ctcaatcc agagacagg gactaatgca ctgtacaatc tgcttacct tgccctctc 5280 tcttgccaaa gtgtgcttca gaaatatata ctgctttaaa aaagataaa agatatcct 5340 tttacaagtg gctttacatt tcctaaaatg ccataagaaa atgcaatc tggtactgt 5400 atggggaaaa aaatgtccaa gtttgtgtaa aaccagtgca ttcagcttg caagttactg 5460 aacacataa tgctgtttta atttgtttt atatcagtta aattcacaa taatgtagat 5520 agaaaaattt acagaaagg aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaagct 5580 tatgataatt ttgaatgca ttatttttt ttgtgccat gcatttttt tctcaccaaa 5640 tgaccttacc tgtaatacag tcttgtttgt ctgtttacaa ccatgtattt attgcaatgt 5700 acatactgta atgttaattg taaattatct gttcttatta aaacatcatc ccatgatggg 5760 atggtgttga tatatttgga aactctttggt gagagaatga atggtgtgta tacatactct 5820 gtacatttt cttttctcct gtaatatagt cttgtcacct tagagcttt ttatggaaga 5880 ttcaagaaaa ctataaaata cttaaagata tataaattta aaaaaacata gctgcaggtc 5940 tttggtccca gggctgtgcc ttactttaa ccaatatttt cttctgtttt gctgcatttg 6000 aaagtaaca gtggagctag ggctgggcat tttacatcca ggctttaat tgattagaat 6060 tctgccaata ggtggatttt acaaaccac agacaacctc tgaagattc tgagaccct 6120 ttgagacaga agctcttaag tactcttgc cagggagcag cactgcatgt gtgatggttg 6180 ttgccatct gttgatcagg aactacttca gctacttgca tttgattat tcctttttt 6240 tttttttaa ctcggaaaca caactgggga atatattct ttcccagtga ttaaacaa 6300 tctttttctt ttttaagt ccttttggct tctgagctc ataggaaat ggacttgatt 6360 tgaaattgga gccagagttt actcgtgttg gttatctatt catcagcttc ctgacatgtt 6420 aagagaatac attaagaga aaatactgtt ttttaatcct aaaatttttc ttccactaag 6480 ataaaccaaa tgtccttaca tatatgtaaa cccatctatt taaacgcaaa ggtgggttga 6540 tgtcagttta catagcagaa agcattcact atcctctaag atttgtttct gcaaaacttt 6600 cattgcttta gaattttaaa atttcacctt gtacaatggc cagcccctaa agcaggaaac 6660 atttataatg gattatatgg aaacatcctc ccagtacttg cccagccctt gaatcatgtg 6720 gcttttcagt gaaggaaag attcttttc taggaaaaat gagcctattt tattttattt 6780 tattttattt tttgacacaa actgtagatt ttagcagccc tggcccaaag gaatttgatt 6840 acttttgttt taaacagtac aaaggggaca ctataattac aaaaacatcc ttaactgatt 6900 tgagttgttt ttattcttt ggatatattt tcagagtggt aaattgtgtg tgagaattac 6960 aaatgattat tcttttagtg gtttcttagc ctctcttaca gcccacgggg atagtactgt 7020 acatcaatac cttcatatga aatttttata tgcaatgaaa ataaagcat gggttgattc 7080 tgcctatta tgactcaatc ttttacaaat aaaagattat tcattttaaa ttatagttca 7140 atcagcatgt ctcttaggat actgaacgtg gttgaatga areatagtg acatcataag 7200 7260 taccaaaatt acttagatgg cctataagat taagcatggt gttttctaag caagctttga 7320 aaggggcctt ccatacttac ttaattgaat attctgggat attgaaaatt attcagatac 7380 ttgacaatta tttttggtta cctactccgc aaactacaaa gttttaaagga ctcaacaata 7440 agttaatgag acacagtgtt tgctttcatg gagcttacag tctggagggg acaaaggctt 7500 aaacaatact catataatta tatatgtgat cagtacaatg aaggagctca gtggggtaaa 7560 taggagaa cctgaacttg atctgttccg gagggccaca gaaggcttcc ttgaggcctt 7620 7680 acaggaagag gaaggggatc cagacaagaa acatttgcaa agatcttgag gcataaatga 7740 gcttgagaca tctggagaaa ctgaggaaaa gtgagagagt aggcagggcc tggagccgca 7800 gagccattgc taaccatcct gtgtgagata tcccccattc tgtagcttta ttctcataac 7860 cctgctcaat tttctttata acacttctca cagatttata tacgtgtttg tttttgttat 7920 ctgtctctcc caccagacca cagctccatg agagcaaggt ctttgcttac caatatatca 7980 ctagcactta aaactatgcc tggtacacag taggttctta atatgtgttg aatatagcca 8040 tcaaattgat attggatata attcaatctg ataagatatt ttgagatatt aaagagtttt 8100 taacttgata ccataaaaaa aaaaaaaaaa 8130 <210> 20 <211> 748 <212> PRT <213> Homo sapiens <400> 20 Met Lys Arg Asn Thr Cys Asp Leu Leu Ser Arg Ser Lys Ser Ala Ser 1 5 10 15 Glu Glu Thr Leu His Ser Ser Asn Glu Glu Glu Asp Pro Phe Arg Gly 20 25 30 Met Glu Pro Tyr Leu Val Arg Arg Leu Ser Cys Arg Asn Ile Gln Leu 35 40 45 Pro Pro Leu Ala Phe Arg Gln Leu Glu Gln Ala Asp Leu Lys Ser Glu 50 55 60 Ser Glu Asn Ile Gln Arg Pro Thr Ser Leu Pro Leu Lys Ile Leu Pro 65 70 75 80 Leu Ile Ala Ile Thr Ser Ala Glu Ser Ser Gly Phe Asp Val Asp Asn 85 90 95 Gly Thr Ser Ala Gly Arg Ser Pro Leu Asp Pro Met Thr Ser Pro Gly 100 105 110 Ser Gly Leu Ile Leu Gln Ala Asn Phe Val His Ser Gln Arg Arg Glu 115 120 125 Ser Phe Leu Tyr Arg Ser Asp Ser Asp Tyr Asp Leu Ser Pro Lys Ser 130 135 140 Met Ser Arg Asn Ser Ser Ile Ala Ser Asp Ile His Gly Asp Asp Leu 145 150 155 160 Ile Val Thr Pro Phe Ala Gln Val Leu Ala Ser Leu Arg Thr Val Arg 165 170 175 Asn Asn Phe Ala Ala Leu Thr Asn Leu Gln Asp Arg Ala Pro Ser Lys 180 185 190 Arg Ser Pro Met Cys Asn Gln Pro Ser Ile Asn Lys Ala Thr Ile Thr 195 200 205 Glu Glu Ala Tyr Gln Lys Leu Ala Ser Glu Thr Leu Glu Glu Leu Asp 210 215 220 Trp Cys Leu Asp Gln Leu Glu Thr Leu Gln Thr Arg His Ser Val Ser 225 230 235 240 Glu Met Ala Ser Asn Lys Phe Lys Arg Met Leu Asn Arg Glu Leu Thr 245 250 255 His Leu Ser Glu Met Ser Arg Ser Gly Asn Gln Val Ser Glu Phe Ile 260 265 270 Ser Asn Thr Phe Leu Asp Lys Gln His Glu Val Glu Ile Pro Ser Pro 275 280 285 Thr Gln Lys Glu Lys Glu Lys Lys Lys Arg Pro Met Ser Gln Ile Ser 290 295 300 Gly Val Lys Lys Leu Met His Ser Ser Ser Leu Thr Asn Ser Ser Ile 305 310 315 320 Pro Arg Phe Gly Val Lys Thr Glu Gln Glu Asp Val Leu Ala Lys Glu 325 330 335 Leu Glu Asp Val Asn Lys Trp Gly Leu His Val Phe Arg Ile Ala Glu 340 345 350 Leu Ser Gly Asn Arg Pro Leu Thr Val Ile Met His Thr Ile Phe Gln 355 360 365 Glu Arg Asp Leu Leu Lys Thr Phe Lys Ile Pro Val Asp Thr Leu Ile 370 375 380 Thr Tyr Leu Met Thr Leu Glu Asp His Tyr His Ala Asp Val Ala Tyr 385 390 395 400 His Asn Asn Ile His Ala Ala Asp Val Val Gln Ser Thr His Val Leu 405 410 415 Leu Ser Thr Pro Ala Leu Glu Ala Val Phe Thr Asp Leu Glu Ile Leu 420 425 430 Ala Ala Ile Phe Ala Ser Ala Ile His Asp Val Asp His Pro Gly Val 435 440 445 Ser Asn Gln Phe Leu Ile Asn Thr Asn Ser Glu Leu Ala Leu Met Tyr 450 455 460 Asn Asp Ser Ser Val Leu Glu Asn His His Leu Ala Val Gly Phe Lys 465 470 475 480 Leu Leu Gln Glu Glu Asn Cys Asp Ile Phe Gln Asn Leu Thr Lys Lys 485 490 495 Gln Arg Gln Ser Leu Arg Lys Met Val Ile Asp Ile Val Leu Ala Thr 500 505 510 Asp Met Ser Lys His Met Asn Leu Leu Ala Asp Leu Lys Thr Met Val 515 520 525 Glu Thr Lys Lys Val Thr Ser Ser Gly Val Leu Leu Leu Asp Asn Tyr 530 535 540 Ser Asp Arg Ile Gln Val Leu Gln Asn Met Val His Cys Ala Asp Leu 545 550 555 560 Ser Asn Pro Thr Lys Pro Leu Gln Leu Tyr Arg Gln Trp Thr Asp Arg 565 570 575 Ile Met Glu Glu Phe Phe Arg Gln Gly Asp Arg Glu Arg Glu Arg Gly 580 585 590 Met Glu Ile Ser Pro Met Cys Asp Lys His Asn Ala Ser Val Glu Lys 595 600 605 Ser Gln Val Gly Phe Ile Asp Tyr Ile Val His Pro Leu Trp Glu Thr 610 615 620 Trp Ala Asp Leu Val His Pro Asp Ala Gln Asp Ile Leu Asp Thr Leu 625 630 635 640 Glu Asp Asn Arg Glu Trp Tyr Gln Ser Thr Ile Pro Gln Ser Pro Ser 645 650 655 Pro Ala Pro Asp Asp Pro Glu Glu Gly Arg Gln Gly Gln Thr Glu Lys 660 665 670 Phe Gln Phe Glu Leu Thr Leu Glu Glu Asp Gly Glu Ser Asp Thr Glu 675 680 685 Lys Asp Ser Gly Ser Gln Val Glu Glu Asp Thr Ser Cys Ser Asp Ser 690 695 700 Lys Thr Leu Cys Thr Gln Asp Ser Glu Ser Thr Glu Ile Pro Leu Asp 705 710 715 720 Glu Gln Val Glu Glu Glu Ala Val Gly Glu Glu Glu Glu Ser Gln Pro 725 730 735 Glu Ala Cys Val Ile Asp Asp Arg Ser Pro Asp Thr 740 745 <210> twenty one <211> 20 <212> DNA <213> Artificial sequence <220> <223> PDE4D7_Forward Primer <400> twenty one gaacattcaa cgaccaacca 20 <210> twenty two <211> 20 <212> DNA <213> Artificial sequence <220> <223> PDE4D7_Reverse Primer <400> twenty two tgccattgtc cacatcaaaa 20 <210> twenty three <211> 27 <212> DNA <213> Artificial sequence <220> <223> PDE4D7 probe <400> twenty three ctgccgctga ttgctatcac ttctgca 27 <210> twenty four <211> twenty two <212> DNA <213> Artificial sequence <220> <223> PDE4D7 forward primer 2 <400> twenty four cgctgattgc tatcacttct gc 22 <210> 25 <211> twenty four <212> DNA <213> Artificial sequence <220> <223> PDE4D7 reverse primer <400> 25 gtcgttgact gtggacaaaa tttg 24 <210> 26 <211> 34 <212> DNA <213> Artificial sequence <220> <223> PDE4D7 probe 2 <400> 26 ttcccttgga tcccatgacc agcccataag ggaa 34 <210> 27 <211> 8130 <212> DNA <213> Homo sapiens <400> 27 agattatagc ccagcgtacg agaagcacga gtcctatagt tggcgtaccc tgaggcctgc 60 cagttcctgc cttaatgcat atgtagtcgt aattgagttc tgacacggcc ttggatgttt 120 ctgtcctaaa tagctgacat tgcatcttca agactgtcat tccagttggc ttttgagtgg 180 atacgtgcag tgagatcatt gacactggaa acactagttc ccattttaat tacttaaaac 240 accacgatga aaagaaatac ctgtgatttg ctttctcgga gcaaaagtgc ctctgaggaa 300 acactacatt ccagtaatga agaggaagac cctttccgcg gaatggaacc ctatcttgtc 360 cggagacttt catgtcgcaa tattcagctt ccccctctcg ccttcagaca gttggaacaa 420 gctgacttga aaagtgaatc agagaacatt caacgaccaa ccagcctccc cctgaagatt 480 ctgccgctga ttgctatcac ttctgcagaa tccagtggtt ttgatgtgga caatggcaca 540 tctgcgggac ggagtccctt ggatcccatg accagcccag gatccgggct aattctccaa 600 gcaaattttg tccacagtca acgacgggag tccttcctgt atcgatccga cagcgattat 660 gacctctctc caaagtctat gtcccggaac tcctccattg ccagtgatat acacggagat 720 gacttgattg tgactccatt tgctcaggtc ttggccagtc tgcgaactgt acgaaacaac 780 tttgctgcat taactaattt gcaagatcga gcacctagca aaagatcacc catgtgcaac 840 caaccatcca tcaacaaagc caccataaca gaggaggcct accagaaact ggccagcgag 900 accctggagg agctggactg gtgtctggac cagctagaga ccctacagac caggcactcc 960 gtcagtgaga tggcctccaa caagtttaaa aggatgctta atcgggagct cacccatctc 1020 tctgaaatga gtcggtctgg aaatcaagtg tcagagttta tatcaacac attcttagat 1080 aagcaacatg aagtggaat tccttctcca actcagaagg aaaggagaa aaagaaaga 1140 ccaatgtctc agatcagtgg agtcaagaa ttgatgcaca gctctagtct gactattca 1200 agtatcccaa ggtttggagt taaactgaa ggaagatg tccttgccaa ggaactagaa 1260 gatgtgaaca aatggggtct tcatgttttc agaatagcag agttgtctgg taaccggccc 1320 ttgactgtta tcatgcacac cattttcag gaacgggatt tattaaaaac atttaaaatt 1380 ccagtagata ctttaattac atatcttatg actctcgaag accattacca tgctgatgtg 1440 gcctatcaca acaatatcca tgctgcagat gttgtccagt ctactcatgt gctattatct 1500 acacctgctt height height shoes height height shoes height 1560 gcaatacatg atgtagatca tcctggtgtg tccaatcaat ttctgatcaa tacaactct 1620 gaacttgcct tgatgtacaa tgattcctca gtcttagaga accatcattt ggctgtgggc 1680 tttaaattgc ttcaggaga aactgtgac attttccaga atttgaccaa aaaacaaaga 1740 caatctttaa ggaaaatggt cattgacatc gtacttgcaa cagatgtc aaaacacatg 1800 aatctactgg ctgatttgaa gactatggtt gaactaaga aagtgacaag ctctggagtt 1860 cttctcttg atattattc cgataggatt caggttctc agaatatggt gcactgtgca 1920 gatctgagca acccaaaa gcctctccag ctgtaccgcc agtggacgga ccggataatg 1980 gaggagttct tccgccaagg agaccgagag agggacgtg gcatggagat aagccccatg 2040 tgtgacaagc acatgctc cgtggaaaaa tcacaggtgg gcttcataga ctatattgtt 2100 catcccctct gggagacatg ggcagacctc gtccaccctg acggcccagga tattttggac 2160 actttggagg acaatcgtga atggtaccag agcacaatcc ctcagagccc ctctcctgca 2220 cctgatgacc cagaggagggg ccggcaggggt caactgaga aattccagtt tgaactact 2280 ttagaggaag atggtgagtc agacacggaa aaggacagtg gcagtcaagt ggaagagac 2340 actagctgca gtgactccaa gactcttgt actcagact cagagctac tgaaattccc 2400 cttgatgaac aggttgaaga ggaggcagta ggggaagaag aggaagcca gcctgaagcc 2460 tgtgtcatag atgatcgttc tcctgacacg taacagtgca aaaactttca tgccttttt 2520 ttttttaagt agaaaaattg ttccaagt gcatgtcaca tgccacaacc acggtcacac 2580 ctcactgtca tctgccagga cgtttgttga acaaactga ccttgactac tcagtccagc 2640 gctcaggaat atcgtaacca gttttcac ctccatgtca tccgagcaag gtggacatct 2700 tcacgaacag cgttttaac aagatttcag cttggtagag ctgacaagc agataaaatc 2760 tactccaaat tatttcaag agagtgtgac tcatcaggca gcccaaagt tattggact 2820 tggggttctt atttccttttttgtttgc atattttca gagaaaggc attgcacaga 2880 gtgaacttaa tggacgaagc aaaaatg tcagacag gatagcac gatctgtta 2940 ccagtaggag gaggatgagc cacagaaatt gcatatttt ctaatttca gtcttcctga 3000 tacatgactg atagtgtgg ttcagtgagc tgcactgacc tctacatttt gtatgatatg 3060 taaaacagat ttttgtaga gcttacttt attattaat gtattgaggt attattatta 3120 aaaaaaacta tgttcagaac ttcatctgcc actggttatt ttttctaag gagtaacttg 3180 caagttttca gtacaaatct gtgctacact ggataaaaat ctaatttatg aattttactt 3240 gcaccttata gttcatagca attaactgat ttgtagtgat tcattgtttg ttttatatac 3300 caatgacttc catattttaa aagagaaaaa caactttatg ttgcaggaaa cccttttgtgt 3360 aagtcttat tatttacttt gcattttgtt tcactctttc cagataagca gagttgctct 3420 tcaccagtgt ttttcttcat gtgcaaagtg actatttgtt ctataatact tttatgtgtg 3480 ttatatcaaa tgtgtcttaa gcttcatgca aactcagtca tcagttcgtg ttgtctgaag 3540 caagtgggag atatataaat acccagtagc taaaatggtc agtcttttt agatgttttc 3600 ctacttagta tctcctaata acgttttgct gtgtcactag atgttcattt cacaagtgca 3660 tgtctttcta ataatccaca catttcatgc tctaataatc cacacatttc atgctcattt 3720 ttattgtttt tacagccagt tatagtaaga aaaaggtttt tccccttgtg ctgctttata 3780 atttagcgtg tgtctgaacc ttatccatgt ttgctagatg aggtcttgtc aaatatatca 3840 ctaccattgt caccggtgaa aagaaacagg tagttaagtt agggttaaca ttcatttcaa 3900 ccacgaggtt gtatatcatg actagctttt actcttggtt tacagagaaa agttaaacag 3960 ccaactaggc agttttaag aatattaaca atatattaac aaacaccaat acaactaatc 4020 ctatttggtt ttaatgattt caccatggga ttaagaacta tatcaggaac atccctgaga 4080 aacggtttta agtgtagcaa ctactcttcc ttaatggaca gccacataac gtgtaggaag 4140 tcctttatca cttatcctcg atccataagc atactctgca gaggggaact acttctttaa 4200 acacatggag ggaaagaaga tgatgccact ggcaccagag ggttagtact gtgatgcatc 4260 ctaaaatatt tattatattg gtaaaaattc tggttaaata aaaaattaga gatcactctt 4320 ggctgatttc agcaccagga actgtattac agttttagag attaattcct agtgtttacc 4380 tgattatagc agttggcatc atggggcatt taattctgac tttatcccca cgtcagcctt 4440 aataaagtct tctttacctt ctctatgaag actttaaagc ccaaataatc atttttcaca 4500 ttgatattca agaattgaga tagatagaag ccaaagtggg tatctgacaa gtggaaaatc 4560 aaacgtttaa gagaattac aactctgaaa agcattatta tgtggaactt ctcaggagc 4620 ctcctgggga ctggaagta agtcatcagc caggcaatg actcatgctg aagagagtcc 4680 ccatttcagt cccctgagat ctagctgatg cttagatcct ttgaataaa aattatgtct 4740 ttataactct gatctttac attaagcaga agaggaatca actaagttaat tgcaggtttt 4800 ctactctgtt tcctctgtaa agatcagatg gtaatctttc aaataagaaaaataaga 4860 cgtatgtttg accaagtagt ttcacaagaa tatttgggaa cttgttttctt ttaattttat 4920 ttgtccctga gtgaagtcta gaagaaagg taaagagtct agagtttt cctctttcca 4980 aaacattctc attcctcc tccctacact tagtatttcc cccacagagt gcctagaatc 5040 ttaataatga aaaataa aaagcagcaat atgtcattaa aaatccaga cctgaaaggg 5100 taaagggttt atactgcac taataagag aggcttttt ttttctttcc agttttgttgg 5160 ttttaatgg taccgtgttg taagatacc cactaatgga caatcaatt gcagaaaagg 5220 ctcaatcc agagacagg gactaatgca ctgtacaatc tgcttacct tgccctctc 5280 tcttgccaaa gtgtgcttca gaaatatata ctgctttaaa aaagataaa agatatcct 5340 tttacaagtg gctttacatt tcctaaaatg ccataagaaa atgcaatc tggtactgt 5400 atggggaaaa aaatgtccaa gtttgtgtaa aaccagtgca ttcagcttg caagttactg 5460 aacacataa tgctgtttta atttgtttt atatcagtta aattcacaa taatgtagat 5520 agaaaaattt acagaaagg aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaagct 5580 tatgataatt ttgaatgca ttatttttt ttgtgccat gcatttttt tctcaccaaa 5640 tgaccttacc tgtaatacag tcttgtttgt ctgtttacaa ccatgtattt attgcaatgt 5700 acatactgta atgttaattg taaattatct gttcttatta aaacatcatc ccatgatggg 5760 atggtgttga tatatttgga aactctttggt gagagaatga atggtgtgta tacatactct 5820 gtacatttt cttttctcct gtaatatagt cttgtcacct tagagcttt ttatggaaga 5880 ttcaagaaaa ctataaaata cttaaagata tataaattta aaaaaacata gctgcaggtc 5940 tttggtccca gggctgtgcc ttactttaa ccaatatttt cttctgtttt gctgcatttg 6000 aaaggtaaca gtggagctag ggctggggcat tttacatcca ggcttttaat tgattagaat 6060 tctgccaata ggtggatttt acaaaaccac agaaccctc tgaaagattc tgagaccctt 6120 ttgagacaga agctcttaag tacttcttgc cagggagcag cactgcatgt gtgatggttg 6180 tttgccatct gttgatcagg aactacttca gctacttgca tttgattatt tccttttttt 6240 ttttttttaa ctcggaaaca caactggga aatatattct ttcccagtga ttataaacaa 6300 tctttttctt ttttttaagt ccttttggct tctagagctc ataggaaaat ggacttgatt 6360 tgaaattgga gccagagttt actcgtgttg gttatctatt catcagcttc ctgacatgtt 6420 aagagaatac attaagaga aaatactgtt ttttaatcct aaaatttttc ttccactaag 6480 ataaaccaaa tgtccttaca tatatgtaaa cccatctatt taaacgcaaa ggtgggttga 6540 tgtcagttta catagcagaa agcattcact atcctctaag atttgtttct gcaaaacttt 6600 cattgcttta gaattttaaa atttcacctt gtacaatggc cagcccctaa agcaggaaac 6660 atttataatg gattatatgg aaacatcctc ccagtacttg cccagccctt gaatcatgtg 6720 gcttttcagt gaaggaaag attcttttc taggaaaaat gagcctattt tattttattt 6780 tattttattt tttgacacaa actgtagatt ttagcagccc tggcccaaag gaatttgatt 6840 acttttgttt taaacagtac aaaggggaca ctataattac aaaaacatcc ttaactgatt 6900 tgagttgttt ttattcttt ggatatattt tcagagtggt aaattgtgtg tgagaattac 6960 aaatgattat tcttttagtg gtttcttagc ctctcttaca gcccacgggg atagtactgt 7020 acatcaatac cttcatatga aatttttata tgcaatgaaa ataaagcat gggttgattc 7080 tgcctatta tgactcaatc ttttacaaat aaaagattat tcattttaaa ttatagttca 7140 atcagcatgt ctcttaggat actgaacgtg gttgaatga areatagtg acatcataag 7200 7260 taccaaaatt acttagatgg cctataagat taagcatggt gttttctaag caagctttga 7320 aaggggcctt ccatacttac ttaattgaat attctgggat attgaaaatt attcagatac 7380 ttgacaatta tttttggtta cctactccgc aaactacaaa gttttaaagga ctcaacaata 7440 agttaatgag acacagtgtt tgctttcatg gagcttacag tctggagggg acaaaggctt 7500 aaacaatact catataatta tatatgtgat cagtacaatg aaggagctca gtggggtaaa 7560 taagcaggaa cctgaacttg atctgttccg gagggccaca gaaggcttcc ttgaggcctt 7620 gagaaagtga tttgcatctg agttctgaag gattgtaaga ggtaactagg gaaaaagttg 7680 acaggaagag gaaggggatc cagacaagaa acatttgcaa agatcttgag gcataaatga 7740 gcttgagaca tctggagaaa ctgaggaaaa gtgagagagt aggcagggcc tggagccgca 7800 gagccattgc taaccatcct gtgtgagata tcccccattc tgtagcttta ttctcataac 7860 cctgctcaat tttctttata acacttctca cagatttata tacgtgtttg ttttgttat 7920 ctgtctctcc caccagacca cagctccatg agagcaaggt ctttgcttac caatatatca 7980 ctagcactta aaactatgcc tggtacacag taggttctta atatgtgttg aatatagcca 8040 tcaaattgat attggatata attcaatctg ataagatatt ttgagatatt aaagagtttt 8100 taacttgata ccataaaaaa aaaaaaaaa 8130 <210> 28 <211> 687 <212> PRT <213> Homo sapiens <400> 28 Met Ala Phe Val Trp Asp Pro Leu Gly Ala Thr Val Pro Gly Pro Ser 1 5 10 15 Thr Arg Ala Lys Ser Arg Leu Arg Phe Ser Lys Ser Tyr Ser Phe Asp 20 25 30 Val Asp Asn Gly Thr Ser Ala Gly Arg Ser Pro Leu Asp Pro Met Thr 35 40 45 Ser Pro Gly Ser Gly Leu Ile Leu Gln Ala Asn Phe Val His Ser Gln 50 55 60 Arg Arg Glu Ser Phe Leu Tyr Arg Ser Asp Ser Asp Tyr Asp Leu Ser 65 70 75 80 Pro Lys Ser Met Ser Arg Asn Ser Ser Ile Ala Ser Asp Ile His Gly 85 90 95 Asp Asp Leu Ile Val Thr Pro Phe Ala Gln Val Leu Ala Ser Leu Arg 100 105 110 Thr Val Arg Asn Asn Phe Ala Ala Leu Thr Asn Leu Gln Asp Arg Ala 115 120 125 Pro Ser Lys Arg Ser Pro Met Cys Asn Gln Pro Ser Ile Asn Lys Ala 130 135 140 Thr Ile Thr Glu Glu Ala Tyr Gln Lys Leu Ala Ser Glu Thr Leu Glu 145 150 155 160 Glu Leu Asp Trp Cys Leu Asp Gln Leu Glu Thr Leu Gln Thr Arg His 165 170 175 Ser Val Ser Glu Met Ala Ser Asn Lys Phe Lys Arg Met Leu Asn Arg 180 185 190 Glu Leu Thr His Leu Ser Glu Met Ser Arg Ser Gly Asn Gln Val Ser 195 200 205 Glu Phe Ile Ser Asn Thr Phe Leu Asp Lys Gln His Glu Val Glu Ile 210 215 220 Pro Ser Pro Thr Gln Lys Glu Lys Glu Lys Lys Lys Arg Pro Met Ser 225 230 235 240 Gln Ile Ser Gly Val Lys Lys Leu Met His Ser Ser Ser Leu Thr Asn 245 250 255 Ser Ser Ile Pro Arg Phe Gly Val Lys Thr Glu Gln Glu Asp Val Leu 260 265 270 Ala Lys Glu Leu Glu Asp Val Asn Lys Trp Gly Leu His Val Phe Arg 275 280 285 Ile Ala Glu Leu Ser Gly Asn Arg Pro Leu Thr Val Ile Met His Thr 290 295 300 Ile Phe Gln Glu Arg Asp Leu Leu Lys Thr Phe Lys Ile Pro Val Asp 305 310 315 320 Thr Leu Ile Thr Tyr Leu Met Thr Leu Glu Asp His Tyr His Ala Asp 325 330 335 Val Ala Tyr His Asn Asn Ile His Ala Ala Asp Val Val Gln Ser Thr 340 345 350 His Val Leu Leu Ser Thr Pro Ala Leu Glu Ala Val Phe Thr Asp Leu 355 360 365 Glu Ile Leu Ala Ala Ile Phe Ala Ser Ala Ile His Asp Val Asp His 370 375 380 Pro Gly Val Ser Asn Gln Phe Leu Ile Asn Thr Asn Ser Glu Leu Ala 385 390 395 400 Leu Met Tyr Asn Asp Ser Ser Val Leu Glu Asn His His Leu Ala Val 405 410 415 Gly Phe Lys Leu Leu Gln Glu Glu Asn Cys Asp Ile Phe Gln Asn Leu 420 425 430 Thr Lys Lys Gln Arg Gln Ser Leu Arg Lys Met Val Ile Asp Ile Val 435 440 445 Leu Ala Thr Asp Met Ser Lys His Met Asn Leu Leu Ala Asp Leu Lys 450 455 460 Thr Met Val Glu Thr Lys Lys Val Thr Ser Ser Gly Val Leu Leu Leu 465 470 475 480 Asp Asn Tyr Ser Asp Arg Ile Gln Val Leu Gln Asn Met Val His Cys 485 490 495 Ala Asp Leu Ser Asn Pro Thr Lys Pro Leu Gln Leu Tyr Arg Gln Trp 500 505 510 Thr Asp Arg Ile Met Glu Glu Phe Phe Arg Gln Gly Asp Arg Glu Arg 515 520 525 Glu Arg Gly Met Glu Ile Ser Pro Met Cys Asp Lys His Asn Ala Ser 530 535 540 Val Glu Lys Ser Gln Val Gly Phe Ile Asp Tyr Ile Val His Pro Leu 545 550 555 560 Trp Glu Thr Trp Ala Asp Leu Val His Pro Asp Ala Gln Asp Ile Leu 565 570 575 Asp Thr Leu Glu Asp Asn Arg Glu Trp Tyr Gln Ser Thr Ile Pro Gln 580 585 590 Ser Pro Ser Pro Ala Pro Asp Asp Pro Glu Glu Gly Arg Gln Gly Gln 595 600 605 Thr Glu Lys Phe Gln Phe Glu Leu Thr Leu Glu Glu Asp Gly Glu Ser 610 615 620 Asp Thr Glu Lys Asp Ser Gly Ser Gln Val Glu Glu Asp Thr Ser Cys 625 630 635 640 Ser Asp Ser Lys Thr Leu Cys Thr Gln Asp Ser Glu Ser Thr Glu Ile 645 650 655 Pro Leu Asp Glu Gln Val Glu Glu Glu Ala Val Gly Glu Glu Glu Glu 660 665 670 Ser Gln Pro Glu Ala Cys Val Ile Asp Asp Arg Ser Pro Asp Thr 675 680 685 <210> 29 <211> 8395 <212> DNA <213> Homo sapiens <400> 29 ttctcactgc cctgcggtgt tttgaactgc cttcttacag acgtcataca gcccttgagg 60 aatagtttct gcctggtgag attgaatgat agttctcatt cacaaaaccc tggattctaa 120 gcagggacac acagaaatta ctttcgcagg taaatcagcc cacccagcca aagtgtggag 180 agatttgttc cttggctgac ttctttgctc cacggagagg agtgttttcc tgtgcttgcc 240 ctgaaatgga acttccttga cagctctccc gtgttacagt acctcccggt cattttcttt 300 ttctctctct ctacctgcgc tcttcgagtg tcagaaacct ttaaagctgt tactatggaa 360 ttgcaaaaaa gagatcaagt gactctttca ctatgctggt ttcccttgtg acccagatga 420 agaatcaatt cagaattcag ttcctccctt ggcattgcaa gacacagaag aaactgtcac 480 ttcctaacag cctagtactg gagtaaattc agtatgaagg aagaaagcgc tcctgcgtgt 540 tagaaccttg cccatgagct ggaccgagga caggagatgg actccaggaa aattggattt 600 cttcaagcag cctcccttgg aaatggaata tctttaaaat cttctttgca gaaagacagt 660 tagaatgtat taatcagaat agttgaagac ttattttcct ttttattttt tttcaaaatg 720 agcattatta tgaagccaag atcccgatct acaagttccc taaggactgc agaggcagtt 780 tgttttgatg tggacaatg cacatctgcg ggacggagtc ccttggatcc catgaccagc 840 ccaggatccg ggctaattct ccaagcaaat tttgtccaca gtcaacgacg ggagtccttc 900 ctgtatcgat ccgacagcga ttatgacctc tctccaaagt ctatgtcccg gaactcctcc 960 attgccagtg atatacacgg agatgacttg attgtgactc catttgctca ggtcttggcc 1020 agtctgcgaa ctgtacgaaa caactttgct gcattaacta atttgcaaga tcgagcacct 1080 agcaaaagat cacccatgtg caaccaacca tccatcaaca aagccaccat aacagaggag 1140 gcctaccaga aactggccag cgagaccctg gaggagctgg actggtgtct ggaccagcta 1200 gagaccctac agaccaggca ctccgtcagt gagatggcct ccaacaagtt taaaaggatg 1260 cttaatcggg agctcaccca tctctctgaa atgagtcggt ctggaaatca agtgtcagag 1320 tttatatcaa acacattctt agataagcaa catgaagtgg aaattccttc tccaactcag 1380 aaggaaaagg agaaaaagaa aagaccaatg tctcagatca gtggagtcaa gaaattgatg 1440 cacagctcta gtctgactaa ttcaagtatc ccaaggtttg gagttaaaac tgaacaagaa 1500 gatgtccttg ccaaggaact agaagatgtg aacaaatggg gtcttcatgt tttcagaata 1560 gcagagttgt ctggtaaccg gcccttgact gttatcatgc acaccatttt tcaggaacgg 1620 gatttattaa aaacatttaa aattccagta gatactttaa ttacatatct tatgactctc 1680 gaagaccatt accatgctga tgtggcctat cacaacaata tccatgctgc agatgttgtc 1740 cagtctactc atgtgctatt atctacacct gctttggagg ctgtgtttac agatttggag attcttgcag caatttttgc cagtgcaata catgatgtag atcatcctgg tgtgtccaat caatttctga tcaatacaaa ctctgaactt gccttgatgt acaatgattc ctcagtctta gagaaccatc atttggctgt gggctttaa ttgcttcagg aagaaaactg tgacattttc cagaatttga ccaaaaaaca aagacaatct ttaaggaaaa tggtcattga catcgtactt gcaacagata tgtcaaaaca catgaatcta ctggctgatt tgaagactat ggttgaaact aagaaagtga caagctctgg agttcttctt cttgataatt attccgatag gattcaggtt cttcagaata tggtgcactg tgcagatctg agcaacccaa caaagcctct ccagctgtac cgccagtgga cggaccggat aatggaggag ttcttccgcc aaggagaccg 2280 cgtggcatgg agtaagccc catgtgtgac aagcacaatg cttccgtgga aaaatcacag gtgggcttca tagactatat tgttcatccc ctctggggaga catgggcaga cctcgtccac cctgacgccc aggatatttt ggacactttg gaggacaatc gtgaatggta ccagagcaca atccctcaga gcccctctcc tgcacctgat gacccagagg agggccggca gggtcaaact 2520 gagaaattcc agtttgaact aactttagag gaagatggtg agtcagacac ggaaaggac 2580 agtggcagtc aagtggaaga agacactagc tgcagtgact ccaagactct ttgtactcaa 2640 gactcagagt ctactgaaat tccccttgat gaacaggttg aagaggaggc agtaggggaa 2700 gaagaaa gccagcctga agcctgtgtc atagatgatc gttctcctga cacgtaacag 2760 tgcaaaaact ttcatgcctt tttttttttt aagtagaaaa attgtttcca aagtgcatgt 2820 cacatgccac aaccacggtc acacctcact gtcatctgcc aggacgtttg ttgaacaaaa 2880 ctgaccttga ctactcagtc cagcgctcag gaatatcgta accagttttt tcacctccat 2940 gtcatccgag caaggtggac atcttcacaga acagcgtttt taacaagatt tcagcttggt 3000 agagctgaca aagcagataa aatctactcc aaattatttt caagagagtg tgactcatca 3060 ggcagcccaa aagtttattg gacttggggt ttctattcct ttttatttgt ttgcaatatt 3120 ttcagaagaa aggcattgca cagagtgaac ttaatggacg aagcaacaaa tatgtcaaga 3180 acaggacata gcacgaatct gttaccagta ggaggat gagccacaga aattgcataa 3240 ttttctaatt tcaagcttc ctgatacatg actgaatagt gtggttcagt gagctgcact 3300 gacctctaca tttgtatga tatgtaaaac agattttg tagagcttac ttttatt 3360 aaatgtattg aggtattata tttaaaaaaa actatgttca gaacttcatc tgccactggt 3420 tattttttc taggagta cttgcaagtt ttcagtaca atctgtgcta cactggataa 3480 aaatctaatt tatgaatttt acttgcacct tagttcat agcaattac tgatttgtag 3540 tgattcattg ttgttttat ataccaatga cttccatatt ttaaaagaga aaaacaactt 3600 tatgttgcag gaaacccttt ttgtaagtct ttattatta ctttgcattt tgttcactc 3660 tttccagata agcagagttg ctctcacca gtgttttct tcatgtgcaa agtgactatt 3720 tgttctataa tacttttatg tgtgttatat caatgtgtc ttaagcttca tgcaactca 3780 gtcatcagtt cgtgttgtct gaagcaagtg ggagatatat aaatacccag tagctaaaat 3840 ggtcagtctt ttttagatt ttcctactt agtatctctct ataacgttt tgctgtgtca 3900 ctagatgttc atttcacaag tgcatgtctt tctaataatc cacacatttc atgctctaat 3960 aatccacaca tttcatgctc atttttattg tttttacagc cagttatagt aagaaaaagg 4020 tttttcccct tgtgctgctt tataatttag cgtgtgtctg aaccttatcc atgtttgcta 4080 gatgaggtct tgtcaaatat atcactacca ttgtcaccgg tgaaaagaaa caggtagtta 4140 agttagggtt aacattcatt tcaaccacga ggttgtatat catgactagc ttttactctt 4200 ggtttacaga gaaaagttaa acagccaact aggcagtttt taagaatatt aacaatatat 4260 taacaaacac caatacaact aatcctattt ggttttaatg atttcaccat gggattaaga 4320 actatatcag gaacatccct gagaaacggt tttaagtgta gcaactactc ttccttaatg 4380 gacagccaca taacgtgtag gaagtccttt atcacttatc ctcgatccat aagcatatct 4440 tgcagagggg aactacttct ttaaacacat ggagggaaag aagatgatgc cactggcacc 4500 agagggttag tactgtgatg catcctaaaa tatttattat attggtaaaa attctggtta 4560 aataaaaaat tagagatcac tcttggctga tttcagcacc aggaactgta ttacagtttt 4620 agagattaat tcctagtgtt tacctgatta tagcagttgg catcatgggg catttaattc 4680 tgactttatc cccacgtcag ccttataaa gtctcttta ccttcttat gagacttta 4740 aagcccaaat atcattttt cacattgata ttcagaatt gagatagata gaagccaag 4800 tgggtatctg acagtggaa atcaacgt ttagagaa ttacactct gaaagcatt 4860 tatatgtgga acttctcaag gagcctcctg gggactggaa agtaagtcat cagccaggca 4920 aatgactcat gctgaagaga gtccccattt cagtcccctg agatctagct gatgcttaga 4980 tcctttgaaa taaaattat gtctttataa ctctgatctt ttacataag cagaagagga 5040 atcaactagt taattgcaag gtttctactc tgtttcctct gtaagatca gatggtaatc 5100 tttcaataa gaaaaaaata aagacgtatg tttgaccaag tagtttcaca agaatattg 5160 ggaacttgtt tcttttaatt ttattgtcc ctgagtgaag tctagaaga aaggtaaga 5220 gtctagagtt tattcctct tccaaacat tctcattcct ctcctcccta cacttagtat 5280 ttcccccaca gagtgcctag atcttaata atgaataaaa taaaaagcag caatgtca 5340 ttaacaaatc cagacctgaa agggtaagg gtttataact gcactataa agagaggctc 5400 ttttttttc ttccagttg ttggtttta atggtaccgt gttgtaaaga tacccactaa 5460 tggacaatca aattgcagaa aaggctcaat atccagaga cagggactaa tgcactgtac 5520 aatctgctta tccttgccct tctctctgc caagtgtgc ttcagaata tatactgctt 5580 taaaaaagaa taaaagaata tccttttaca agtggcttta cattcctaa atgccataa 5640 gaaaatgcaa tatctgggta ctgtatgggg aaaaaatgt ccaagtttgt gtaaaaccag 5700 tgcatttcag cttgcaagtt actgaacaca ataatgctgt ttatatttg ttatatca 5760 gttaaaatttc acaataatgt agatagaca attackacagac aaggaaa aaacttgaa 5820 tgaaatggat tttacagaa gctttatgat aattttgaa tgcattattt attttgtg 5880 ccatgcatttt tttctcac caaatgacct tacctgtaat acagcttgt tgtctgttt 5940 acaaccatgt atttattgca atgtacatac tgtaatgtta attgtaaatt atctgttctt 6000 attaaaacat catcccatga tgggatggtg ttgatatatt tggaactct tggtgagaga 6060 atgaatggtg tgtatacata ctctgtacat tttctttc tcctgtaata tagtcttgtc 6120 accttagagc ttgtttatgg aagattcaag aaactataa atacttaa gatatataa 6180 tttaaaaaaa catagctgca gtctttggt cccaggggctg tgccttaact ttaccata 6240 ttttctctg tttgctgca ttgaaggt aacagtggag ctagggctgg gcattttaca 6300 tccaggcttt taattgatta gattctgcc ataggtgga ttttacaaaa ccacagacaa 6360 cctctgaaag attctgagac ccttttgaga cagaagctct taagtacttc ttgccaggga 6420 gcagcactgc atgtgtgatg gttgtttgcc atctgttgat caggaactac ttcagctact 6480 tgcatttgat tattccttt tttttttt tattactcgga aacacaactg gggaaatata 6540 ttctttccca gtgattataa acaatctttttttttttt aagtcctttt ggcttctaga 6600 gctcatagga aaatggactt gatttgaat tggagccaga gtttactcgt gttggttatc 6660 tattcatcag cttcctgaca tgttaagaga atacattaaa gagaaaatac tgttttttaa 6720 tcctaaaatt ttctctccac taagataac CAatgtcct tacatatatg taaacccatc 6780 tatttaaacg caaaggtggg ttgatgtcag tttacatagc agaaagcatt cactatcctc 6840 taagatttgt ttctgcaaaa ctttcattgc tttagaattt taaaatttca ccttgtacaa 6900 tggccagccc ctaaagcagg aaacatttat aatggattat atggaaacat cctcccagta 6960 cttgcccagc ccttgaatca tgtggcttt cagtgaaagg aaagattctt tttctaggaa 7020 aaatgagcct attttttt attttttt attttttgac acaaactgta gattttagca 7080 gccctggccc aaaggaattt gattactttt gttttaaaca gtacaaaggg gacactataa 7140 ttacaaaaac atccttaact gatttgagtt gtttttattt ctttggatat attttcagag 7200 tggtaaattg tgtgtgagaa ttacaaatga ttatctttt agtggtttct tagcctctct 7260 tacagcccac ggggatagta ctgtacatca ataccttcat atgaaatttt tatatgcaat 7320 gaaataaaaa gcatgggttg attctgccta tttatgactc aatcttttac aaataaaaga 7380 ttattcattt taaattatag ttcaatcagc atgtctctta ggatactgaa cgtggttgaa 7440 atgaaaggat agtgacatca taagttagta ctgatattca taaccaaata aagccaactt 7500 gagtaatttt gctacattaa aattaccaa attackattag atggcctata agattaagca 7560 tggtgttttc taagcaagct tgaagggg ccttccatac ttactttatt gatatttctg 7620 ggatattgaa attattcag atacttgaca attatttg gttacctact ccgcaaacta 7680 caaagtttta aggactcac ataagttaa tgagacacag tgttgcttt catggagctt 7740 acagtctgga ggggacaaag gcttaaacaa tactcatata attatatg tgatcagtac 7800 aatgaaggag ctcagtgggg taaatagca ggaacctgaa cttgatctgt tccggaggc 7860 cacagaaggc ttccttgagg ccttgagaaa gtgatttgca tctgagttct gaaggattgt 7920 aagaggtaac tagggaaaa gttgacagga agaggaaggg gatccagaca agaaacattt 7980 gcaaagtct tgaggcataa atgagcttga gatactgga gaactgagg aaagtgaga 8040 gagtaggcag ggcctggagc cgcagagcca ttgctaacca tcctgtgtga gatatccccc 8100 attctgtagc tttattctca taaccctgct caatttctt tataacactt ctcacagatt 8160 tatatacgtg ttgttttg tatatctgtct ctcccaccag accacagctc catgagagca 8220 aggtctttgc ttaccaatat atcactagca cttaaaacta tgcctggtac acagtaggtt 8280 cttaatatgt gttgaatata gccatcaaat tgatattgga tataattcaa tctgataaga 8340 tattttgaga tattaaagag tttttaactt gataccataa aaaaaaaaaa aaaaa 8395 <210> 30 <211> 679 <212> PRT <213> Homo sapiens <400> 30 Met Ser Ile Ile Met Lys Pro Arg Ser Arg Ser Thr Ser Ser Leu Arg 1 5 10 15 Thr Ala Glu Ala Val Cys Phe Asp Val Asp Asn Gly Thr Ser Ala Gly 20 25 30 Arg Ser Pro Leu Asp Pro Met Thr Ser Pro Gly Ser Gly Leu Ile Leu 35 40 45 Gln Ala Asn Phe Val His Ser Gln Arg Arg Glu Ser Phe Leu Tyr Arg 50 55 60 Ser Asp Ser Asp Tyr Asp Leu Ser Pro Lys Ser Met Ser Arg Asn Ser 65 70 75 80 Ser Ile Ala Ser Asp Ile His Gly Asp Asp Leu Ile Val Thr Pro Phe 85 90 95 Ala Gln Val Leu Ala Ser Leu Arg Thr Val Arg Asn Asn Phe Ala Ala 100 105 110 Leu Thr Asn Leu Gln Asp Arg Ala Pro Ser Lys Arg Ser Pro Met Cys 115 120 125 Asn Gln Pro Ser Ile Asn Lys Ala Thr Ile Thr Glu Glu Ala Tyr Gln 130 135 140 Lys Leu Ala Ser Glu Thr Leu Glu Glu Leu Asp Trp Cys Leu Asp Gln 145 150 155 160 Leu Glu Thr Leu Gln Thr Arg His Ser Val Ser Glu Met Ala Ser Asn 165 170 175 Lys Phe Lys Arg Met Leu Asn Arg Glu Leu Thr His Leu Ser Glu Met 180 185 190 Ser Arg Ser Gly Asn Gln Val Ser Glu Phe Ile Ser Asn Thr Phe Leu 195 200 205 Asp Lys Gln His Glu Val Glu Ile Pro Ser Pro Thr Gln Lys Glu Lys 210 215 220 Glu Lys Lys Lys Arg Pro Met Ser Gln Ile Ser Gly Val Lys Lys Leu 225 230 235 240 Met His Ser Ser Ser Leu Thr Asn Ser Ser Ile Pro Arg Phe Gly Val 245 250 255 Lys Thr Glu Gln Glu Asp Val Leu Ala Lys Glu Leu Glu Asp Val Asn 260 265 270 Lys Trp Gly Leu His Val Phe Arg Ile Ala Glu Leu Ser Gly Asn Arg 275 280 285 Pro Leu Thr Val Ile Met His Thr Ile Phe Gln Glu Arg Asp Leu Leu 290 295 300 Lys Thr Phe Lys Ile Pro Val Asp Thr Leu Ile Thr Tyr Leu Met Thr 305 310 315 320 Leo Glu Asp His Tyr His Ala Asp Val Ala Tyr His Asn Asn Ile His 325 330 335 Ala Ala Asp Val Val Gln Ser Thr His Val Leu Leu Ser Thr Pro Ala 340 345 350 Leu Glu Ala Val Phe Thr Asp Leu Glu Ile Leu Ala Ala Ile Phe Ala 355 360 365 Ser Ala Ile His Asp Val Asp His Pro Gly Val Ser Asn Gln Phe Leu 370 375 380 Ile Asn Thr Asn Ser Glu Leu Ala Leu Met Tyr Asn Asp Ser Ser Val 385 390 395 400 Leu Glu Asn His His Leu Ala Val Gly Phe Lys Leu Leu Gln Glu Glu 405 410 415 Asn Cys Asp Ile Phe Gln Asn Leu Thr Lys Lys Gln Arg Gln Ser Leu 420 425 430 Arg Lys Met Val Ile Asp Ile Val Leu Ala Thr Asp Met Ser Lys His 435 440 445 Met Asn Leu Leu Ala Asp Leu Lys Thr Met Val Glu Thr Lys Lys Val 450 455 460 Thr Ser Ser Gly Val Leu Leu Leu Asp Asn Tyr Ser Asp Arg Ile Gln 465 470 475 480 Val Leu Gln Asn Met Val His Cys Ala Asp Leu Ser Asn Pro Thr Lys 485 490 495 Pro Leu Gln Leu Tyr Arg Gln Trp Thr Asp Arg Ile Met Glu Glu Phe 500 505 510 Phe Arg Gln Gly Asp Arg Glu Arg Glu Arg Gly Met Glu Ile Ser Pro 515 520 525 Met Cys Asp Lys His Asn Ala Ser Val Glu Lys Ser Gln Val Gly Phe 530 535 540 Ile Asp Tyr Ile Val His Pro Leu Trp Glu Thr Trp Ala Asp Leu Val 545 550 555 560 His Pro Asp Ala Gln Asp Ile Leu Asp Thr Leu Glu Asp Asn Arg Glu 565 570 575 Trp Tyr Gln Ser Thr Ile Pro Gln Ser Pro Ser Pro Ala Pro Asp Asp 580 585 590 Pro Glu Glu Gly Arg Gln Gly Gln Thr Glu Lys Phe Gln Phe Glu Leu 595 600 605 Thr Leu Glu Glu Asp Gly Glu Ser Asp Thr Glu Lys Asp Ser Gly Ser 610 615 620 Gln Val Glu Glu Asp Thr Ser Cys Ser Asp Ser Lys Thr Leu Cys Thr 625 630 635 640 Gln Asp Ser Glu Ser Thr Glu Ile Pro Leu Asp Glu Gln Val Glu Glu [[ID=2o]]645 650 655 Glu Ala Val Gly Glu Glu Glu Glu Ser Gln Pro Glu Ala Cys Val Ile 660 665 670 Asp Asp Arg Ser Pro Asp Thr 675 <210> 31 <211> 26 <212> DNA <213> Artificial sequence <220> <223> PDE4D9 Forward primer <400> 31 atgagcatta ttatgaagcc aagatc 26 <210> 32 <211> 22 <212> DNA <213> Artificial sequence <220> It should be noted that in the original text, "645 650 655" was misspelled as "645 650 655" in the English translation. It should be "645 650 655". The corrected translation is as follows: 565 570 575 Trp Tyr Gln Ser Thr Ile Pro Gln Ser Pro Ser Pro Ala Pro Asp Asp 580 585 590 Pro Glu Glu Gly Arg Gln Gly Gln Thr Glu Lys Phe Gln Phe Glu Leu 595 600 605 Thr Leu Glu Glu Asp Gly Glu Ser Asp Thr Glu Lys Asp Ser Gly Ser 610 615 620 Gln Val Glu Glu Asp Thr Ser Cys Ser Asp Ser Lys Thr Leu Cys Thr 625 630 635 640 Gln Asp Ser Glu Ser Thr Glu Ile Pro Leu Asp Glu Gln Val Glu Glu 645 650 655 Glu Ala Val Gly Glu Glu Glu Glu Ser Gln Pro Glu Ala Cys Val Ile 660 665 670 Asp Asp Arg Ser Pro Asp Thr [[ID=Q7]] 675 <210> 31 <211> 26 <212> DNA <213> Artificial sequence <220> <223> PDE^D9 Forward primer <400> 31 atgagcatta ttatgaagcc aagatc 26 <210> 32 <211> 22 <00023x3> <212> DNA <00oo2384> <213> Artificial sequence <220> <223> Reverse primer of PDE4D9 <400> 32 gtgccattgt ccacatcaaa ac 22 <210> 33 <211> 27 <212> DNA <213> Artificial sequence <220> <223> PDE4D9 probe <400> 33 ctacaagttc cctaaggact gcagagg 27 <210> 34 <211> 1435 <212> DNA <213> Homo sapiens <400> 34 ggcggggcct gcttctcctc agcttcaggc ggctgcgacg agccctcagg cgaacctctc 60 ggctttcccg cgcggcgccg cctcttgctg cgcctccgcc tcctcctctg ctccgccacc 120 ggcttcctcc tcctgagcag tcagcccgcg cgccggccgg ctccgttatg gcgacccgca 180 gccctggcgt cgtgattagt gatgatgaac caggttatga ccttgattta ttttgcatac 240 ctaatcatta tgctgaggat ttggaaaggg tgtttattcc tcatggacta attatggaca 300 ggactgaacg tcttgctcga gatgtgatga aggagatggg aggccatcac attgtagccc 360 tctgtgtgct caaggggggc tataaattct ttgctgacct gctggattac atcaaagcac 420 tgaatagaaa tagtgataga tccattccta tgactgtaga tttatcaga ctgaagagct 480 attgtaatga ccagtcaaca gggacacataa aagtaattgg tggagatgat ctctcaactt 540 taactggaaa gaatgtcttg attgtggaag atataattga cactggcaaa acaatgcaga 600 ctttgctttc cttggtcagg foottaatc caaagatggt caaggtcgca agcttgctgg 660 tgaaaaggac cccacgaagt gttggatata agccagactt tgttggattt gaaattccag 720 acaagtttgt tgtaggatat gcccttgact ataatgaata cttcagggat ttgaatcatg 780 tttgtgtcat tagtgaaact ggaaaagcaa aatacaaagc ctaagatgag agttcaagtt 840 gagtttggaa acatctggag tcctattgac atcgccagta aaattatcaa tgttctagtt 900 ctgtggccat ctgcttagta gagctttttg catgtatctt ctaagaattt tatctgtttt 960 gtactttaga aatgtcagtt gctgcattcc taaactgttt atttgcacta tgagcctata 1020 gactatcagt tccctttggg cggattgttg tttaacttgt aaatgaaaaa attctcttaa 1080 accacagcac tattgagtga aacattgaac tcatatctgt aagaaataaa gagaagatat 1140 attagttttt taattggtat tttaattttt atatatgcag gaaagaatag aagtgattga 1200 atattgttaa ttataccacc gtgtgttaga aaagtaagaa gcagtcaatt ttcacatcaa 1260 agacagcatc taagaagttt tgttctgtcc tggaattatt ttagtagtgt ttcagtaatg 1320 ttgactgtat tttccaactt gttcaaatta ttaccagtga atctttgtca gcagttccct 1380 tttaaatgca aatcaataaa ttcccaaaaa tttaaaaaaa aaaaaaaaaa aaaaa 1435 <210> 35 <211> 218 <212> PRT <213> Homo sapiens <400> 35 Met Ala Thr Arg Ser Pro Gly Val Val Ile Ser Asp Asp Glu Pro Gly 1 5 10 15 Tyr Asp Leu Asp Leu Phe Cys Ile Pro Asn His Tyr Ala Glu Asp Leu 20 25 30 Glu Arg Val Phe Ile Pro His Gly Leu Ile Met Asp Arg Thr Glu Arg 35 40 45 Leu Ala Arg Asp Val Met Lys Glu Met Gly Gly His His Ile Val Ala 50 55 60 Leu Cys Val Leu Lys Gly Gly Tyr Lys Phe Phe Ala Asp Leu Leu Asp 65 70 75 80 Tyr Ile Lys Ala Leu Asn Arg Asn Ser Asp Arg Ser Ile Pro Met Thr 85 90 95 Val Asp Phe Ile Arg Leu Lys Ser Tyr Cys Asn Asp Gln Ser Thr Gly 100 105 110 Asp Ile Lys Val Ile Gly Gly Asp Asp Leu Ser Thr Leu Thr Gly Lys 115 120 125 Asn Val Leu Ile Val Glu Asp Ile Ile Asp Thr Gly Lys Thr Met Gln 130 135 140 Thr Leu Leu Ser Leu Val Arg Gln Tyr Asn Pro Lys Met Val Lys Val 145 150 155 160 Ala Ser Leu Leu Val Lys Arg Thr Pro Arg Ser Val Gly Tyr Lys Pro 165 170 175 Asp Phe Val Gly Phe Glu Ile Pro Asp Lys Phe Val Val Gly Tyr Ala 180 185 190 Leu Asp Tyr Asn Glu Tyr Phe Arg Asp Leu Asn His Val Cys Val Ile 195 200 205 Ser Glu Thr Gly Lys Ala Lys Tyr Lys Ala 210 215 <210> 36 <211> 24 <212> DNA <213> artificial sequence <220> <223> Forward primer of HPRT1 <400> 36 gaggatttgg aaagggtgtt tatt 24 <210> 37 <211> 21 <212> DNA <213> Artificial sequence <220> <223> Reverse primer of HPRT1 <400> 37 acagagggct acaatgtgat g 21 <210> 38 <211> 26 <212> DNA <213> Artificial sequence <220> <223> HPRT1 probe <400> 38 acgtcttgct cgagatgtga tgaagg 26 <210> 39 <211> 1771 <212> DNA <213> Homo sapiens <400> 39 ggcggccagg ccgggcgcgg agtgggcgcg cggggccgga ggaggggcca gcgaccgcgg 60 caccgcctgt gcccgcccgc ccctccgcag ccgctactta agaggctcca gcgccggccc 120 cgccctagtg cgttacttac ctcgactctt agcttgtcgg ggacggtaac cgggacccgg 180 tgtctgctcc tgtcgccttc gcctcctaat ccctagccac tatgcgtgag tgcatctcca 240 tccacgttgg ccaggctggt gtccagattg gcaatgcctg ctgggagctc tactgcctgg 300 aacacggcat ccagcccgat ggccagatgc caagtgacaa gaccattggg ggaggagatg 360 actccttcaa caccttcttc agtgagacgg gcgctggcaa gcacgtgccc cgggctgtgt 420 ttgtagactt ggaacccaca gtcattgatg aagttcgcac tggcacctac cgccagctct 480 tccaccctga gcagctcatc acaggcaagg aagatgctgc caataactat gcccgagggc 540 actacaccat tggcaaggag atcattgacc ttgtgttgga ccgaattcgc aagctggctg 600 accagtgcac cggtcttcag ggcttcttgg ttttccacag ctttggtggg ggaactggtt 660 ctgggttcac ctccctgctc atggaacgtc tctcagttga ttatggcaag aagtccaagc 720 tggagttctc catttaccca gcaccccagg tttccacagc tgtagttgag ccctacaact 780 ccatcctcac cacccacacc accctggagc actctgattg tgccttcatg gtagacaatg 840 aggccatcta tgacatctgt cgtagaaacc tcgatatcga gcgcccaacc tacactaacc 900 ttaaccgcct tattagccag attgtgtcct ccatcactgc ttccctgaga tttgatggag 960 ccctgaatgt tgacctgaca gaattccaga ccaacctggt gccctacccc cgcatccact 1020 tccctctggc cacatatgcc cctgtcatct ctgctgagaa agcctaccat gaacagcttt 1080 ctgtagcaga gatcaccaat gcttgctttg agccagccaa ccagatggtg aaatgtgacc 1140 ctcgccatgg taaatacatg gcttgctgcc tgttgtaccg tggtgacgtg gttcccaaag 1200 atgtcaatgc tgccattgcc accatcaaaa ccaagcgcag catccagttt gtggattggt 1260 gccccactgg cttcaaggtt ggcatcaact accagcctcc cactgtggtg cctggtggag 1320 acctggccaa ggtacagaga gctgtgtgca tgctgagcaa caccacagcc attgctgagg 1380 cctgggctcg ctggaccac aagtttgacc tgatgtatgc caagcgtgcc tttgttcact 1440 ggtacgtggg tgaggggatg gaggaaggcg agttttcaga ggcccgtgaa gatatggctg 1500 cccttgagaa ggattatgag gaggttggtg tggattctgt tgaaggagag ggtgaggaag 1560 aaggagagga atactaatta tccattcctt ttggccctgc agcatgtcat gctcccagaa 1620 tttcagcttc agcttaactg acagacgtta aagctttctg gttagattgt tttcacttgg 1680 tgatcatgtc ttttccatgt gtacctgtaa tatttttcca tcatatctca aagtaaagtc 1740 attaacatca aaaaaaaaaa aaaaaaaaaa a 1771 <210> 40 <211> 451 <212> PRT <213> Homo sapiens <400> 40 Met Arg Glu Cys Ile Ser Ile His Val Gly Gln Ala Gly Val Gln Ile 1 5 10 15 Gly Asn Ala Cys Trp Glu Leu Tyr Cys Leu Glu His Gly Ile Gln Pro 20 25 30 Asp Gly Gln Met Pro Ser Asp Lys Thr Ile Gly Gly Gly Asp Asp Ser 35 40 45 Phe Asn Thr Phe Phe Ser Glu Thr Gly Ala Gly Lys His Val Pro Arg 50 55 60 Ala Val Phe Val Asp Leu Glu Pro Thr Val Ile Asp Glu Val Arg Thr 65 70 75 80 Gly Thr Tyr Arg Gln Leu Phe His Pro Glu Gln Leu Ile Thr Gly Lys 85 90 95 Glu Asp Ala Ala Asn Asn Tyr Ala Arg Gly His Tyr Thr Ile Gly Lys 100 105 110 Glu Ile Ile Asp Leu Val Leu Asp Arg Ile Arg Lys Leu Ala Asp Gln 115 120 125 Cys Thr Gly Leu Gln Gly Phe Leu Val Phe His Ser Phe Gly Gly Gly 130 135 140 Thr Gly Ser Gly Phe Thr Ser Leu Leu Met Glu Arg Leu Ser Val Asp 145 150 155 160 Tyr Gly Lys Lys Ser Lys Leu Glu Phe Ser Ile Tyr Pro Ala Pro Gln 165 170 175 Val Ser Thr Ala Val Val Glu Pro Tyr Asn Ser Ile Leu Thr Thr His 180 185 190 Thr Thr Leu Glu His Ser Asp Cys Ala Phe Met Val Asp Asn Glu Ala 195 200 205 Ile Tyr Asp Ile Cys Arg Arg Asn Leu Asp Ile Glu Arg Pro Thr Tyr 210 215 220 Thr Asn Leu Asn Arg Leu Ile Ser Gln Ile Val Ser Ser Ile Thr Ala 225 230 235 240 Ser Leu Arg Phe Asp Gly Ala Leu Asn Val Asp Leu Thr Glu Phe Gln 245 250 255 Thr Asn Leu Val Pro Tyr Pro Arg Ile His Phe Pro Leu Ala Thr Tyr 260 265 270 Ala Pro Val Ile Ser Ala Glu Lys Ala Tyr His Glu Gln Leu Ser Val 275 280 285 Ala Glu Ile Thr Asn Ala Cys Phe Glu Pro Ala Asn Gln Met Val Lys 290 295 300 Cys Asp Pro Arg His Gly Lys Tyr Met Ala Cys Cys Leu Leu Tyr Arg 305 310 315 320 Gly Asp Val Val Pro Lys Asp Val Asn Ala Ala Ile Ala Thr Ile Lys 325 330 335 Thr Lys Arg Ser Ile Gln Phe Val Asp Trp Cys Pro Thr Gly Phe Lys 340 345 350 Val Gly Ile Asn Tyr Gln Pro Pro Thr Val Val Pro Gly Gly Asp Leu 355 360 365 Ala Lys Val Gln Arg Ala Val Cys Met Leu Ser Asn Thr Thr Ala Ile 370 375 380 Ala Glu Ala Trp Ala Arg Leu Asp His Lys Phe Asp Leu Met Tyr Ala 385 390 395 400 Lys Arg Ala Phe Val His Trp Tyr Val Gly Glu Gly Met Glu Glu Gly 405 410 415 Glu Phe Ser Glu Ala Arg Glu Asp Met Ala Ala Leu Glu Lys Asp Tyr 420 425 430 Glu Glu Val Gly Val Asp Ser Val Glu Gly Glu Gly Glu Glu Glu Gly 435 440 445 Glu Glu Tyr 450 <210> 41 <211> twenty two <212> DNA <213> Artificial sequence <220> <223> TUBA1B_Forward Primer <400> 41 tgactccttc aacaccttct tc 22 <210> 42 <211> 18 <212> DNA <213> Artificial sequence <220> <223> TUBA1B_reverse primer <400> 42 tgccagtgcg aacttcat 18 <210> 43 <211> twenty four <212> DNA <213> Artificial sequence <220> <223> TUBA1B probe <400> 43 ccgggctgtg tttgtagact tgga 24 <210> 44 <211> 5416 <212> DNA <213> Homo sapiens <400> 44 agtgggccgc catgttgtcg gagtgaaagg taagggggag cgagagcgcc agagagagaa 60 gatcgggggg ctgaaatcca tcttcatcct accgctccgc ccgtgttggt ggaatgagcg 120 ttgcatgtgt cttgaagaga aaagcagtgc tttggcagga ctctttcagc ccccacctga 180 aacatcaccc tcaagaacca gctaatccca acatgcctgt tgttttgaca tctggaacag 240 ggtcgcaagc gcagccacaa ccagctgcaa atcaggctct tgcagctggg actcactcca 300 gccctgtccc aggatctata ggagttgcag gccgttccca ggacgacgct atggtggact 360 acttctttca gaggcagcat ggtgagcagc ttgggggagg aggaagtgga ggaggcggct 420 ataataatag caaacatcga tggcctactg gggataacat tcatgcagaa catcaggtgc 480 gttccatgga tgaactgaat catgattttc aagcacttgc tctggaggga agagcgatgg 540 gagagcagct cttgccaggt aaaaagtttt gggaaacaga tgaatccagc aaagatggac 600 caaaaggaat attcctgggt gatcaatggc gagacagtgc ctggggaaca tcagatcatt 660 cagtttccca gccaatcatg gtgcagagaa gacctggtca gagtttccat gtgaacagtg 720 aggtcaattc tgtactgtcc ccacgatcgg agagtggggg actaggcgtt agcatggtgg 780 agtatgtgtt gagctcatcc ccgggcgatt cctgtctaag aaaaggagga tttggcccaa 840 gggatgcaga cagtgatgaa aacgacaaag gtgaaaagaa gaacaagggt acgtttgatg 900 gagataagct aggagatttg aaggaggagg gtgatgtgat ggacaagacc aatggtttac cagtgcagaa tgggattgat gcagacgtca aagattttag ccgtacccct ggtaattgcc agaactctgc taatgaagtg gatcttctgg gtccaaacca gatggttct gagggcttag cccagctgac cagcaccaat ggtgccaagc ctgtggagga tttctccaac atggagtccc aggtgtccc cttggacccc atggaacatg tgggcatgga gcctcttcag tttgattatt caggcacgca ggtacctgtg caggcagcag cagcaactgt gggacttttt cactacaatt 1320. ctcaacaaca gctgttccaa agacctaatg cgcttgctgt ccagcagttg acagctgctc agcagcagca gtatgcactg gcagctgctc atcagccgca catcggttta gctcccgctg cgtttgtccc caatccatac atcatcagcg ctgctcccc agggacggac ccctacacag ctggattggc tgcagcagcg acactaggcc cagctgtggt ccctcaccag tattatggag ttactccctg gggagtctac cctgccagtc ttttccagca gcaagctgcc gctgccgctg cagcaacta ttcagctaat cacagacca ccccacaggc tcagcaagga cagcagcagg ttctccgtgg aggagccagc caacgtcctt tgaccccaaa ccagaaccag cagggacagc 1680 aaacggatcc ccttgtggca gctgcagcag tgaattctgc ccttgcattt ggacaaggtc 1740 tggcagcagg catgccaggt tatccggtgt tggctcctgc tgcttactat gaccaaactg 1800 gtgcccttgt agtgaatgca ggcgcgagaa atggtcttgg agctcctgtt cgacttgtag 1860 ctcctgcccc agtcatcatt agttcctcag ctgcacaagc agctgttgca gcagccgcag 1920 cttcagcaaa tggagcagct ggtggtcttg ctggaacaac aaatggacca tttcgccctt 1980 taggaacaca gcagcctcag ccccagcccc agcagcagcc caataacaac ctggcatcca 2040 gttctttcta cggcaacaac tctctgaaca gcaattcaca gagcagctcc ctcttctccc 2100 agggctctgc ccagcctgcc aacacatcct tgggattcgg aagtagcagt tctctcggcg 2160 ccaccctggg atccgccctt ggagggtttg gaacagcagt tgcaaactcc aacactggca 2220 gtggctcccg ccgtgactcc ctgactggca gcagtgacct ttataagagg acatcgagca 2280 gcttgacccc cattggacac agtttttata acggccttag cttttcctcc tctcctggac 2340 ccgtgggcat gcctctccct agtcagggac caggacattc acagacacca cctccttccc 2400 tctcttcaca tggatcctct tcaagcttaa acctgggagg actcacgaat ggcagtggaa 2460 gatacatctc tgctgctcca ggcgctgaag ccaagtaccg cagtgcaagc agcgcctcca 2520 gcctcttcag cccgagcagc actcttttct cttcctctcg tttgcgatat ggaatgtctg 2580 atgtcatgcc ttctggcagg agcaggcttt tggaagattt tcgaaacaac cggtacccca 2640 atttacaact gcgggagatt gctggacata taatggaatt ttcccaagac cagcatgggt 2700 ccagattcat tcagctgaaa ctggagcgtg ccacaccagc tgagcgccag cttgtcttca 2760 atgaaatcct ccaggctgcc taccaactca tggtggatgt gtttggtaat tacgtcattc 2820 agaagttctt tgaatttggc agtcttgaac agaagctggc tttggcagaa cggattcgag 2880 gccacgtcct gtcattggca ctacagatgt atggctgccg tgttatccag aaagctcttg 2940 agtttattcc ttcagaccag caggtaatta atgagatggt tcgggaacta gatggccatg 3000 tcttgaagtg tgtgaaagat cagaatggca atcacgtggt tcagaaatgc attgaatgtg 3060 3120. tacagcccca gtctttgcaa tttatcatcg atgcgtttaa gggacaggta tttgccttat ccacacatcc ttatggctgc cgagtgattc agagaatcct ggagcactgt ctccctgacc 3180. agcactccc tattttagag gagcttcacc agcacacaga gcagcttgta caggatcaat atggaaatta tgtaatccaa catgtactgg agcacggtcg tcctgaggat aaaagcaaaa ttgtagcaga aatccgaggc aatgtacttg tattgagtca gcacaaattt gcaagcaatg ttgtggagaa gtgtgttact cacgcctcac gtacggagcg cgctgtgctc atcgatgagg 3420 tgtgcaccat gaacgacggt ccccacagtg ccttatacac catgatgaag gaccagtatg ccaactacgt ggtccagaag atgattgacg tggcggagcc aggccagcgg aagatcgtca 3540. tgcataagat ccggccccac atcgcaactc ttcgtaagta cacctatggc aagcacattc tggccaagct ggagaagtac tacatgaaga acggtgttga cttagggccc atctgtggcc cccctaatgg tatcatctga ggcagtgtca cccgctgttc cctcattccc gctgacctca 3720 ctggcccact ggcaaatcca accagcaacc agaaatgttc tagtagtag tctgagacgg 3780. gcaagtggtt gctccaggat tactccctcc tccaaaaag gatcaatc cacgagtgga 3840 aaagcctttg taatttaat ttttacac atacatgta ctatttttt taattgacta 3900 attgccctgc tgttttactg gtgtatagga tacttgtaca taggtacca atgtacatgg 3960 gaggccacat atttgttca ctgttgtatc tatatttcac atgtggaaac ttcaggggtg 4020 gttggtttaa aaaaaaaaaaaaaaaaagctttttag 4080 ctcatttgcc tggccggca gtttgcaa tagcttcc ccacctcctc atttagtaa 4140 aaaaaaaaaaaaaaaaaacctgagaa gtttgaattg tagttaatg acccaaact 4200 ggcatttaac actgtttata aaaaatatat attatatatta attatatatta atgaaaag 4260 gtttcagagt tgctaaagct tcagttgtg acataagtt tatgaaattc taaaaaatgc 4320 cttttttgga gactatatta tgctgagaa ggctgttcgt gaggagga tgcgagcacc 4380 cagaacgtct ttgaggctg ggcggtgtg attgtttact gcctactgga tttttcta 4440 ttaacattga aaggtaaat ctgattattt agcatgagaa aaaaaatcc aactctgctt 4500 ttggtcttgc ttctaaat fathers tacttggtgt agactttgca fathers tttgtagtat tttcttgttt tgatgtctaa tctgtatcta taatgtaccc tagtagtcga acatactttt gattgtacaa ttgtacattt gtatacctgt aatgtaaatg tggagaagtt tgaatcaaca taacacgtt ttttggtaag aaaagagaat tagccagccc tgtgcattca gtgtatattc tcacctttta tggtcgtagc atatagtgtt gtatattgta aattgtaatt tcaaccagaa gtaaattttt ttcttttgaa ggaataaatg ttctttatac agcctagtta atgtttaaaa agaaaaaaat agcttggttt tatttgtcat ctagtctcaa gtatagcgag attctttcta aatgttattc aagattgagt tctcactagt gtttttttaa tcctaaaaaa gtaatgtttt gattttgtga cagtcaaaag gacgtgcaaa agtctagcct tgcccgagct ttccttacaa tcagagcccc tctcaccttg taaagtgtga atcgcccttc ccttttgtac family ctgtattttg cattttgtct acttgtaagt cattgtaaca cattgtcaat tttccttgtt tgaataga attgtaacac tacacggtgt acatttccag agccttgtgt atatttccaa tgaacttttt tgcaagcaca cttgtaacca tatgtgtata attaacaaac 5280 ctgtgtatgc ttatgcctgg gcaactattt tttgtaactc ttgtgtagat tgtctctaaa 5340 caatgtgtga tctttatttt gaaaaataca gaactttgga atctgaaaaa aaaaaaaaaa 5400 aaaaaaaaaa aaaaaa 5416 <210> 45 <211> 5410 <212> DNA <213> Homo sapiens <400> 45 agtgggccgc catgttgtcg gagtgaaagg taagggggag cgagagcgcc agagagagaa 60 gatcgggggg ctgaaatcca tcttcatcct accgctccgc ccgtgttggt ggaatgagcg 120 ttgcatgtgt cttgaagaga aaagcagtgc tttggcagga ctctttcagc ccccacctga 180 aacatcaccc tcaagaacca gctaatccca acatgcctgt tgttttgaca tctggaacag 240 ggtcgcaagc gcagccacaa ccagctgcaa atcaggctct tgcagctggg actcactcca 300 gccctgtccc aggatctata ggagttgcag gccgttccca ggacgacgct atggtggact 360 acttctttca gaggcagcat ggtgagcagc ttgggggagg aggaagtgga ggaggcggct 420 ataatatag siaacatcga tggcctactg gggaataacat tcatgcagaa catcaggtgc 480 gttccatgga tgactgaat catgatttc aagcacttgc tctggaggga agagcgatgg 540 gagagcagct cttgccaggt aaaagtttt gggaaacaga tgaatccagc aagatggac 600 caaaaggaat attcctgggt gatcaatggc gagacagtgc ctggggaaca tcagatcatt 660 cagtttccca gccaatcatg gtgcagagaa gacctggtca gagttttccat gtgaacagtg 720 aggtcaatc tgtactgtcc ccacgatcgg agagtgggg actaggcgtt agcatggtgg 780 agtatgtgtt gagctcatcc ccgggcgatt cctgtctaag aaaggagga tttggcccaa 840 gggatgcaga cagtgatgaa acgacaaag gtgaaaagaa gaacaagggt acgttttgatg 900 gagataagct aggatttg aaggaggagg gtgatgtgat ggacaagacc aatggtttac 960 cagtgcagaa tgggattgat gcagacgtca aagattttag ccgtacccct ggtaattgcc 1020 agaactctgc taatgaagtg gatctctctg gtccaacca gatggttct gaggggcttg 1080 cccagctgac cagcaccaat gtgccaagc ctgtggagga tttctccaac atggagtccc 1140 agagtgtccc cttggacccc atggaacatg tgggcatgga gcctcttcag tttgattatt 1200 caggcacgca ggtacctgtg gactcagcag cagcaactgt gggacttttt gactacaatt 1260 ctcaacaaca gctgttccaa agacctaatg cgcttgctgt ccagcagttg acagctgctc 1320 agcagcagca gtatgcactg gcagctgctc atcagccgca catcggttta gctcccgctg 1380 cgtttgtccc caatccatac atcatcagcg ctgctccccc agggacggac ccctacacag 1440 ctggattggc tgcagcagcg acactaggcc cagctgtggt ccctcaccag tattatggag 1500 ttactccctg gggagtctac cctgccagtc ttttccagca gcaagctgcc gctgccgctg 1560 cagcaactaa ttcagctaat caacagacca ccccacaggc tcagcaagga cagcagcagg 1620 ttctccgtgg aggagccagc caacgtcctt tgaccccaaa ccagaaccag cagggacagc 1680 aaacggatcc ccttgtggca gctgcagcag tgaattctgc ccttgcattt ggacaaggtc 1740 tggcagcagg catgccaggt tatccggtgt tggctcctgc tgcttactat gaccaaactg 1800 gtgcccttgt agtgaatgca ggcgcgagaa atggtcttgg agctcctgtt cgacttgtag 1860 ctcctgcccc agtcatcatt agttcctcag ctgcacaagc agctgttgca gcagccgcag 1920 cttcagcaaa tggagcagct ggtggtcttg ctggaacaac aaatggacca tttcgccctt 1980 taggaacaca gcagcctcag ccccagcccc agcagcagcc caataacaac ctggcatcca 2040 gttctttcta cggcaacaac tctctgaaca gcaattcaca gagcagctcc ctcttctccc 2100 agggctctgc ccagcctgcc aacacatcct tgggattcgg aagtagcagt tctctcggcg 2160 ccaccctggg atccgccctt ggagggtttg gaacagcagt tgcaaactcc aacactggca 2220 gtggctcccg ccgtgactcc ctgactggca gcagtgacct ttataagagg acatcgagca 2280 gcttgacccc cattggacac agtttttata acggccttag cttttcctcc tctcctggac 2340 ccgtgggcat gcctctccct agtcagggac caggacattc acagacacca cctccttccc 2400 tctcttcaca tggatcctct tcaagcttaa acctgggagg actcacgaat ggcagtggaa 2460 gatacatctc tgctgctcca ggcgctgaag ccaagtaccg cagtgcaagc agcgcctcca 2520 gcctcttcag cccgagcagc actcttttct cttcctctcg tttgcgatat ggaatgtctg 2580 atgtcatgcc ttctggcagg agcaggcttt tggaagattt tcgaaacaac cggtacccca 2640 atttacaact gcgggagatt gctggacata taatggaatt ttcccaagac cagcatgggt 2700 ccagattcat tcagctgaaa ctggagcgtg ccacaccagc tgagcgccag cttgtcttca 2760 atgaaatcct ccaggctgcc taccaactca tggtggatgt gtttggtaat tacgtcattc 2820 agaagttctt tgaatttggc agtcttgaac agaagctggc tttggcagaa cggattcgag 2880 gccacgtcct gtcattggca ctacagatgt atggctgccg tgttatccag aaagctcttg 2940 agtttattcc ttcagaccag cagaatgaga tggttcggga actagatggc catgtcttga 3000 agtgtgtgaa agatcagaat ggcaatcacg tggttcagaa atgcattgaa tgtgtacagc 3060 cccagtcttt gcaatttatc atcgatgcgt ttaagggaca ggtatttgcc ttatccacac 3120 atccttatgg ctgccgagtg attcagagaa tcctggagca ctgtctccct gaccagacac 3180 tccctatttt agaggagctt caccagcaca cagagcagct tgtacaggat caatatggaa 3240 attatgtaat ccaacatgta ctggagcacg gtcgtcctga ggataaaagc aaaattgtag 3300 cagaaatccg aggcaatgta cttgtattga gtcagcacaa atttgcaagc aatgttgtgg agaagtgtgt tactcacgcc tcacgtacgg agcgcgctgt gctcatcgat gaggtgtgca 3420. 3480. cggtccccac agtgccttat acaccatgat gaaggaccag tatgccaact acgtggtcca gagatgatt gacgtggcgg agccaggcca gcggagatc gtcatgcata 3540 agatccggcc ccacatcgca actcttcgta actctcact tggcaagcac attctggcca 3600. agctggagaa gtactacatg aagaacggtg ttgacttagg gcccatctgt ggccccccta atggtatcat ctgaggcagt gtcacccgct gttccctcat tcccgctgac ctcactggcc 3720. cactggcaaa tccaaccagc aaccagaat gttctagtgt aggtctgag acgggcaagt ggttgctcca ggattactcc ctcctccaaa aaaggaatca aatccacgag tggaaaagcc tttgtaatt tattttatt acacataaca tgtactattt tttttaattg actaattgcc ctgctgtttt actggtgtat aggatacttg tacataggta accaatgtac atgggaggcc acatattttg ttcactgttg tatctatatt tcacatgtgg aaactttcag ggtggttggt ttaaaaaaaaaaaagctt taaaaaaaaaaaaaaag gaaaggtttt ttagctcatt 4080 tgcctgccg gcaagttttg caatagctc ttcccacct cctcatttta gtaaaaaaca 4140 aaaaaaaaaaaaacctg agaagtttga attgtagtta atgacccca aactggcatt 4200 taacactgtt taaaaaaat attattattattattattattattaatga aaggttttca 4260 gagttgctaa agcttcagtt tgtgacatta agtttagaa attctaaaaa atgccttttt 4320 tggagactat attatgctga agaagctgt tcgtgaggag gagatgcgag cacccagaac 4380 gtcttttgag gctgggcggg tgtgattgtt tactgcctac tggatttt tctattaaca 4440 ttgaaaggta aaatctgatt atttagcatg agaaaaaaaa atccactct gctttggtc 4500 ttgcttctat aaatatatag tgtatacttg gtgtagactt tgcatatata caaatttgta 4560 gtattttct gttttgatgt ctaatctgta tctataatgt accctagtag tcgaacatac 4620 ttttgattgt acaattgtac atttgtatac ctgtaatgta aatgtggaga agttttgaatc 4680 aacataaaca cgttttttgg taagaaaga gattagcca gccctgtgca ttcagtgtat 4740 attctcacct tttatggtcg tagcatatag tgttgtatat tgtaaattgt aatttcaacc 4800 agaagtaaat ttttttcttt tgaaggaata aatgttcttt atacagccta gttaatgttt 4860 aaaaagaaaa aatagcttg gttttattg tcatctagtc tcaagtatag cgagattctt 4920 tctaaatgtt attcaagatt gagttctcac tagtgttttt ttaatcctaa aaaagtaatg 4980 ttttgattt gtgacagtca aaaggacgtg caaaagtcta gccttgcccg agctttcctt 5040 acaatcagag cccctctcac cttgtaaagt gtgaatcgcc cttcccttt gtacagaaga 5100 tgaactgtat tttgcatttt gtctacttgt aagtgaatgt aacatactgt caattttcct 5160 tgtttgaata tagaattgta acactacacg gtgtacattt ccagagcctt gtgtatattt 5220 ccaatgaact ttttgcaag cacacttgta accatatgtg tataattaac aaacctgtgt 5280 atgcttatgc ctgggcaact atttttgta actcttgtgt agattgtctc taaacaatgt 5340 gtgatcttta ttttgaaaaa tacagaactt tggaatctga aaaaaaaaa aaaaaaaaa 5400 aaaaaaaaaa 5410 <210> 46 <211> 1188 <212> PRT <213> Homo sapiens <400> 46 Met Ser Val Ala Cys Val Leu Lys Arg Lys Ala Val Leu Trp Gln Asp 1 5 10 15 Ser Phe Ser Pro His Leu Lys His His Pro Gln Glu Pro Ala Asn Pro 20 25 30 Asn Met Pro Val Val Leu Thr Ser Gly Thr Gly Ser Gln Ala Gln Pro 35 40 45 Gln Pro Ala Ala Asn Gln Ala Leu Ala Ala Gly Thr His Ser Ser Pro 50 55 60 Val Pro Gly Ser Ile Gly Val Ala Gly Arg Ser Gln Asp Asp Ala Met 65 70 75 80 Val Asp Tyr Phe Phe Gln Arg Gln His Gly Glu Gln Leu Gly Gly Gly 85 90 95 Gly Ser Gly Gly Gly Gly Tyr Asn Asn Ser Lys His Arg Trp Pro Thr 100 105 110 Gly Asp Asn Ile His Ala Glu His Gln Val Arg Ser Met Asp Glu Leu 115 120 125 Asn His Asp Phe Gln Ala Leu Ala Leu Glu Gly Arg Ala Met Gly Glu 130 135 140 Gln Leu Leu Pro Gly Lys Lys Phe Trp Glu Thr Asp Glu Ser Ser Lys 145 150 155 160 Asp Gly Pro Lys Gly Ile Phe Leu Gly Asp Gln Trp Arg Asp Ser Ala 165 170 175 Trp Gly Thr Ser Asp His Ser Val Ser Gln Pro Ile Met Val Gln Arg 180 185 190 Arg Pro Gly Gln Ser Phe His Val Asn Ser Glu Val Asn Ser Val Leu 195 200 205 Ser Pro Arg Ser Glu Ser Gly Gly Leu Gly Val Ser Met Val Glu Tyr 210 215 220 Val Leu Ser Ser Ser Pro Gly Asp Ser Cys Leu Arg Lys Gly Gly Phe 225 230 235 240 Gly Pro Arg Asp Ala Asp Ser Asp Glu Asn Asp Lys Gly Glu Lys Lys 245 250 255 Asn Lys Gly Thr Phe Asp Gly Asp Lys Leu Gly Asp Leu Lys Glu Glu 260 265 270 Gly Asp Val Met Asp Lys Thr Asn Gly Leu Pro Val Gln Asn Gly Ile 275 280 285 Asp Ala Asp Val Lys Asp Phe Ser Arg Thr Pro Gly Asn Cys Gln Asn 290 295 300 Ser Ala Asn Glu Val Asp Leu Leu Gly Pro Asn Gln Asn Gly Ser Glu 305 310 315 320 Gly Leu Ala Gln Leu Thr Ser Thr Asn Gly Ala Lys Pro Val Glu Asp 325 330 335 Phe Ser Asn Met Glu Ser Gln Ser Val Pro Leu Asp Pro Met Glu His 340 345 350 Val Gly Met Glu Pro Leu Gln Phe Asp Tyr Ser Gly Thr Gln Val Pro 355 360 365 Val Asp Ser Ala Ala Ala Thr Val Gly Leu Phe Asp Tyr Asn Ser Gln 370 375 380 Gln Gln Leu Phe Gln Arg Pro Asn Ala Leu Ala Val Gln Gln Leu Thr 385 390 395 400 Ala Ala Gln Gln Gln Gln Tyr Ala Leu Ala Ala Ala His Gln Pro His 405 410 415 Ile Gly Leu Ala Pro Ala Ala Phe Val Pro Asn Pro Tyr Ile Ile Ser 420 425 430 Ala Ala Pro Pro Gly Thr Asp Pro Tyr Thr Ala Gly Leu Ala Ala Ala 435 440 445 Ala Thr Leu Gly Pro Ala Val Val Pro His Gln Tyr Tyr Gly Val Thr 450 455 460 Pro Trp Gly Val Tyr Pro Ala Ser Leu Phe Gln Gln Gln Ala Ala Ala 465 470 475 480 Ala Ala Ala Ala Thr Asn Ser Ala Asn Gln Gln Thr Thr Pro Gln Ala 485 490 495 Gln Gln Gly Gln Gln Gln Val Leu Arg Gly Gly Ala Ser Gln Arg Pro 500 505 510 Leu Thr Pro Asn Gln Asn Gln Gln Gly Gln Gln Thr Asp Pro Leu Val 515 520 525 Ala Ala Ala Ala Val Asn Ser Ala Leu Ala Phe Gly Gln Gly Leu Ala 530 535 540 Path Gly Met Pro Gly Tyr Pro Val Leu Path Pro Path Path Tyr Tyr Asp 545 550 555 560 Gln Thr Gly Ala Leu Val Val Asn Ala Gly Ala Arg Asn Gly Leu Gly 565 570 575 Path Pro Val Arg Leu Val Path Pro Path Pro Val Ile Ile Ser Ser Ser 580 585 590 Ala Ala Gln Ala Ala Val Ala Ala Ala Ala Ser Ala Asn Gly Ala 595 600 605 Ala Gly Gly Leu Ala Gly Thr Thr Asn Gly Pro Phe Arg Pro Leu Gly 610 615 620 Thr Gln Gln Pro Gln Pro Gln Pro Gln Gln Gln Pro Asn Asn Asn Leu 625 630 635 640 Ala Ser Ser Ser Phe Tyr Gly Asn Asn Ser Leu Asn Ser Asn Ser Gln 645 650 655 Ser Ser Ser Leu Phe Ser Gln Gly Ser Ala Gln Pro Ala Asn Thr Ser 660 665 670 Leu Gly Phe Gly Ser Ser Ser Ser Leu Gly Ala Thr Leu Gly Ser Ala 675 680 685 Leu Gly Gly Phe Gly Thr Ala Val Ala Asn Ser Asn Thr Gly Ser Gly 690 695 700 Ser Arg Arg Asp Ser Leu Thr Gly Ser Ser Asp Leu Tyr Lys Arg Thr 705 710 715 720 Ser Ser Ser Leu Thr Pro Ile Gly His Ser Phe Tyr Asn Gly Leu Ser 725 730 735 Phe Ser Ser Ser Pro Gly Pro Val Gly Met Pro Leu Pro Ser Gln Gly 740 745 750 Pro Gly His Ser Gln Thr Pro Pro Pro Ser Leu Ser Ser His Gly Ser 755 760 765 Ser Ser Ser Leu Asn Leu Gly Gly Leu Thr Asn Gly Ser Gly Arg Tyr 770 775 780 Ile Ser Ala Ala Pro Gly Ala Glu Ala Lys Tyr Arg Ser Ala Ser Ser 785 790 795 800 Ala Ser Ser Leu Phe Ser Pro Ser Ser Thr Leu Phe Ser Ser Ser Arg 805 810 815 Leu Arg Tyr Gly Met Ser Asp Val Met Pro Ser Gly Arg Ser Arg Leu 820 825 830 Leu Glu Asp Phe Arg Asn Asn Arg Tyr Pro Asn Leu Gln Leu Arg Glu 835 840 845 Ile Ala Gly His Ile Met Glu Phe Ser Gln Asp Gln His Gly Ser Arg 850 855 860 Phe Ile Gln Leu Lys Leu Glu Arg Ala Thr Pro Ala Glu Arg Gln Leu 865 870 875 880 Val Phe Asn Glu Ile Leu Gln Ala Ala Tyr Gln Leu Met Val Asp Val 885 890 895 Phe Gly Asn Tyr Val Ile Gln Lys Phe Phe Glu Phe Gly Ser Leu Glu 900 905 910 Gln Lys Leu Ala Leu Ala Glu Arg Ile Arg Gly His Val Leu Ser Leu 915 920 925 Ala Leu Gln Met Tyr Gly Cys Arg Val Ile Gln Lys Ala Leu Glu Phe 930 935 940 Ile Pro Ser Asp Gln Gln Val Ile Asn Glu Met Val Arg Glu Leu Asp 945 950 955 960 Gly His Val Leu Lys Cys Val Lys Asp Gln Asn Gly Asn His Val Val 965 970 975 Gln Lys Cys Ile Glu Cys Val Gln Pro Gln Ser Leu Gln Phe Ile Ile 980 985 990 Asp Ala Phe Lys Gly Gln Val Phe Ala Leu Ser Thr His Pro Tyr Gly 995 1000 1005 Cys Arg Val Ile Gln Arg Ile Leu Glu His Cys Leu Pro Asp Gln 1010 1015 1020 Thr Leu Pro Ile Leu Glu Glu Leu His Gln His Thr Glu Gln Leu 1025 1030 1035 Val Gln Asp Gln Tyr Gly Asn Tyr Val Ile Gln His Val Leu Glu 1040 1045 1050 His Gly Arg Pro Glu Asp Lys Ser Lys Ile Val Ala Glu Ile Arg 1055 1060 1065 Gly Asn Val Leu Val Leu Ser Gln His Lys Phe Ala Ser Asn Val 1070 1075 1080 Val Glu Lys Cys Val Thr His Ala Ser Arg Thr Glu Arg Ala Val 1085 1090 1095 Leu Ile Asp Glu Val Cys Thr Met Asn Asp Gly Pro His Ser Ala 1100 1105 1110 Leu Tyr Thr Met Met Lys Asp Gln Tyr Ala Asn Tyr Val Val Gln 1115 1120 1125 Lys Met Ile Asp Val Ala Glu Pro Gly Gln Arg Lys Ile Val Met 1130 1135 1140 His Lys Ile Arg Pro His Ile Ala Thr Leu Arg Lys Tyr Thr Tyr 1145 1150 1155 Gly Lys His Ile Leu Ala Lys Leu Glu Lys Tyr Tyr Met Lys Asn 1160 1165 1170 Gly Val Asp Leu Gly Pro Ile Cys Gly Pro Pro Asn Gly Ile Ile 1175 1180 1185 <210> 47 <211> 1186 <212> PRT [[ID=#35]]<213> Homo sapiens <400> 47 Met Ser Val Ala Cys Val Leu Lys Arg Lys Ala Val Leu Trp Gln Asp 1 5 10 15 Ser Phe Ser Pro His Leu Lys His His Pro Gln Glu Pro Ala Asn Pro 20 25 30 Asn Met Pro Val Val Leu Thr Ser Gly Thr Gly Ser Gln Ala Gln Pro 35 40 45 Gln Pro Ala Ala Asn Gln Ala Leu Ala Ala Gly Thr His Ser Ser Pro 50 55 60 Val Pro Gly Ser Ile Gly Val Ala Gly Arg Ser Gln Asp Asp Ala Met 65 70 75 80 Val Asp Tyr Phe Phe Gln Arg Gln His Gly Glu Gln Leu Gly Gly Gly 85 90 95 Gly Ser Gly Gly Gly Gly Tyr Asn Asn Ser Lys His Arg Trp Pro Thr 100 105 110 Gly Asp Asn Ile His Ala Glu His Gln Val Arg Ser Met Asp Glu Leu 115 120 125 Asn His Asp Phe Gln Ala Leu Ala Leu Glu Gly Arg Ala Met Gly Glu 130 135 140 Gln Leu Leu Pro Gly Lys Lys Phe Trp Glu Thr Asp Glu Ser Ser Lys 145 150 155 160 Asp Gly Pro Lys Gly Ile Phe Leu Gly Asp Gln Trp Arg Asp Ser Ala 165 170 175 Trp Gly Thr Ser Asp His Ser Val Ser Gln Pro Ile Met Val Gln Arg 180 185 190 Arg Pro Gly Gln Ser Phe His Val Asn Ser Glu Val Asn Ser Val Leu 195 200 205 Ser Pro Arg Ser Glu Ser Gly Gly Leu Gly Val Ser Met Val Glu Tyr 210 215 220 Val Leu Ser Ser Ser Pro Gly Asp Ser Cys Leu Arg Lys Gly Gly Phe 225 230 235 240 Gly Pro Arg Asp Ala Asp Ser Asp Glu Asn Asp Lys Gly Glu Lys Lys 245 250 255 Asn Lys Gly Thr Phe Asp Gly Asp Lys Leu Gly Asp Leu Lys Glu Glu 260 265 270 Gly Asp Val Met Asp Lys Thr Asn Gly Leu Pro Val Gln Asn Gly Ile 275 280 285 Asp Ala Asp Val Lys Asp Phe Ser Arg Thr Pro Gly Asn Cys Gln Asn 290 295 300 Ser Ala Asn Glu Val Asp Leu Leu Gly Pro Asn Gln Asn Gly Ser Glu 305 310 315 320 Gly Leu Ala Gln Leu Thr Ser Thr Asn Gly Ala Lys Pro Val Glu Asp 325 330 335 Phe Ser Asn Met Glu Ser Gln Ser Val Pro Leu Asp Pro Met Glu His 340 345 350 Val Gly Met Glu Pro Leu Gln Phe Asp Tyr Ser Gly Thr Gln Val Pro 355 360 365 Val Asp Ser Ala Ala Ala Thr Val Gly Leu Phe Asp Tyr Asn Ser Gln 370 375 380 Gln Gln Leu Phe Gln Arg Pro Asn Ala Leu Ala Val Gln Gln Leu Thr 385 390 395 400 Ala Ala Gln Gln Gln Gln Tyr Ala Leu Ala Ala Ala His Gln Pro His 405 410 415 Ile Gly Leu Ala Pro Ala Ala Phe Val Pro Asn Pro Tyr Ile Ile Ser 420 425 430 Ala Ala Pro Pro Gly Thr Asp Pro Tyr Thr Ala Gly Leu Ala Ala Ala 435 440 445 Ala Thr Leu Gly Pro Ala Val Val Pro His Gln Tyr Tyr Gly Val Thr 450 455 460 Pro Trp Gly Val Tyr Pro Ala Ser Leu Phe Gln Gln Gln Ala Ala Ala 465 470 475 480 Ala Ala Ala Ala Thr Asn Ser Ala Asn Gln Gln Thr Thr Pro Gln Ala 485 490 495 Gln Gln Gly Gln Gln Gln Val Leu Arg Gly Gly Ala Ser Gln Arg Pro 500 505 510 Leu Thr Pro Asn Gln Asn Gln Gln Gly Gln Gln Thr Asp Pro Leu Val 515 520 525 Ala Ala Ala Ala Val Asn Ser Ala Leu Ala Phe Gly Gln Gly Leu Ala 530 535 540 Ala Gly Met Pro Gly Tyr Pro Val Leu Ala Pro Ala Ala Tyr Tyr Asp 545 550 555 560 Gln Thr Gly Ala Leu Val Val Asn Ala Gly Ala Arg Asn Gly Leu Gly 565 570 575 Ala Pro Val Arg Leu Val Ala Pro Ala Pro Val Ile Ile Ser Ser Ser 580 585 590 Ala Ala Gln Ala Ala Val Ala Ala Ala Ala Ala Ser Ala Asn Gly Ala 595 600 605 Ala Gly Gly Leu Ala Gly Thr Thr Asn Gly Pro Phe Arg Pro Leu Gly 610 615 620 Thr Gln Gln Pro Gln Pro Gln Pro Gln Gln Gln Pro Asn Asn Asn Leu 625 630 635 640 Ala Ser Ser Ser Phe Tyr Gly Asn Asn Ser Leu Asn Ser Asn Ser Gln 645 650 655 Ser Ser Ser Leu Phe Ser Gln Gly Ser Ala Gln Pro Ala Asn Thr Ser 660 665 670 Leu Gly Phe Gly Ser Ser Ser Ser Leu Gly Ala Thr Leu Gly Ser Ala 675 680 685 Leu Gly Gly Phe Gly Thr Ala Val Ala Asn Ser Asn Thr Gly Ser Gly 690 695 700 Ser Arg Arg Asp Ser Leu Thr Gly Ser Ser Asp Leu Tyr Lys Arg Thr 705 710 715 720 Ser Ser Ser Leu Thr Pro Ile Gly His Ser Phe Tyr Asn Gly Leu Ser 725 730 735 Phe Ser Ser Ser Pro Gly Pro Val Gly Met Pro Leu Pro Ser Gln Gly 740 745 750 Pro Gly His Ser Gln Thr Pro Pro Pro Ser Leu Ser Ser His Gly Ser 755 760 765 Ser Ser Ser Leu Asn Leu Gly Gly Leu Thr Asn Gly Ser Gly Arg Tyr 770 775 780 Ile Ser Ala Ala Pro Gly Ala Glu Ala Lys Tyr Arg Ser Ala Ser Ser 785 790 795 800 Ala Ser Ser Leu Phe Ser Pro Ser Ser Thr Leu Phe Ser Ser Ser Arg 805 810 815 Leu Arg Tyr Gly Met Ser Asp Val Met Pro Ser Gly Arg Ser Arg Leu 820 825 830 Leu Glu Asp Phe Arg Asn Asn Arg Tyr Pro Asn Leu Gln Leu Arg Glu 835 840 845 Ile Ala Gly His Ile Met Glu Phe Ser Gln Asp Gln His Gly Ser Arg 850 855 860 Phe Ile Gln Leu Lys Leu Glu Arg Ala Thr Pro Ala Glu Arg Gln Leu 865 870 875 880 Val Phe Asn Glu Ile Leu Gln Ala Ala Tyr Gln Leu Met Val Asp Val 885 890 895 Phe Gly Asn Tyr Val Ile Gln Lys Phe Phe Glu Phe Gly Ser Leu Glu 900 905 910 Gln Lys Leu Ala Leu Ala Glu Arg Ile Arg Gly His Val Leu Ser Leu 915 920 925 Ala Leu Gln Met Tyr Gly Cys Arg Val Ile Gln Lys Ala Leu Glu Phe 930 935 940 Ile Pro Ser Asp Gln Gln Asn Glu Met Val Arg Glu Leu Asp Gly His 945 950 955 960 Val Leu Lys Cys Val Lys Asp Gln Asn Gly Asn His Val Val Gln Lys 965 970 975 Cys Ile Glu Cys Val Gln Pro Gln Ser Leu Gln Phe Ile Ile Asp Ala 980 985 990 Phe Lys Gly Gln Val Phe Ala Leu Ser Thr His Pro Tyr Gly Cys Arg 995 1000 1005 Val Ile Gln Arg Ile Leu Glu His Cys Leu Pro Asp Gln Thr Leu 1010 1015 1020 Pro Ile Leu Glu Glu Leu His Gln His Thr Glu Gln Leu Val Gln 1025 1030 1035 Asp Gln Tyr Gly Asn Tyr Val Ile Gln His Val Leu Glu His Gly 1040 1045 1050 Arg Pro Glu Asp Lys Ser Lys Ile Val Ala Glu Ile Arg Gly Asn 1055 1060 1065 Val Leu Val Leu Ser Gln His Lys Phe Ala Ser Asn Val Val Glu 1070 1075 1080 Lys Cys Val Thr His Ala Ser Arg Thr Glu Arg Ala Val Leu Ile 1085 1090 1095 Asp Glu Val Cys Thr Met Asn Asp Gly Pro His Ser Ala Leu Tyr 1100 1105 1110 Thr Met Met Lys Asp Gln Tyr Ala Asn Tyr Val Val Gln Lys Met 1115 1120 1125 Ile Asp Val Ala Glu Pro Gly Gln Arg Lys Ile Val Met His Lys 1130 1135 1140 Ile Arg Pro His Ile Ala Thr Leu Arg Lys Tyr Thr Tyr Gly Lys 1145 1150 1155 His Ile Leu Ala Lys Leu Glu Lys Tyr Tyr Met Lys Asn Gly Val 1160 1165 1170 Asp Leu Gly Pro Ile Cys Gly Pro Pro Asn Gly Ile Ile 1175 1180 1185 <210> 48 <211> twenty two <212> DNA <213> Artificial sequence <220> <223> PUM1_Forward Primer <400> 48 gccagcttgt cttcaatgaa at 22 <210> 49 <211> twenty one <212> DNA <213> Artificial sequence <220> <223> PUM1_reverse primer <400> 49 caaagccagc ttctgttcaa g 21 <210> 50 <211> twenty four <212> DNA <213> Artificial sequence <220> <223> PUM1 probe <400> 50 atccaccatg agttggtagg cagc 24 <210> 51 <211> 1921 <212> DNA <213> Homo sapiens <400> 51 ggcggaagtg acattatcaa cgcgcgccag gggttcagtg aggtcgggca ggttcgctgt 60 ggcgggcgcc tgggccgccg gctgtttaac ttcgcttccg ctggcccata gtgatctttg 120 cagtgaccca gcatcactgt ttcttggcgt gtgaagataa cccaaggaat tgaggaagtt 180 gctgagaaga gtgtgctgga gatgctctag gaaaaaattg aatagtgaga cgagttccag 240 cgcaagggtt tctggtttgc caagaagaaa gtgaacatca tggatcagaa caacagcctg 300 ccaccttacg ctcagggctt ggcctcccct cagggtgcca tgactcccgg aatccctatc 360 tttagtccaa tgatgcctta tggcactgga ctgaccccac agcctattca gaacaccaat 420 agtctgtcta ttttggaaga gcaacaaagg cagcagcagc aacaacaaca gcagcagcag 480 cagcagcagc agcaacagca acagcagcag cagcagcagc agcagcagca gcagcagcag 540 cagcagcagc agcagcagca acaggcagtg gcagctgcag ccgttcagca gtcaacgtcc 600 cagcaggcaa cacagggaac ctcaggccag gcaccacagc tcttccactc acagactctc 660 acaactgcac ccttgccggg caccactcca ctgtatccct cccccatgac tcccatgacc 720 cccatcactc ctgccacgcc agcttcggag agttctggga ttgtaccgca gctccaaaat 780 attgtatcca cagtgaatct tggttgtaaa cttgacctaa agaccattgc acttcgtgcc 840 cgaaacgccg aatataatcc caagcggttt gctgcggtaa tcatgaggat aagagagcca 900 cgaaccacgg cactgatttt cagttctggg aaaatggtgt gcacaggagc caagagtgaa 960 gaacagtcca gactggcagc aagaaaatat gctagagttg tacagaagtt gggtttcca 1020 gctaagttct tggacttcaa gattcagaat atggtgggga gctgtgatgt gaagtttcct 1080 ataaggttag aaggccttgt gctcacccac caacaattta gtagttatga gccagagtta 1140 tttcctggtt taatctacag aatgatcaaa cccagaattg ttctccttat ttttgtttct 1200 ggaaaagttg tattaacagg tgctaaagtc agagcaagaa tttatgaagc atttgaaaac 1260 atctacccta ttctaaaggg attcaggaag acgacgtaat ggctctcatg tacccttgcc 1320 tcccccacc ccttcttttt ttttttttaa acaaatcagt ttgttttggt acctttaaat 1380 ggtggtgttg tgagaagatg gatgttgagt tgcagggtgt ggcaccaggt gatgcccttc 1440 tgtaagtgcc caccgcggga tgccgggaag gggcattatt tgtgcactga gaacaccgcg 1500 cagcgtgact gtgagttgct cataccgtgc tgctatctgg gcagcgctgc ccatttattt 1560 atatgtagat tttaaacact gctgttgaca agttggtttg agggagaaaa ctttaagtgt 1620 taaagccacc tctataattg attggacttt ttaattttaa tgtttttccc catgaaccac 1680 agtttttata tttctaccag aaaagtaaaa atctttttta aaagtgttgt ttttctaatt 1740 tataactcct aggggttatt tctgtgccag acacattcca cctctccagt attgcaggac 1800 agaatatatg tgttaatgaa aatgaatggc tgtacatatt tttttctttc ttcagagtac 1860 tctgtacaat aaatgcagtt tataaaagtg ttagattgtt gttaaaaaaa aaaaaaaaaa 1920 a 1921 <210> 52 <211> 339 <212> PRT <213> Homo sapiens <400> 52<​​​​Pro Gln Gly Ala Met Thr Pro Gly Ile Pro Ile Phe Ser Pro Met Met 20 25 30 Pro Tyr Gly Thr Gly Leu Thr Pro Gln Pro Ile Gln Asn Thr Asn Ser 35 40 45 Leu Ser Ile Leu Glu Glu Gln Gln Arg Gln Gln Gln Gln Gln Gln Gln 50 55 60 Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln 65 70 75 80 Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Ala 85 90 95 Val Ala Ala Ala Ala Val Gln Gln Ser Thr Ser Gln Gln Ala Thr Gln 100 105 110 Gly Thr Ser Gly Gln Ala Pro Gln Leu Phe His Ser Gln Thr Leu Thr 115 120 125 Thr Ala Pro Leu Pro Gly Thr Thr Pro Leu Tyr Pro Ser Pro Met Thr 130 135 140 Pro Met Thr Pro Ile Thr Pro Ala Thr Pro Ala Ser Glu Ser Ser Gly 145 150 155 160 Ile Val Pro Gln Leu Gln Asn Ile Val Ser Thr Val Asn Leu Gly Cys 165 170 175 Lys from Asp to Lys Thr Ile to Arg to Arg Asn to Glu Tyr 180 185 190 Asn Pro Lys Arg Phe Ala Ala Val Ile Met Arg Ile Arg Glu Pro Arg 195 200 205 Thr Thr Ala Leu Ile Phe Ser Ser Gly Lys Met Val Cys Thr Gly Ala 210 215 220 Lys Ser Glu Glu Gln Ser Arg Leu Ala Ala Arg Lys Tyr Ala Arg Val 225 230 235 240 Val Gln Lys Leu Gly Phe Pro Ala Lys Phe Leu Asp Phe Lys Ile Gln 245 250 255 Asn Met Val Gly Ser Cys Asp Val Lys Phe Pro Ile Arg Leu Glu Gly 260 265 270 Leu Val Leu Thr His Gln Gln Phe Ser Ser Glu Pro Glu Leu Phe 275 280 285 Pro Gly Leopard Tyr Arg Met Leopard Lys Pro Arg Leopard Val Leo Leopard 290,295,300 Phe Val Ser Gly Lys Val Val Leu Thr Gly Ala Lys Val Arg Ala Glu 305 310 315 320 Ile Tyr Glu Ala Phe Glu Asn Ile Tyr Pro Ile Leu Lys Gly Phe Arg 325 330 335 Lys Thr Thr <210> 53 <211> twenty three <212> DNA <213> Artificial sequence <220> <223> TBP_Forward Primer <400> 53 gccaagaaga aagtgaacat cat 23 <210> 54 <211> 20 <212> DNA <213> Artificial sequence <220> <223> TBP_reverse primer <400> 54 atagggattc cgggagtcat 20 <210> 55 <211> twenty four <212> DNA <213> Artificial sequence <220> <223> TBP probe <400> 55 tcagaacaac agcctgccac ctta 24 <210> 56 <211> 1852 <212> DNA <213> Homo sapiens <400> 56 accgccgaga ccgcgtccgc cccgcgagca cagagcctcg cctttgccga tccgccgccc 60 gtccacaccc gccgccagct caccatggat gatgatatcg ccgcgctcgt cgtcgacaac 120 ggctccggca tgtgcaaggc cggcttcgcg ggcgacgatg ccccccgggc cgtcttcccc 180 tccatcgtgg ggcgccccag gcaccagggc gtgatggtgg gcatgggtca gaaggattcc 240 tatgtgggcg acgaggccca gagcaagaga ggcatcctca ccctgaagta ccccatcgag 300 cacggcatcg tcaccaactg ggacgacatg gagaaaatct ggcaccacac cttctacaat 360 gagctgcgtg tggctcccga ggagcacccc gtgctgctga ccgaggcccc cctgaacccc 420 aaggccaacc gcgagaagat gacccagatc atgtttgaga ccttcaacac cccagccatg 480 tacgttgcta tccaggctgt gctatccctg tacgcctctg gccgtaccac tggcatcgtg 540 atggactccg gtgacggggt cacccacact gtgcccatct acgaggggta tgccctcccc 600 catgccatcc tgcgtctgga cctggctggc cgggacctga ctgactacct catgaagatc 660 ctcaccgagc gcggctacag cttcaccacc acggccgagc gggaaatcgt gcgtgacatt 720 aaggagaagc tgtgctacgt cgccctggac ttcgagcaag agatggccac ggctgcttcc 780 agctcctccc tggagaagag ctacgagctg cctgacggcc aggtcatcac cattggcaat 840 gagcggttcc gctgccctga ggcactcttc cagccttcct tcctgggcat ggagtcctgt 900 ggcatccacg aaactacctt caactccatc atgaagtgtg acgtggacat ccgcaaagac ctgtacgcca acacagtgct gtctggcggc accaccatgt accctggcat tgccgacagg 1020 atgcagaagg agatcactgc cctggcaccc agcacaatga agatcaagc cattgctcct 1080. cctgagcgca agtactccgt gtggatcggc ggctccatcc tggcctcgct gtccaccttc 1140 cagcagatgt ggatcagcaa gcaggagtat gacgagtccg gccctccat cgtccaccgc aaatgcttct aggcggacta tgacttagtt gcgttacacc ctttcttgac aaaacctaac ttgcgcagaa aacaagatga gattggcatg gctttatttg ttttttttgt tttgttttgg tttttttttt ttttttggct tgactcagga tttaaaaact ggacggtga aggtgacagc agtcggttgg agcgagcatc ccccaaagtt cacaatgtgg ccgaggactt tgattgcaca ttgttgtttt tttaatagtc attccaaata tgagatgcgt tgttacagga agtcccttgc catcctaaaa gccaccccac ttctctctaa ggagaatggc ccagtcctct cccaagtcca cacaggggag gtgatagcat tgctttcgtg taattatgt aatgcaaaat ttttttaatc ttcgccttaa tactttttta ttttgtttta ttttgaatga tgagccttcg tgccccccct 1680 tccccctttt ttgtccccca acttgagatg tatgaaggct tttggtctcc ctgggagtgg 1740 gtggaggcag ccagggctta cctgtacact gacttgagac cagttgaata aaagtgcaca 1800 ccttaaaaat gaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aa 1852 <210> 57 <211> 375 <212> PRT <213> Homo sapiens <400> 57 Met Asp Asp Asp Ile Ala Ala Leu Val Val Asp Asn Gly Ser Gly Met 1 5 10 15 Cys Lys Ala Gly Phe Ala Gly Asp Asp Ala Pro Arg Ala Val Phe Pro 20 25 30 Ser Ile Val Gly Arg Pro Arg His Gln Gly Val Met Val Gly Met Gly 35 40 45 Gln Lys Asp Ser Tyr Val Gly Asp Glu Ala Gln Ser Lys Arg Gly Ile 50 55 60 Leu Thr Leu Lys Tyr Pro Ile Glu His Gly Ile Val Thr Asn Trp Asp 65 70 75 80 Asp Met Glu Lys Ile Trp His His Thr Phe Tyr Asn Glu Leu Arg Val 85 90 95 Ala Pro Glu Glu His Pro Val Leu Leu Thr Glu Ala Pro Leu Asn Pro 100 105 110 Lys Ala Asn Arg Glu Lys Met Thr Gln Ile Met Phe Glu Thr Phe Asn 115 120 125 Thr Pro Ala Met Tyr Val Ala Ile Gln Ala Val Leu Ser Leu Tyr Ala 130 135 140 Ser Gly Arg Thr Thr Gly Ile Val Met Asp Ser Gly Asp Gly Val Thr 145 150 155 160 His Thr Val Pro Ile Tyr Glu Gly Tyr Ala Leu Pro His Ala Ile Leu 165 170 175 Arg Leu Asp Leu Ala Gly Arg Asp Leu Thr Asp Tyr Leu Met Lys Ile 180 185 190 Leu Thr Glu Arg Gly Tyr Ser Phe Thr Thr Thr Ala Glu Arg Glu Ile 195 200 205 Val Arg Asp Ile Lys Glu Lys Leu Cys Tyr Val Ala Leu Asp Phe Glu 210 215 220 Gln Glu Met Ala Thr Ala Ala Ser Ser Ser Ser Leu Glu Lys Ser Tyr 225 230 235 240 Glu Leu Pro Asp Gly Gln Val Ile Thr Ile Gly Asn Glu Arg Phe Arg 245 250 255 Cys Pro Glu Ala Leu Phe Gln Pro Ser Phe Leu Gly Met Glu Ser Cys 260 265 270 Gly Ile His Glu Thr Thr Phe Asn Ser Ile Met Lys Cys Asp Val Asp 275 280 285 Ile Arg Lys Asp Leu Tyr Ala Asn Thr Val Leu Ser Gly Gly Thr Thr 290 295 300 Met Tyr Pro Gly Ile Ala Asp Arg Met Gln Lys Glu Ile Thr Ala Leu 305 310 315 320 Ala Pro Ser Thr Met Lys Ile Lys Ile Ile Ala Pro Pro Glu Arg Lys 325 330 335 Tyr Ser Val Trp Ile Gly Gly Ser Ile Leu Ala Ser Leu Ser Thr Phe 340 345 350 Gln Gln Met Trp Ile Ser Lys Gln Glu Tyr Asp Glu Ser Gly Pro Ser 355 360 365 Ile Val His Arg Lys Cys Phe 370 375 <210> 58 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Forward primer of ACTB<0003३36><400> 58 ccaaccgcga gaagatga 18 <210> 59 <211> 20 <212> DNA <213> Artificial sequence <220> <223> ACTB reverse primer <400> 59 ccagaggcgt acagggatag 20 <210> 60 <211> 23 <212> DNA <213> Artificial sequence <220> <223> ACTB probe <400> 60 ccatgtacgt tgctatccag gct 23 <210> 61 <211> 1229 <212> DNA <213> Homo sapiens <400> 61 gtctgacggg cgatggcgca gccaatagac aggagcgcta tccgcggttt ctgattggct 60 actttgttcg cattataaaa ggcacgcgcg ggcgcgaggc ccttctctcg ccaggcgtcc 120 tcgtggaagt gacatcgtct ttaaaccctg cgtggcaatc cctgacgcac cgccgtgatg 180 cccagggaag acagggcgac ctggaagtcc aactacttcc ttaagatcat ccaactattg 240 gatgattatc cgaaatgttt cattgtggga gcagacaatg tgggctccaa gcagatgcag 300 cagatccgca tgtcccttcg cgggaaggct gtggtgctga tgggcaagaa caccatgatg 360 cgcaaggcca tccgagggca cctggaaaac aacccagctc tggagaaact gctgcctcat 420 atccggggga atgtgggctt tgtgttcacc aaggaggacc tcactgagat cagggacatg 480 ttgctggcca ataaggtgcc agctctctgcc cgtgctggtg ccattgcccc atgtgaagtc 540 actgtgccag cccagaacac tggtctcggg cccgaaga cctccttttt ccaggcttta 600 ggtatcacca ctaaaatctc caggggcacc attgaaatcc tgagtgatgt gcagctgatc 660 aagactggag acaaagtggg agccagcgaa gccacgctgc tgaacatgct caacatctcc 720 cccttctcct ttgggctggt catccagcag gtgttcgaca atggcagcat ctacaaccct 780 gaagtgcttg atatcacaga ggaaactctg cattctcgct tcctggaggg tgtccgcaat 840 gttgccagtg tctgtctgca gattggctac ccaactgttg catcagtacc ccattctatc 900 atcaacgggt aaaacgagt cctggccttg tctgtggaga cggattacac cttcccactt 960 gctgaaaagg tcaaggcctt cttggctgat ccatctgcct ttgtggctgc tgcccctgtg 1020 gctgctgcca ccacagctgc tcctgctgct gctgcagccc cagctaaggt tgaagccaag 1080 gaagagtcgg aggagtcgga cgaggatatg ggatttggtc tctttgacta atcaccaaaa 1140 agcaaccaac ttagccagtt ttatttgcaa aacaaggaaa taaaggctta cttctttaaa 1200 aagtaaaaaa aaaaaaaaaa aaaaaaaaa 1229 <210> 62 <211> 317 <212> PRT <213> Homo sapiens <400> 62 Met Pro Arg Glu Asp Arg Ala Thr Trp Lys Ser Asn Tyr Phe Leu Lys 1 5 10 15 Ile Ile Gln Leu Leu Asp Asp Tyr Pro Lys Cys Phe Ile Val Gly Ala 20 25 30 Asp Asn Val Gly Ser Lys Gln Met Gln Gln Ile Arg Met Ser Leu Arg 35 40 45 Gly Lys Ala Val Val Leu Met Gly Lys Asn Thr Met Met Arg Lys Ala 50 55 60 Ile Arg Gly His Leu Glu Asn Asn Pro Ala Leu Glu Lys Leu Leu Pro 65 70 75 80 His Ile Arg Gly Asn Val Gly Phe Val Phe Thr Lys Glu Asp Leu Thr 85 90 95 Glu Ile Arg Asp Met Leu Leu Ala Asn Lys Val Pro Ala Ala Ala Arg 100 105 110 Ala Gly Ala Ile Ala Pro Cys Glu Val Thr Val Pro Ala Gln Asn Thr 115 120 125 Gly Leu Gly Pro Glu Lys Thr Ser Phe Phe Gln Ala Leu Gly Ile Thr 130 135 140 Thr Lys Ile Ser Arg Gly Thr Ile Glu Ile Leu Ser Asp Val Gln Leu 145 150 155 160 Ile Lys Thr Gly Asp Lys Val Gly Ala Ser Glu Ala Thr Leu Leu Asn 165 170 175 Met Leu Asn Ile Ser Pro Phe Ser Phe Gly Leu Val Ile Gln Gln Val 180 185 190 Phe Asp Asn Gly Ser Ile Tyr Asn Pro Glu Val Leu Asp Ile Thr Glu 195 200 205 Glu Thr Leu His Ser Arg Phe Leu Glu Gly Val Arg Asn Val Ala Ser 210 215 220 Val Cys Leu Gln Ile Gly Tyr Pro Thr Val Ala Ser Val Pro His Ser 225 230 235 240 Ile Ile Asn Gly Tyr Lys Arg Val Leu Ala Leu Ser Val Glu Thr Asp 245 250 255 Tyr Thr Phe Pro Leu Ala Glu Lys Val Lys Ala Phe Leu Ala Asp Pro 260 265 270 Ser Ala Phe Val Ala Ala Ala Pro Val Ala Ala Ala Thr Thr Ala Ala 275 280 285 Pro Ala Ala Ala Ala Ala Pro Ala Lys Val Glu Ala Lys Glu Glu Ser 290 295 300 Glu Glu Ser Asp Glu Asp Met Gly Phe Gly Leu Phe Asp 305 310 315 <210> 63 <211> 317 <212> PRT <213> Homo sapiens <400> 63 Met Pro Arg Glu Asp Arg Ala Thr Trp Lys Ser Asn Tyr Phe Leu Lys 1 5 10 15 Ile Ile Gln Leu Leu Asp Asp Tyr Pro Lys Cys Phe Ile Val Gly Ala 20 25 30 Asp Asn Val Gly Ser Lys Gln Met Gln Gln Ile Arg Met Ser Leu Arg 35 40 45 Gly Lys Ala Val Val Leu Met Gly Lys Asn Thr Met Met Arg Lys Ala 50 55 60 Ile Arg Gly His Leu Glu Asn Asn Pro Ala Leu Glu Lys Leu Leu Pro 65 70 75 80 His Ile Arg Gly Asn Val Gly Phe Val Phe Thr Lys Glu Asp Leu Thr 85 90 95 Glu Ile Arg Asp Met Leu Leu Ala Asn Lys Val Pro Ala Ala Ala Arg 100 105 110 Ala Gly Ala Ile Ala Pro Cys Glu Val Thr Val Pro Ala Gln Asn Thr 115 120 125 Gly Leu Gly Pro Glu Lys Thr Ser Phe Phe Gln Ala Leu Gly Ile Thr 130 135 140 Thr Lys Ile Ser Arg Gly Thr Ile Glu Ile Leu Ser Asp Val Gln Leu 145 150 155 160 Ile Lys Thr Gly Asp Lys Val Gly Ala Ser Glu Ala Thr Leu Leu Asn 165 170 175 Met Leu Asn Ile Ser Pro Phe Ser Phe Gly Leu Val Ile Gln Gln Val 180 185 190 Phe Asp Asn Gly Ser Ile Tyr Asn Pro Glu Val Leu Asp Ile Thr Glu 195 200 205 Glu Thr Leu His Ser Arg Phe Leu Glu Gly Val Arg Asn Val Ala Ser 210 215 220 Val Cys Leu Gln Ile Gly Tyr Pro Thr Val Ala Ser Val Pro His Ser 225 230 235 240 Ile Ile Asn Gly Tyr Lys Arg Val Leu Ala Leu Ser Val Glu Thr Asp 245 250 255 Tyr Thr Phe Pro Leu Ala Glu Lys Val Lys Ala Phe Leu Ala Asp Pro 260 265 270 Ser Ala Phe Val Ala Ala Ala Pro Val Ala Ala Ala Thr Thr Ala Ala 275 280 285 Pro Ala Ala Ala Ala Ala Pro Ala Lys Val Glu Ala Lys Glu Glu Ser 290 295 300 Glu Glu Ser Asp Glu Asp Met Gly Phe Gly Leu Phe Asp 305 310 315 <210> 64 <211> 18 <212> DNA <213> Artificial sequence <220> <223> RPLP0_Forward Primer <400> 64 taaaccctgc gtggcaat 18 <210> 65 <211> 27 <212> DNA <213> Artificial sequence <220> <223> RPLP0_reverse primer <400> 65 acatttcgga taatcatcca atagttg 27 <210> 66 <211> twenty four <212> DNA <213> Artificial sequence <220> <223> RPLP0 probe <400> 66 aagtagttgg acttccaggt cgcc 24 <210> 67 <211> 2458 <212> DNA <213> Homo sapiens <400> 67 cagaagaagg cagcgcccaa ggcgcatgcg cagcggtcac tcccgctgta tattaaggcg 60 ccggcgatcg cggcctgagg ctgctcccgg acaagggcaa cgagcgtttc gtttggactt 120 ctcgacttga gtgcccgcct ccttcgccgc cgcctctgca gtcctcagcg cagttatgcc 180 cagttcttcc cgctgtgggg acacgaccac ggaggaatcc ttgcttcagg gactcgggac 240 cctgctggac cccttcctcg ggtttagggg atgtggggac caggagaaag tcaggatccc 300 taagagtctt ccctgcctgg atggatgagt ggcttcttct ccacctagat tctttccaca 360[[ID=二十一]] [[ID=二十二]]ggagccagca tacttcctga acatggagag tgttgttcgc cgctgcccat tcttatcccg 420[[ID=二十三]] [[ID=二十四]]agtcccccag gcctttctgc agaaagcagg caaatctctg ttgttctatg cccaaaactg 480[[ID=二十五]] [[ID=二十六]]ccccaagatg atggaagttg gggccaagcc agcccctcgg gcattgtcca ctgcagcagt 540[[ID=二十七]] [[ID=二十八]]acactaccaa cagatcaaag aaacccctcc ggccagtgag aaagacaaaa ctgctaaggc 600[[ID=二十九]] [[ID=三十]]caaggtccaa cagactcctg atggatccca gcagagtcca gatggcacac agcttccgtc 660 It should be noted that there seems to be an error in the line numbering in the original text where "[[ID=二十一]]" and "[[ID=二十二]]" etc. are used instead of consecutive numbers. This has been maintained in the translation for consistency with the original. Also, the 7 - digit tags " " etc. are preserved exactly as they are. tggacacccc ttgcctgcca caagccaggg cactgcaagc aaatgccctt tcctggcagc 720 acagatgaat cagagaggca gcagtgtctt ctgcaaagcc agtcttgagc ttcaggagga 780 tgtgcaggaa atgaatgccg tgaggaaaga ggttgctgaa acctcagcag gccccagtgt 840 ggttagtgtg aaaaccgatg gaggggatcc cagtggactg ctgaagaact tccaggacat 900 catgcaaaag caaagaccag aaagagtgtc tcatcttctt caagataact tgccaaaatc 960 tgtttccact tttcagtatg atcgtttctt tgagaaaaaa attgatgaga aaaagaatga 1020 ccacacctat cgagttttta aaactgtgaa ccggcgagca cacatcttcc ccatggcaga 1080 tgactattca gactccctca tcaccaaaaa gcaagtgtca gtctggtgca gtaatgacta 1140 cctaggaatg agtcgccacc cacgggtgtg tggggcagtt atggacactt tgaaacaaca 1200 tggtgctggg gcaggtggta ctagaaatat ttctggaact agtaaattcc atgtggactt 1260 agagcgggag ctggcagacc tccatgggaa agatgccgca ctcttgtttt cctcgtgctt 1320 tgtggccaat gactcaaccc tcttcaccct ggctaagatg atgccaggct gtgagattta 1380 ctctgattct gggaaccatg cctccatgat ccaagggatt cgaaacagcc gagtgccaaa 1440 gtacatcttc cgccacaatg atgtcagcca cctcagagaa ctgctgcaaa gatctgaccc 1500 ctcagtcccc aagattgtgg catttgaaac tgtccattca atggatgggg cggtgtgccc 1560 actggaagag ctgtgtgatg tggcccatga gtttggagca atcaccttcg tggatgaggt 1620 ccacgcagtg gggctttatg gggctcgagg cggagggatt ggggatcggg atggagtcat 1680 gccaaaaatg gacatcattt ctggaacact tggcaaagcc tttggttgtg ttggagggta 1740 catcgccagc acgagttctc tgattgacac cgtacggtcc tatgctgctg gcttcatctt 1800 caccacctct ctgccaccca tgctgctggc tggagccctg gagtctgtgc ggatcctgaa 1860 gagcgctgag ggacgggtgc ttcgccgcca gcaccagcgc aacgtcaaac tcatgagaca 1920 gatgctaatg gatgccggcc tccctgttgt ccactgcccc agccacatca tccctgtgcg 1980 ggttgcagat gctgctaaaa acacagaagt ctgtgatgaa ctaatgagca gacataacat 2040 ctacgtgcaa gcaatcaatt accctacggt gccccgggga gaagagctcc tacggattgc 2100 ccccacccct caccacacac cccagatgat gaactacttc cttgagaatc tgctagtcac 2160 atggaagcaa gtggggctgg aactgaagcc tcattcctca gctgagtgca acttctgcag 2220 gaggccactg cattttgaag tgatgagtga aagagagaag tcctatttct caggcttgag 2280 caagttggta tctgctcagg cctgagcatg acctcaatta tttcacttaa ccccaggcca 2340 ttatcatatc cagatggtct tcagagttgt ctttatatgt gaattaagtt atattaaatt 2400 ttaatctata gtaaaaacat agtcctggaa ataaattctt gcttaaatgg tgaaaaaa 2458 <210> 68 <211> 2281 <212> DNA <213> Homo sapiens <400> 68 cagaagaagg cagcgcccaa ggcgcatgcg cagcggtcac tcccgctgta tattaaggcg 60 ccggcgatcg cggcctgagg ctgctcccgg acaagggcaa cgagcgtttc gtttggactt 120 ctcgacttga gtgcccgcct ccttcgccgc cgcctctgca gtcctcagcg cagtctttcc 180 acaggagcca gcatacttcc tgaacatgga gagtgttgtt cgccgctgcc cattcttatc 240 ccgagtcccc caggcctttc tgcagaaagc aggcaaatct ctgttgttct atgcccaaaa 300 360. ctgccccaag atgatggaag ttggggccaa gccagcccct cgggcattgt ccactgcagc agtacactac caacagatca aagaaacccc tccggccagt gagaagaca aaactgctaa ggccaaggtc caacagactc ctgatggatc ccagcagagt ccagatggca cacagcttcc gtctggacac cccttgcctg ccacaagcca gggcactgca agcaaatgcc ctttcctggc 540 agcacagatg aatcagagag gcagcagtgt cttctgcaaa gccagtcttg agcttcagga ggatgtgcag gaatgaatg ccgtgagga agaggttgct gaaacctcag caggccccag tgtggttagt gtgaaaaccg atggagggga tcccagtgga ctgctgaaga acttccagga 720 catcatgca aagcaaagac cagaaagagt gtctcatctt cttcaagata acttgccaaa atctgtttcc acttttcagt atgatcgttt ctttgagaaa aaaattgatg agaaaaaaga 840 tgaccacacc tatcgagttt ttaaaactgt gaaccggcga gcacacatct tccccatggc agatgactat tcagactccc tcatcaccaa aaagcaagtg tcagtctggt gcagtaatga ctacctagga atgagtcgcc acccacgggt gtgtggggca gttatggaca ctttgaaaca acatggtgct ggggcaggtg gtactagaaa tatttctgga actagtaaat tccatgtgga 1080 cttagagcgg gagctggcag acctccatgg gaaagatgcc gcactcttgt tttcctcgtg 1140 ctttgtggcc aatgactcaa ccctcttcac cctggctaag atgatgccag gctgtgagat 1200 ttactctgat tctgggaacc atgcctccat gatccaaggg attcgaaaca gccgagtgcc 1260 aaagtacatc ttccgccaca atgatgtcag ccacctcaga gaactgctgc aaagatctga 1320 cccctcagtc cccaagattg tggcatttga aactgtccat tcaatggatg gggcggtgtg 1380 cccactggaa gagctgtgtg atgtggccca tgagtttgga gcaatcacct tcgtggatga 1440 ggtccacgca gtggggcttt atggggctcg aggcggaggg attggggatc gggatggagt 1500 catgccaaaa atggacatca tttctggaac acttggcaaa gcctttggtt gtgttggagg 1560 gtacatcgcc agcacgagtt ctctgattga caccgtacgg tcctatgctg ctggcttcat 1620 cttcaccacc tctctgccac ccatgctgct ggctggagcc ctggagtctg tgcggatcct 1680 gaagagcgct gagggacggg tgcttcgccg ccagcaccag cgcaacgtca aactcatgag 1740 acagatgcta atggatgccg gcctccctgt tgtccactgc cccagccaca tcatccctgt 1800 gcgggttgca gatgctgcta aaaacacaga agtctgtgat gaactaatga gcagacataa 1860 catctacgtg caagcaatca attaccctac ggtgccccgg ggagaagagc tcctacggat 1920 tgcccccacc cctcaccaca caccccagat gatgaactac ttccttgaga atctgctagt 1980 cacatggaag caagtggggc tggaactgaa gcctcattcc tcagctgagt gcaacttctg 2040 caggaggcca ctgcattttg aagtgatgag tgaaagagag aagtcctatt tctcaggctt 2100 gagcaagttg gtatctgctc aggcctgagc atgacctcaa ttatttcact taaccccagg 2160<000358​​​​​​​​​​​​​​​​​​​​Ala Phe Leu Gln Lys Ala Gly Lys Ser Leu Leu Phe Tyr Ala Gln Asn 20 25 30 Cys Pro Lys Met Met Glu Val Gly Ala Lys Pro Ala Pro Arg Ala Leu 35 40 45 Ser Thr Ala Ala Val His Tyr Gln Gln Ile Lys Glu Thr Pro Pro Ala 50 55 60 Ser Glu Lys Asp Lys Thr Ala Lys Ala Lys Val Gln Gln Thr Pro Asp 65 70 75 80 Gly Ser Gln Gln Ser Pro Asp Gly Thr Gln Leu Pro Ser Gly His Pro 85 90 95 Leu Pro Ala Thr Ser Gln Gly Thr Ala Ser Lys Cys Pro Phe Leu Ala 100 105 110 Ala Gln Met Asn Gln Arg Gly Ser Ser Val Phe Cys Lys Ala Ser Leu 115 120 125 Glu Leu Gln Glu Asp Val Gln Glu Met Asn Ala Val Arg Lys Glu Val 130 135 140 Ala Glu Thr Ser Ala Gly Pro Ser Val Val Ser Val Lys Thr Asp Gly 145 150 155 160 Gly Asp Pro Ser Gly Leu Leu Lys Asn Phe Gln Asp Ile Met Gln Lys 165 170 175 Gln Arg Pro Glu Arg Val Ser His Leu Leu Gln Asp Asn Leu Pro Lys 180 185 190 Ser Val Ser Thr Phe Gln Tyr Asp Arg Phe Phe Glu Lys Lys Ile Asp 195 200 205 Glu Lys Lys Asn Asp His Thr Tyr Arg Val Phe Lys Thr Val Asn Arg 210 215 220 Arg Ala His Ile Phe Pro Met Ala Asp Asp Tyr Ser Asp Ser Leu Ile 225 230 235 240 Thr Lys Lys Gln Val Ser Val Trp Cys Ser Asn Asp Tyr Leu Gly Met 245 250 255 Ser Arg His Pro Arg Val Cys Gly Ala Val Met Asp Thr Leu Lys Gln 260 265 270 His Gly Ala Gly Ala Gly Gly Thr Arg Asn Ile Ser Gly Thr Ser Lys 275 280 285 Phe His Val Asp Leu Glu Arg Glu Leu Ala Asp Leu His Gly Lys Asp 290 295 300 Ala Ala Leu Leu Phe Ser Ser Cys Phe Val Ala Asn Asp Ser Thr Leu 305 310 315 320 Phe Thr Leu Ala Lys Met Met Pro Gly Cys Glu Ile Tyr Ser Asp Ser 325 330 335 Gly Asn His Ala Ser Met Ile Gln Gly Ile Arg Asn Ser Arg Val Pro 340 345 350 Lys Tyr Ile Phe Arg His Asn Asp Val Ser His Leu Arg Glu Leu Leu 355 360 365 Gln Arg Ser Asp Pro Ser Val Pro Lys Ile Val Ala Phe Glu Thr Val 370 375 380 His Ser Met Asp Gly Ala Val Cys Pro Leu Glu Glu Leu Cys Asp Val 385 390 395 400 Ala His Glu Phe Gly Ala Ile Thr Phe Val Asp Glu Val His Ala Val 405 410 415 Gly Leu Tyr Gly Ala Arg Gly Gly Gly Ile Gly Asp Arg Asp Gly Val 420 425 430 Met Pro Lys Met Asp Ile Ile Ser Gly Thr Leu Gly Lys Ala Phe Gly 435 440 445 Cys Val Gly Gly Tyr Ile Ala Ser Thr Ser Ser Leu Ile Asp Thr Val 450 455 460 Arg Ser Tyr Ala Ala Gly Phe Ile Phe Thr Thr Ser Leu Pro Pro Met 465 470 475 480 Leu Leu Ala Gly Ala Leu Glu Ser Val Arg Ile Leu Lys Ser Ala Glu 485 490 495 Gly Arg Val Leu Arg Arg Gln His Gln Arg Asn Val Lys Leu Met Arg 500 505 510 Gln Met Leu Met Asp Ala Gly Leu Pro Val Val His Cys Pro Ser His 515 520 525 Ile Ile Pro Val Arg Val Ala Asp Ala Ala Lys Asn Thr Glu Val Cys 530 535 540 Asp Glu Leu Met Ser Arg His Asn Ile Tyr Val Gln Ala Ile Asn Tyr 545 550 555 560 Pro Thr Val Pro Arg Gly Glu Glu Leu Leu Arg Ile Ala Pro Thr Pro 565 570 575 His His Thr Pro Gln Met Met Asn Tyr Phe Leu Glu Asn Leu Leu Val 580 585 590 Thr Trp Lys Gln Val Gly Leu Glu Leu Lys Pro His Ser Ser Ala Glu 595 600 605 Cys Asn Phe Cys Arg Arg Pro Leu His Phe Glu Val Met Ser Glu Arg 610 615 620 Glu Lys Ser Tyr Phe Ser Gly Leu Ser Lys Leu Val Ser Ala Gln Ala 625 630 635 640 <210> 70 <211> 640 <212> PRT <213> Homo sapiens <400> 70 Met Glu Ser Val Val Arg Arg Cys Pro Phe Leu Ser Arg Val Pro Gln 1 5 10 15 Ala Phe Leu Gln Lys Ala Gly Lys Ser Leu Leu Phe Tyr Ala Gln Asn 20 25 30 Cys Pro Lys Met Met Glu Val Gly Ala Lys Pro Ala Pro Arg Ala Leu 35 40 45 Ser Thr Ala Ala Val His Tyr Gln Gln Ile Lys Glu Thr Pro Pro Ala 50 55 60 Ser Glu Lys Asp Lys Thr Ala Lys Ala Lys Val Gln Gln Thr Pro Asp 65 70 75 80 Gly Ser Gln Gln Ser Pro Asp Gly Thr Gln Leu Pro Ser Gly His Pro 85 90 95 Leu Pro Ala Thr Ser Gln Gly Thr Ala Ser Lys Cys Pro Phe Leu Ala 100 105 110 Ala Gln Met Asn Gln Arg Gly Ser Ser Val Phe Cys Lys Ala Ser Leu 115 120 125 Glu Leu Gln Glu Asp Val Gln Glu Met Asn Ala Val Arg Lys Glu Val 130 135 140 Ala Glu Thr Ser Ala Gly Pro Ser Val Val Ser Val Lys Thr Asp Gly 145 150 155 160 Gly Asp Pro Ser Gly Leu Leu Lys Asn Phe Gln Asp Ile Met Gln Lys 165 170 175 Gln Arg Pro Glu Arg Val Ser His Leu Leu Gln Asp Asn Leu Pro Lys 180 185 190 Ser Val Ser Thr Phe Gln Tyr Asp Arg Phe Phe Glu Lys Lys Ile Asp 195 200 205 Glu Lys Lys Asn Asp His Thr Tyr Arg Val Phe Lys Thr Val Asn Arg 210 215 220 Arg Ala His Ile Phe Pro Met Ala Asp Asp Tyr Ser Asp Ser Leu Ile 225 230 235 240 Thr Lys Lys Gln Val Ser Val Trp Cys Ser Asn Asp Tyr Leu Gly Met 245 250 255 Ser Arg His Pro Arg Val Cys Gly Ala Val Met Asp Thr Leu Lys Gln 260 265 270 His Gly Ala Gly Ala Gly Gly Thr Arg Asn Ile Ser Gly Thr Ser Lys 275 280 285 Phe His Val Asp Leu Glu Arg Glu Leu Ala Asp Leu His Gly Lys Asp 290 295 300 Ala Ala Leu Leu Phe Ser Ser Cys Phe Val Ala Asn Asp Ser Thr Leu 305 310 315 320 Phe Thr Leu Ala Lys Met Met Pro Gly Cys Glu Ile Tyr Ser Asp Ser 325 330 335 Gly Asn His Ala Ser Met Ile Gln Gly Ile Arg Asn Ser Arg Val Pro 340 345 350 Lys Tyr Ile Phe Arg His Asn Asp Val Ser His Leu Arg Glu Leu Leu 355 360 365 Gln Arg Ser Asp Pro Ser Val Pro Lys Ile Val Ala Phe Glu Thr Val 370 375 380 His Ser Met Asp Gly Ala Val Cys Pro Leu Glu Glu Leu Cys Asp Val 385 390 395 400 Ala His Glu Phe Gly Ala Ile Thr Phe Val Asp Glu Val His Ala Val 405 410 415 Gly Leu Tyr Gly Ala Arg Gly Gly Gly Ile Gly Asp Arg Asp Gly Val 420 425 430 Met Pro Lys Met Asp Ile Ile Ser Gly Thr Leu Gly Lys Ala Phe Gly 435 440 445 Cys Val Gly Gly Tyr Ile Ala Ser Thr Ser Ser Leu Ile Asp Thr Val 450 455 460 Arg Ser Tyr Ala Ala Gly Phe Ile Phe Thr Thr Ser Leu Pro Pro Met 465 470 475 480 Leu Leu Ala Gly Ala Leu Glu Ser Val Arg Ile Leu Lys Ser Ala Glu 485 490 495 Gly Arg Val Leu Arg Arg Gln His Gln Arg Asn Val Lys Leu Met Arg 500 505 510 Gln Met Leu Met Asp Ala Gly Leu Pro Val Val His Cys Pro Ser His 515 520 525 Ile Ile Pro Val Arg Val Ala Asp Ala Ala Lys Asn Thr Glu Val Cys 530 535 540 Asp Glu Leu Met Ser Arg His Asn Ile Tyr Val Gln Ala Ile Asn Tyr 545 550 555 560 Pro Thr Val Pro Arg Gly Glu Glu Leu Leu Arg Ile Ala Pro Thr Pro 565 570 575 His His Thr Pro Gln Met Met Asn Tyr Phe Leu Glu Asn Leu Leu Val 580 585 590 Thr Trp Lys Gln Val Gly Leu Glu Leu Lys Pro His Ser Ser Ala Glu 595 600 605 Cys Asn Phe Cys Arg Arg Pro Leu His Phe Glu Val Met Ser Glu Arg 610 615 620 Glu Lys Ser Tyr Phe Ser Gly Leu Ser Lys Leu Val Ser Ala Gln Ala 625 630 635 640 <210> 71 <211> 17 <212> DNA <213> Artificial sequence <220> <223> ALAS-1_Forward Primer <400> 71 agccacatca tccctgt 17 <210> 72 <211> twenty two <212> DNA <213> Artificial sequence <220> <223> ALAS-1_reverse primer <400> 72 cgtagatgtt atgtctgctc at 22 <210> 73 <211> twenty two <212> DNA <213> Artificial sequence <220> <223> ALAS-1 probe <400> 73 tttagcagca tctgcaaccc gc 22 <210> 74 <211> 4543 <212> DNA <213> Homo sapiens <400> 74 atgcgtacgc tcgctggccc cgccccctag cgccgcggtc ggagccattt cgccgattcc 60 tccatgcgag ttgctgtgcg tttctctgtt gtctcggtag aaggccagag tcacacacgg 120 tcctaagagc tgggcaccag gaagcgaagg ctgatctgaa gaagacactt gaatcatggg tgacgttaaa aattttctgt atgcctggtg tggcaaaagg aagatgaccc catcctatga 240 aattaggca gtggggaca aaaacaggca gaattcatg tgtgaggttc aggtggaagg ttataattac actggcatgg gaaattccac caataaaaaa gatgcacaaa gcaatgctgc cagagacttt gttaactatt tggttcgaat aaatgaaata aagagtgaag aagttccagc ttttggggta gcatctccgc ccccacttac tgatactcct gacactacag caaatgctga 480 aggagattta ccaacaacca tgggaggacc tcttcctcca catctggctc tcaaagcaga aaataattct gaggtagggg cctctggcta tggtgttcct gggcccacct gggaccgagg 600 agccaacttg aaggattact actcaagaaa ggaagaacaa cgactctaga atcagaagaa gtggatttaa atgctgggct tcatggaaac tggaccttgg aaaatgctaa agctcgtcta aaccaatatt ttcagaaaga aaagatccaa ggagaata agtacaccca agtgggtcct gatcacaaca ggagctttat tgcagaaatg accatttata tcaagcagct gggcagaagg attttgcac gagaacatgg atcaaataag aaattggcag cacagtcctg 900 tgccctgtca cttgtcagac aactgtacca tcttggagtg gttgaagctt actccggact 960 tacaaagaag agaaaggag agacagtgga gccttacaaa gtaaacctct ctcaagattt 1020 agagcatcag ctgcaaaaca tcattcaaga gctaaatctt gagattttgc ccccgcctga 1080 agatccttct gtgccagttg cactcaacat tggcaaattg gctcagttcg aaccatctca 1140 gcgacaaaac caagtgggtg tggttccttg gtcacctcca caatccaact ggaatccttg 1200 gactagtagc aacattgatg aggggcctct ggcttttgct actccagagc aaataagcat 1260 1320 1380 ccaaaattca gttgtcatta ttagaggggc tactggatgt gggaaaacca cacaggttcc 1440 ccagttcatt ctagatgact ttatccagaa tgaccgagca gcagagtgta acatcgtagt 1500 aactcagccc agaagaatca gtgcggtttc tgtggcagag cgagttgcat ttgaaagagg 1560 agaagagcct ggaaaaagct gtggctacag cgtcgattt gagtctatac ttcctcgtcc 1620 tcatgccagt ataatgtttt gtactgtagg tgtgctcctg agaaaattag aagcaggcat 1680 tcgaggaatc agtcatgtaa ttgtagatga aatacatgaa agagatatta atactgactt 1740 ccttttggta gtactgcgtg atgttgttca ggcttatcct gaagttcgca ttgttcttat 1800 gtctgctact attgatacca gcatgttttg tgaatattc ttcaattgcc ccatcattga 1860 agtttatggg aggacttacc cagttcaaga atattttctg gaagactgca ttcagatgac 1920 ccactttgtt cctccaccaa aagacaaaaa gaagaaggat aaggatgatg atggtggtga 1980 ggatgatgat gcaaattgca acttgatctg tggtgatgaa tatggtccag aaacaaggtt 2040 gagcatgtct caattgaacg aaaaggaaac tccttttgaa ctcatcgagg ctctacttaa 2100 gtacattgaa acccttaatg ttcctggagc tgtgttggtt ttttgcctg gctggaatct 2160 gatttatact atgcagaagc atttggaaat gaatccacat tttggaagcc atcggtatca 2220 gattctaccc ctgcattctc agattcctcg agaggaacag cgcaaagtgt ttgatccagt 2280 accagttgga gtaaccaagg ttattttgtc cacaaatatt gctgaaacaa gcattaccat 2340 aaacgatgtt gtttatgtca ttgactcctg caagcagaaa gtgaaactct tcactgctca 2400 caacaatatg accaactatg ctaccgtatg ggcatcaaaa acaaaccttg agcaacggaa 2460 agggcgagct ggccgagtac ggcctggatt ctgctttcac ctgtgcagcc gagctcgttt 2520 tgagagactt gaaacccaca tgacaccaga gatgttccga acaccattgc atgaaattgc 2580 tcttagcata aaacttctgc gtctaggagg aattggccaa tttctggcca aagcaattga 2640 acctccccct ttggatgctg tgattgaagc agaacacact cttagagagc ttgatgcatt 2700 agatgccaat gatgagttga ctcctttggg acgaatcctg gctaaactcc ccattgagcc 2760 tcgttttggc aaaatgatga taatggggtg tattttctac gtgggagatg ctatctgtac 2820 cattgctgct gctacctgct ttccagagcc tttcatcaat gaaggaaagc ggctgggcta 2880 tatccatcga aattttgctg gaaacagatt ttctgatcac gtagcccttt tatcagtatt 2940 ccaagcctgg gatgatgcta gaatgggtgg agaagaagca gagatacgtt tttgtgagca 3000 aaagactt atatggcta cactaagaat gacctgggaa gccaaagttc agctcaag 3060 gattttgatt aattctgggt ttccagaga ttgttgttg acacaagtgt ttactacac 3120 tggaccagat aaatttgg atgttgttat ctccctcctg gccttttgtg tgtaccccaa 3180 tgtatgctat cataaggaaa agaggaagat tctcaccact gaagggcgta atgcacttat 3240 ccacaatca tctgttaatt gtccttttag tagccagac atgagtacc catctccctt 3300 ctttgtattt gtgaaaga tcgactcg agccatctct gctaaggca tgactttagt 3360 cacccccctg cagttgctc tctttgcctc caagaagctc caatctgatg ggcagattgt 3420 gcttgtagat gactggatta aactgcaaat atctcatgaa gctgctgcct gtatcactgg 3480 tctccgggca gccatggagg ctttggttgt tgagtacc aaacaacctg ctatcatcag 3540 ccagttggac cccgtaaatg aacgtatgct gaacatgatc cgtcagatct ctagaccctc 3600 agctgctggt atcacctta tgatggcag tacacggtat ggagatggtc cacgtcctcc 3660 ciegatggcc cgatacgaca atggaagcgg atagaagg ggaggttcta gttacagtgg 3720 tggaggctat ggcggtggct atagcagtgg aggctatggt agcggaggct atggtggcag 3780 cgccaactcc ttcgggcag gatatggtgc aggtgttggt ggaggctata gaggagtttc 3840 ccgaggtggc tttagaggca actctggagg agactacaga gggcctagtg gaggctacag 3900 aggatctggg ggattccagc gaggaggtgg taggggggcc tatggaactg gctactttgg 3960 acagggaaga ggaggtggcg gctattaaaa cttggttatg tcagttcctg tgtgtagaca 4020 gtaaggaaaa aaaggcatgc tatgtgttac gtgttttttc cagtatgttt atttgccacc 4080 aaaaagtaaa tgcattttca cccattctgt ggttcattgt agtttaagga aaccaagcat 4140 atagatgcat tagtgatttt gtttatatta tgtaaaatat aacgatctct taaaatacc 4200 acagtttgta ttttttcttt aaggagtaaa gatttgcctt taaataactt ggtattttcc 4260 tggctttcgt ttaatacaat agaaaataaa gtattacacc gaatacttgc cgtgtagttt 4320 gtttgttgac ctcgtatgtt agaaaatttt acaatgccag ctacatctgt tgattttaaa 4380 tgtcagagaa gttgtaccct gtttcaaaag tatactaagt gatactactt gtaatagaat 4440 aaatcatctt ggaattgaat tgttaccttt tgaagtaaat actggcaagt gcacaagcca 4500 cataaacctg aataaaactt ttgacctagg gttgaaaaaa aaa 4543 <210> 75 <211> 1270 <212> PRT <213> Homo sapiens <400> 75 Met Gly Asp Val Lys Asn Phe Leu Tyr Ala Trp Cys Gly Lys Arg Lys 1 5 10 15 Met Thr Pro Ser Tyr Glu Ile Arg Ala Val Gly Asn Lys Asn Arg Gln 20 25 30 Lys Phe Met Cys Glu Val Gln Val Glu Gly Tyr Asn Tyr Thr Gly Met 35 40 45 Gly Asn Ser Thr Asn Lys Lys Asp Ala Gln Ser Asn Ala Ala Arg Asp 50 55 60 Phe Val Asn Tyr Leu Val Arg Ile Asn Glu Ile Lys Ser Glu Glu Val 65 70 75 80 Pro Ala Phe Gly Val Ala Ser Pro Pro Pro Leu Thr Asp Thr Pro Asp 85 90 95 Thr Thr Ala Asn Ala Glu Gly Asp Leu Pro Thr Thr Met Gly Gly Pro 100 105 110 Leu Pro Pro His Leu Ala Leu Lys Ala Glu Asn Asn Ser Glu Val Gly 115 120 125 Ala Ser Gly Tyr Gly Val Pro Gly Pro Thr Trp Asp Arg Gly Ala Asn 130 135 140 Leu Lys Asp Tyr Tyr Ser Arg Lys Glu Glu Gln Glu Val Gln Ala Thr 145 150 155 160 Leu Glu Ser Glu Glu Val Asp Leu Asn Ala Gly Leu His Gly Asn Trp 165 170 175 Thr Leu Glu Asn Ala Lys Ala Arg Leu Asn Gln Tyr Phe Gln Lys Glu 180 185 190 Lys Ile Gln Gly Glu Tyr Lys Tyr Thr Gln Val Gly Pro Asp His Asn 195 200 205 Arg Ser Phe Ile Ala Glu Met Thr Ile Tyr Ile Lys Gln Leu Gly Arg 210 215 220 Arg Ile Phe Ala Arg Glu His Gly Ser Asn Lys Lys Leu Ala Ala Gln 225 230 235 240 Ser Cys Ala Leu Ser Leu Val Arg Gln Leu Tyr His Leu Gly Val Val 245 250 255 Glu Ala Tyr Ser Gly Leu Thr Lys Lys Lys Glu Gly Glu Thr Val Glu 260 265 270 Pro Tyr Lys Val Asn Leu Ser Gln Asp Leu Glu His Gln Leu Gln Asn 275 280 285 Ile Ile Gln Glu Leu Asn Leu Glu Ile Leu Pro Pro Pro Glu Asp Pro 290 295 300 Ser Val Pro Val Ala Leu Asn Ile Gly Lys Leu Ala Gln Phe Glu Pro 305 310 315 320 Ser Gln Arg Gln Asn Gln Val Gly Val Val Pro Trp Ser Pro Pro Gln 325 330 335 Ser Asn Trp Asn Pro Trp Thr Ser Ser Asn Ile Asp Glu Gly Pro Leu 340 345 350 Ala Phe Ala Thr Pro Glu Gln Ile Ser Met Asp Leu Lys Asn Glu Leu 355 360 365 Met Tyr Gln Leu Glu Gln Asp His Asp Leu Gln Ala Ile Leu Gln Glu 370 375 380 Arg Glu Leu Leu Pro Val Lys Lys Phe Glu Ser Glu Ile Leu Glu Ala 385 390 395 400 Ile Ser Gln Asn Ser Val Val Ile Ile Arg Gly Ala Thr Gly Cys Gly 405 410 415 Lys Thr Thr Gln Val Pro Gln Phe Ile Leu Asp Asp Phe Ile Gln Asn 420 425 430 Asp Arg Ala Ala Glu Cys Asn Ile Val Val Thr Gln Pro Arg Arg Ile 435 440 445 Ser Ala Val Ser Val Ala Glu Arg Val Ala Phe Glu Arg Gly Glu Glu 450 455 460 Pro Gly Lys Ser Cys Gly Tyr Ser Val Arg Phe Glu Ser Ile Leu Pro 465 470 475 480 Arg Pro His Ala Ser Ile Met Phe Cys Thr Val Gly Val Leu Leu Arg 485 490 495 Lys Leu Glu Ala Gly Ile Arg Gly Ile Ser His Val Ile Val Asp Glu 500 505 510 Ile His Glu Arg Asp Ile Asn Thr Asp Phe Leu Leu Val Val Leu Arg 515 520 525 Asp Val Val Gln Ala Tyr Pro Glu Val Arg Ile Val Leu Met Ser Ala 530 535 540 Thr Ile Asp Thr Ser Met Phe Cys Glu Tyr Phe Phe Asn Cys Pro Ile 545 550 555 560 Ile Glu Val Tyr Gly Arg Thr Tyr Pro Val Gln Glu Tyr Phe Leu Glu 565 570 575 Asp Cys Ile Gln Met Thr His Phe Val Pro Pro Pro Lys Asp Lys Lys 580 585 590 Lys Lys Asp Lys Asp Asp Asp Gly Gly Glu Asp Asp Asp Ala Asn Cys 595 600 605 Asn Leu Ile Cys Gly Asp Glu Tyr Gly Pro Glu Thr Arg Leu Ser Met 610 615 620 Ser Gln Leu Asn Glu Lys Glu Thr Pro Phe Glu Leu Ile Glu Ala Leu 625 630 635 640 Leu Lys Tyr Ile Glu Thr Leu Asn Val Pro Gly Ala Val Leu Val Phe 645 650 655 Leu Pro Gly Trp Asn Leu Ile Tyr Thr Met Gln Lys His Leu Glu Met 660 665 670 Asn Pro His Phe Gly Ser His Arg Tyr Gln Ile Leu Pro Leu His Ser 675 680 685 Gln Ile Pro Arg Glu Glu Gln Arg Lys Val Phe Asp Pro Val Pro Val 690 695 700 Gly Val Thr Lys Val Ile Leu Ser Thr Asn Ile Ala Glu Thr Ser Ile 705 710 715 720 Thr Ile Asn Asp Val Val Tyr Val Ile Asp Ser Cys Lys Gln Lys Val 725 730 735 Lys Leu Phe Thr Ala His Asn Asn Met Thr Asn Tyr Ala Thr Val Trp 740 745 750 Ala Ser Lys Thr Asn Leu Glu Gln Arg Lys Gly Arg Ala Gly Arg Val 755 760 765 Arg Pro Gly Phe Cys Phe His Leu Cys Ser Arg Ala Arg Phe Glu Arg 770 775 780 Leu Glu Thr His Met Thr Pro Glu Met Phe Arg Thr Pro Leu His Glu 785 790 795 800 Ile Ala Leu Ser Ile Lys Leu Leu Arg Leu Gly Gly Ile Gly Gln Phe 805 810 815 Leu Ala Lys Ala Ile Glu Pro Pro Pro Leu Asp Ala Val Ile Glu Ala 820 825 830 Glu His Thr Leu Arg Glu Leu Asp Ala Leu Asp Ala Asn Asp Glu Leu 835 840 845 Thr Pro Leu Gly Arg Ile Leu Ala Lys Leu Pro Ile Glu Pro Arg Phe 850 855 860 Gly Lys Met Met Ile Met Gly Cys Ile Phe Tyr Val Gly Asp Ala Ile 865 870 875 880 Cys Thr Ile Ala Ala Ala Thr Cys Phe Pro Glu Pro Phe Ile Asn Glu 885 890 895 Gly Lys Arg Leu Gly Tyr Ile His Arg Asn Phe Ala Gly Asn Arg Phe 900 905 910 Ser Asp His Val Ala Leu Leu Ser Val Phe Gln Ala Trp Asp Asp Ala 915 920 925 Arg Met Gly Gly Glu Glu Ala Glu Ile Arg Phe Cys Glu His Lys Arg 930 935 940 Leu Asn Met Ala Thr Leu Arg Met Thr Trp Glu Ala Lys Val Gln Leu 945 950 955 960 Lys Glu Ile Leu Ile Asn Ser Gly Phe Pro Glu Asp Cys Leu Leu Thr 965 970 975 Gln Val Phe Thr Asn Thr Gly Pro Asp Asn Asn Leu Asp Val Val Ile 980 985 990 Ser Leu Leu Ala Phe Gly Val Tyr Pro Asn Val Cys Tyr His Lys Glu 995 1000 1005 Lys Arg Lys Ile Leu Thr Thr Glu Gly Arg Asn Ala Leu Ile His 1010 1015 1020 Lys Ser Ser Val Asn Cys Pro Phe Ser Ser Gln Asp Met Lys Tyr 1025 1030 1035 Pro Ser Pro Phe Phe Val Phe Gly Glu Lys Ile Arg Thr Arg Ala 1040 1045 1050 Ile Ser Ala Lys Gly Met Thr Leu Val Thr Pro Leu Gln Leu Leu 1055 1060 1065 Leu Phe Ala Ser Lys Lys Val Gln Ser Asp Gly Gln Ile Val Leu 1070 1075 1080 Val Asp Asp Trp Ile Lys Leu Gln Ile Ser His Glu Ala Ala Ala 1085 1090 1095 Cys Ile Thr Gly Leu Arg Ala Ala Met Glu Ala Leu Val Val Glu 1100 1105 1110 Val Thr Lys Gln Pro Ala Ile Ile Ser Gln Leu Asp Pro Val Asn 1115 1120 1125 Glu Arg Met Leu Asn Met Ile Arg Gln Ile Ser Arg Pro Ser Ala 1130 1135 1140 Ala Gly Ile Asn Leu Met Ile Gly Ser Thr Arg Tyr Gly Asp Gly 1145 1150 1155 Pro Arg Pro Pro Lys Met Ala Arg Tyr Asp Asn Gly Ser Gly Tyr 1160 1165 1170 Arg Arg Gly Gly Ser Ser Tyr Ser Gly Gly Gly Tyr Gly Gly Gly 1175 1180 1185 Tyr Ser Ser Gly Gly Tyr Gly Ser Gly Gly Tyr Gly Gly Ser Ala 1190 1195 1200 Asn Ser Phe Arg Ala Gly Tyr Gly Ala Gly Val Gly Gly Gly Tyr 1205 1210 1215 Arg Gly Val Ser Arg Gly Gly Phe Arg Gly Asn Ser Gly Gly Asp 1220 1225 1230 Tyr Arg Gly Pro Ser Gly Gly Tyr Arg Gly Ser Gly Gly Phe Gln 1235 1240 1245 Arg Gly Gly Gly Arg Gly Ala Tyr Gly Thr Gly Tyr Phe Gly Gln 1250 1255 1260 Gly Arg Gly Gly Gly Gly Tyr 1265 1270 BRIEF DESCRIPTION OF THE DRAWINGS

[0083] In the following diagram:

[0084] Figure 1 A flowchart illustrating an embodiment of a method for preoperative risk stratification of subjects with prostate cancer is shown.

[0085] Figure 2 Figure 5 shows the results of ROC curve analysis of biochemical recurrence (BCR) 5 years after prostate cancer surgery in a cohort of RP patients.

[0086] Figure 3 shows the results of ROC curve analysis of clinical recurrence (CR) 10 years after prostate cancer surgery in a cohort of RP patients, and

[0087] Figure 4 Shown are the results of ROC curve analysis of prostate cancer-specific mortality 10 years after prostate cancer surgery in a cohort of RP patients.

[0088] Detailed description of implementation plan

[0089] Review of Preoperative Risk Stratification

[0090] Figure 1 The diagram illustrates a flow chart illustrating an embodiment of a method for preoperative risk stratification of subjects with prostate cancer.

[0091] The method starts at step S100 .

[0092] In step S102, one or more biological samples are obtained from each patient in the first group of patients (objects) diagnosed with prostate cancer. Preferably, after obtaining the biological samples, for example, for a period of at least one year, or at least two years, or approximately five years, these prostate cancer patients are carried out prostate cancer monitoring.

[0093] In step S104, gene expression profiles of PDE4D7 and DHX9 are obtained for the same or different biological samples obtained from each patient in the first group of patients, for example, by performing RT-qPCR (real-time quantitative PCR) on RNA extracted from each biological sample. Exemplary gene expression profiles include expression levels (e.g., values) of PDE4D7 and DHX9, which can be normalized using values ​​for each of a set of reference genes, such as HPRT1, TUBA1B, PUM1, and / or TBP. In one example, the gene expression profile values ​​of PDE4D7 and DHX9 are normalized relative to one or more reference genes, such as at least one, at least two, at least three, or preferably all of these reference genes, selected from HPRT1, TUBA1B, PUM1, and TBP.

[0094] In step S106, a regression function is determined that assigns a preoperative prognostic risk score based on the gene expression profiles of PDE4D7 and DHX9 obtained for at least some of the biological samples from the first group of patients and the respective results obtained from the monitoring. In one possible embodiment, the standardized gene expression profiles of PDE4D7 and / or DHX9 are first converted to a predetermined range of values, such as the range of 1-5 described above, using a suitable conversion function. As described above, such a conversion can be determined by considering, for example, the frequency distribution of the standardized gene expression profile values ​​of PDE4D7 (or DHX9) from biological samples of a population of prostate cancer subjects (here, the first group of patients) and by determining a conversion that converts the frequency distribution to the desired range. In a specific embodiment, the standardized converted gene expression profile values ​​are determined as shown in equation (1) above.

[0095] In step S108, one or more biological samples are obtained from a patient (subject or individual). The patient may be a new patient or one of the first group.

[0096] In step S110, gene expression profiles of PDE4D7 and DHX9 are obtained, for example, by performing PCR on a biological sample. In one example, the gene expression profile values ​​of PDE4D7 and DHX9 are normalized relative to one or more reference genes, for example, at least one, at least two, at least three, or preferably all of these reference genes, selected from HPRT1, TUBA1B, PUM1, and TBP. This is essentially the same as step S104. Furthermore, the normalized gene expression profiles of PDE4D7 and / or DHX9 may be pre-converted as described with respect to step S106.

[0097] Other reference genes that can be used additionally or alternatively in steps S104 and S110 include: Homo sapiens actin beta mRNA (ACTB); Homo sapiens 60S acidic ribosomal phosphoprotein P0 mRNA (RPLP0); polymerase (RNA) II (DNA-directed) polypeptide A, 220 kDa (POLR2A); beta-2-microglobulin (B2M); and aminolevulinic acid-delta-synthase (ALAS-1).

[0098] In step S112, a regression function is used to determine the patient's preoperative prognostic risk score based on the gene expression profiles of PDE4D7 and DHX9. This will be described in more detail later in the specification. To make the preoperative prognostic score intuitive for the user, its value can also be determined to be within a predefined numerical range, such as a range of 1-5. This can be achieved using the regression function itself or by subsequently converting the output of the regression function to a desired value range. Again, this is similar to other categories used in clinical routine, such as histopathological grade (Gleason) or multi-parametric MRI radiological score (PIRADS).

[0099] In step S114, a treatment recommendation can be provided to, for example, the patient or his / her guardian, physician or other medical staff based on the preoperative prognostic risk score. To this end, the preoperative prognostic risk score can be classified into one of a predetermined risk group based on the value of the preoperative prognostic risk score. Providing treatment recommendations may include one or more of the following: a) proposing a treatment plan for the patient based on the assigned risk group, wherein at least two risk groups are associated with different treatments; b) calculating a prediction of the patient's risk of disease progression before or after prostate surgery; and c) calculating a prediction of the patient's treatment response before or after prostate surgery. Example treatments include at least partial prostatectomy, active treatment selected from radiation therapy, chemotherapy and combinations thereof, and observation alone, i.e., without prostatectomy or active treatment (i.e., active monitoring).

[0100] The method ends at step S116.

[0101] Each risk group may be associated with a respective proposed treatment that varies in aggressiveness. Each proposed treatment may be based on the results of the first group of patients assigned to that risk group and is predicted to provide the least aggressive treatment that does not exceed a threshold clinical risk of developing prostate cancer. In some cases, this may assign a new patient to a risk group associated with a less aggressive proposed treatment than would be the case using other risk analysis methods, such as the Gleason score, NCCN risk category, or preoperative CAPRA score.

[0102] In one embodiment, the gene expression profiles at steps S104 and S110 are determined by detecting mRNA expression using one or more primers and / or probes and / or one or more sets of primers and / or probes.

[0103] Table 1 shows a detailed description of PDE4D7, DHX9 and the one or more reference genes, including their transcript IDs (NCBI RefSeq) and the corresponding amino acid sequences of primer pairs and probes. This table also shows the sense and antisense primers for each gene, as well as the probe sequences that specifically bind to the amplicon.

[0104] Table 1: Example primer and probe nucleic acid sequences

[0105]

[0106]

[0107] Instead of using RT-qPCR, in other embodiments, the gene expression profiles of PDE4D7 and / or DHX9 in steps S104 and S110 can be determined by other means, for example, by performing RNA next generation sequencing (NGS RNAseq) according to standard methods (Illumina, Inc.). In this case, the gene expression profile provided by NGS RNAseq can also be converted into a predetermined numerical range as described above.

[0108] To explore the prognostic ability of PDE4D7 and DHX9 in preoperative patient risk assessment, their correlation with disease recurrence was investigated.

[0109] A combined model based on PDE4D7 and DHX9 gene expression profiles was developed in a surgical cohort and validated for different longitudinal clinical outcomes. Results suggest that the combination of PDE4D7 and DHX9 gene expression profiles in an improved preoperative prognostic risk score may allow better patient stratification to optimize primary treatment decisions. Example

[0110] Patient cohorts and samples

[0111] A radical prostatectomy (RP) patient cohort was used, and its demographic data are shown in Table 2. For the RP patient cohort, small punch biopsies (approximately 1 mm x 2 mm) were collected from representative tumor areas of the prostate removed from 575 patients who had undergone surgery consecutively between 2000 and 2004 at a large clinical center in Germany.

[0112] Table 2: Demographic data of the radical prostatectomy (RP) patient cohort

[0113]

[0114] The table shows the minimum and maximum values ​​of patient age, preoperative PSA, percentage of tumor in biopsy, prostate volume and PSA density in the cohort, while the median values ​​are shown in brackets. For the CAPRA-S risk category, the number and percentage of patients in each risk group are shown. Postoperative pathology is shown (by number and percentage) with pathological Gleason score and Gleason grade group, pathological stage, surgical margin status after prostatectomy, and tumor infiltration status of seminal vesicles and pelvic lymph nodes. In this regard, it should be noted that extracapsular extension is not provided as the main parameter, but is derived from the pathological stage pT3a. Follow-up shows the average and median follow-up period of several months after surgery for all patients. The outcome category illustrates the cumulative 5-year and 10-year biochemical recurrence (BCR) and clinical recurrence to metastasis (CR) after surgical primary treatment. The treatment category lists the cumulative 5-year and 10-year start to salvage radiotherapy (SRT) or salvage androgen deprivation therapy (SADT) after surgery. Mortality is shown with prostate cancer specific survival (PCSS) and overall survival (OS). For all outcomes, the number of men experiencing the outcome / total number of men at the respective 5- or 10-year follow-up is shown, with the percentage of events given in parentheses.

[0115] Laboratory methods

[0116] All laboratory methods used, including oligonucleotide primers and probes for RT-qPCR (quantitative real-time PCR), RNA extraction, and quality control and procedures for including / discarding samples in statistical analyses, were as previously described. R. et al., or in the case of DHX9, based on RNA next generation sequencing (NGS RNAseq) according to standard methods (Illumina, Inc.). Table 1 also lists the primers and probes used for RT-qPCR to measure the genes of interest and reference genes. In the case of NGS RNAseq, the resulting FastQ files were aligned to the human genome and processed according to standard methods. For each gene, its gene expression value in TPM format (transcript per kilobase million; see http: / / www.rna-seqblog.com / rpkm-fpkm-and-tpm-clear-explained (retrieved on October 7, 2018)) was obtained.

[0117] result

[0118] Logistic regression modeling of PDE4D7 and DHX9 expression

[0119] The expression values ​​of PDE4D7 and DHX9 were used in logistic regression modeling to create a combined model. As shown in Table 1 below, in a subcohort of 481 RP patients with a complete 5-year outcome history (169 events, 35.14%), 5-year biochemical recurrence (BCR) after prostate cancer surgery was used as the dependent variable. The logit(p) regression function was converted to p = 1 / (1 + e^(-logit(p)) to calculate the probability p of each patient experiencing biochemical recurrence within 5 years after surgery. Tables 2-6 show the results of logistic regression modeling of the combined expression values ​​of PDE4D7 and DHX9. Table 1 describes the inputs of the logistic regression modeling in terms of cohort size (#481) and the number of positive cases with 5-year biochemical recurrence (BCR) and the number of negative cases without 5-year BCR. Table 2 provides information on model fitting, and Table 3 summarizes the coefficients (or weights) of the regression model and the corresponding statistics. Table 4 summarizes the odds ratios of PDE4D7 and DHX9, while Tables 5 and 6 summarize the classification table and ROC curve analysis data of the "PDE4D7 & DHX9" regression model.

[0120] Table 1: Inputs for logistic regression modeling

[0121] Dependent variable Y 5-year biochemical recurrence (BCR) method Enter Sample size 481 <![CDATA[Positive case a > 169(35.14％) <![CDATA[Negative cases b > 312(64.86％)

[0122] a 5-year BCR = 1

[0123] b 5-year BCR = 0

[0124] Table 2: Overall model fit

[0125]

[0126]

[0127] Table 3: Coefficients and standard errors

[0128] variable coefficient Standard error Wald P PDE4D7 -0.98799 0.17158 33.1574 <0.0001 DHX9 -0.75891 0.17095 19.7082 <0.0001 constant 7.96032 1.38277 33.1409 <0.0001

[0129] Table 4: Odds ratios and 95% confidence intervals

[0130] variable odds ratio 95% CI PDE4D7 0.3723 0.2660-0.5212 DHX9 0.4682 0.3349-0.6545

[0131] Table 5: Classification table (cutoff value p = 0.5).

[0132]

[0133] Table 6: ROC curve analysis

[0134] Area under the ROC curve (AUC) 0.713 Standard error 0.0241 95% confidence interval 0.670-0.753

[0135] Validation of combined models for different longitudinal clinical outcomes

[0136] The combined model was tested to predict various clinically relevant endpoints after surgery, such as biochemical recurrence (BCR), clinical recurrence (progression to local and / or distant metastasis) (CR), and prostate cancer-specific death. The prognostic ability of the combined model was compared with that of PDE4D7 or DHX9 alone for the same various clinically relevant endpoints.

[0137] Figure 2 The results of ROC curve analysis of biochemical recurrence (BCR) 5 years after prostate cancer surgery for a sub-cohort of patients (#481) from the RP patient cohort with complete 5-year follow-up are shown (see also Table 7). As detailed in Table 8, the calculated 5-year AUC (area under the curve) was 0.659 for PDE4D7 alone, 0.624 for DHX9 alone, and 0.713 for the combined model (in Figure 2 The AUCs for the PDE4D7 and PDE4D7 / DHX9 models were significantly different (p = 0.0022). The AUCs for the PDE4D7 and PDE4D7 / DHX9 models were significantly different (p = 0.0022). The AUCs for the PDE4D7 and PDE4D7 / DHX9 models were significantly different (p = 0.0008 ...

[0138] Table 7: Subcohorts

[0139]

[0140]

[0141] a 5-year BCR = 1

[0142] b 5-year BCR = 0

[0143] Table 8: ROC curve analysis

[0144] variable AUC <![CDATA[Standard error c > <![CDATA[95%CI d ]]> PDE4D7 0.659 0.0254 0.615-0.702 DHX9 0.624 0.0280 0.579-0.667 PDE4D7&DHX9 0.713 0.0242 0.670-0.753

[0145] cDeLong ER et al., "Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparameteric approach", Biometrics, Vol. 44, No. 3, pages 837 to 845, 1988.

[0146] b Binomial exact

[0147] Table 9: Pairwise comparison of ROC curves

[0148]

[0149] c DeLong ERet al.

[0150] Figure 3 The results of ROC curve analysis of clinical recurrence (CR) 10 years after prostate cancer surgery for a sub-cohort of patients (#335) from the RP patient cohort with a complete 10-year follow-up are shown (see also Table 10). As detailed in Table 11, the calculated 10-year AUC (area under the curve) was 0.666 for PDE4D7 alone, 0.691 for DHX9 alone, and 0.748 for the combined model (in Figure 3 The AUCs for the PDE4D7 and PDE4D7 & DHX9 models were significantly different (p = 0.0039) compared to the control model (PDE4D7 and PDE4D7 & DHX9, respectively). The standard errors were 0.0364 (PDE4D7), 0.0384 (DHX9), and 0.0314 (PDE4D7 & DHX9), respectively, with 95% confidence intervals of 0.613-0.717 (PDE4D7), 0.639-0.740 (DHX9), and 0.698-0.794 (PDE4D7 & DHX9, respectively). Table 12 shows pairwise comparisons of the ROC curves. As can be seen, the AUCs for the PDE4D7 model alone and the PDE4D7 & DHX9 combination model were significantly different (p = 0.0039).

[0151] Table 10: Subcohorts

[0152] Variable 1 PDE4D7 Variable 2 DHX9 Variable 3 PDE4D7&DHX9 Categorical variables 10-year clinical relapse (CR) Sample size 335 <![CDATA[Positive cases a > 61(18.21％) <![CDATA[Negative case b > 274(81.79％)

[0153] a 10-year CR = 1

[0154] b 10-year CR = 0

[0155] Table 11: ROC curve analysis

[0156] variable AUC <![CDATA[Standard error c > <![CDATA[95%CI d ]]> PDE4D7 0.666 0.0364 0.613-0.717 DHX9 0.691 0.0384 0.639-0.740 PDE4D7&DHX9 0.748 0.0314 0.698-0.794

[0157] c DeLong ERet al.

[0158] d binomial distribution exact

[0159] Table 12: Pairwise comparison of ROC curves

[0160]

[0161] c DeLong ERet al.

[0162] Figure 4 The results of the ROC curve analysis for prostate cancer-specific mortality 10 years after prostate cancer surgery are shown for a sub-cohort of patients (#302) from the RP patient cohort with a complete 10-year follow-up (see also Table 13). As detailed in Table 14, the calculated 10-year AUC (area under the curve) was 0.729 for PDE4D7 alone, 0.622 for DHX9 alone, and 0.754 for the combined model (in Figure 4 The AUCs for the DHX9 and PDE4D7 models were significantly different (p = 0.0403).

[0163] Table 13: Subcohorts

[0164] Variable 1 PDE4D7 Variable 2 DHX9 Variable 3 PDE4D7&DHX9 Categorical variables 10-year prostate cancer-specific mortality Sample size 302 <![CDATA[Positive cases a > 25(8.28％) <![CDATA[Negative cases b > 277(91.72％)

[0165] a 10-year PCSS = 1

[0166] b 10-year PCSS = 0

[0167] Table 14: ROC curve analysis

[0168] variable AUC <![CDATA[Standard error c > <![CDATA[95%CI d ]]> PDE4D7 0.729 0.0588 0.676-0.779 DHX9 0.622 0.0593 0.564-0.676 PDE4D7&DHX9 0.754 0.0481 0.702-0.802

[0169] c DeLong ERet al.

[0170] d binomial distribution exact

[0171] Table 15: Pairwise comparison of ROC curves

[0172]

[0173] c DeLong ERet al.

[0174] The results presented showed that a combined logistic regression model using PDE4D7 and DHX9 gene expression values ​​for predicting biochemical recurrence 5 years after surgery improved the area under the curve (AUC) in ROC analysis by 2.5% (for prostate cancer-specific death as the endpoint) to 8% (for clinical recurrence as the endpoint) compared to using PDE4D7 alone as a prognostic indicator.

[0175] Independent variable testing of the combined model for predicting metastasis after prostate cancer surgery in an independent variable dataset

[0176] Figure 5 The combined model (represented as "PDE4D7 & DHX9" in Table 16) was tested in an independent variable dataset for predicting metastasis after prostate cancer surgery (data from Taylor B Set al., "Integrative genomic profiling of human prostate cancer", Cancer Cell, Vol. 18, No. 1, pages 11 to 22, 2010). As detailed in Table 16, the calculated metastasis classification AUC (area under the curve) for PDE4D7 & DHX9 was 0.736. The standard error was 0.0777, and the 95% confidence interval was 0.651-0.809.

[0177] Table 16: Independent variable dataset

[0178] variable PDE4D7&DHX9 Categorical variables Transfer Category Sample size 129 <![CDATA[Positive case a > 8(6.20％) <![CDATA[Negative cases b > 121(93.8％) Disease prevalence (%) unknown

[0179] a Transfer Type = 1

[0180] b Transfer Category = 0

[0181] Table 17: ROC curve analysis

[0182] AUC 0.736 <![CDATA[Standard error c > 0.0777 <![CDATA[95% confidence interval d > 0.651-0.809 z-statistic 3.029 Significance level p＝0.024

[0183] c DeLong ERet al.

[0184] d binomial distribution exact

[0185] Table 18: Youden Index

[0186] Youden Index J 0.4194 Related standards >-1.16 Sensitivity 75.00 Specificity 66.94

[0187] Logistic regression modeling of PDE4D7&DHX9 combined model and postoperative clinical risk score CAPRA-S to predict postoperative metastasis

[0188] The PDE4D7 & DHX9 combined model and the postoperative clinical risk score CAPRA-S were used in other logistic regression models to generate a further combined model (hereinafter referred to as "PDE4D7 & DHX9 & CAPRA-S"). As shown in Table 19 below, in the independent variable data from Taylor BS et al., the dependent variable was the metastasis category after prostate cancer surgery (see above). The logit(p) regression function was converted to p = 1 / (1 + e^(-logit(p)) to calculate the probability p of metastasis after surgery for each patient. Tables 20-26 show the results of the logistic regression modeling combining PDE4D7 & DHX9 with the CAPRA-S score. Table 19 describes the inputs for the logistic regression modeling based on the sample size (#129) and the number of positive cases with metastasis and negative cases without metastasis. Table 20 provides information on model fitting, and Table 21 summarizes the coefficients (or weights) of the regression model with corresponding statistical information. Table 22 summarizes the odds ratios of PDE4D7 & DHX9 and the CAPRA-S score, while Tables 23 and 24 show the calibration test results of the regression model (according to the Hosmer & Lemeshow test). Finally, Tables 25 and 26 summarize the data of the classification table of the "PDE4D7 & DHX9 & CAPRA-S" regression model and the ROC curve analysis.

[0189] Table 19: Inputs for logistic regression modeling

[0190] Dependent variable Y Transfer Category method Enter Sample size 129 <![CDATA[Positive cases a > 8(6.20％) <![CDATA[Negative cases b > 121(93.8％)

[0191] a Transfer Type = 1

[0192] b Transfer Category = 0

[0193] Table 20: Overall model fit

[0194] Null Model – 2Log Likelihood 59.979 Full Model – 2Log Likelihood 49.989 Chi-square 9.990 DF 2 Significance level p＝0.0068 <![CDATA[Cox&Snell R 2 ]]> 0.0745 <![CDATA[Nagelkerte R 2 ]]> 0.2004

[0195] Table 21: Coefficients and Standard Errors

[0196] variable coefficient Standard error Wald P PDE4D7&DHX9 0.77252 0.42392 3.3208 0.0684 CAPRA-S score 0.25375 0.12488 4.1290 0.0422 constant -2.80880 0.87165 10.3837 0.0013

[0197] Table 22: Odds ratios and 95% confidence intervals

[0198] variable odds ratio 95% CI PDE4D7&DHX9 2.1652 0.9433-4.9699 CAPRA-S score 1.2888 1.0090-1.6463

[0199] Table 23: Hosmer & Lemeshow test

[0200] Chi-square 2.9654 DF 8 Significance level p＝0.9365

[0201] Table 24: Contingency table of Hosmer & Lemeshow test

[0202]

[0203]

[0204] Table 25: Classification table (cutoff value p = 0.5)

[0205]

[0206] Table 26: ROC curve analysis

[0207] AUC 0.713 <![CDATA[Standard error c > 0.0241 <![CDATA[95% confidence interval d > 0.670-0.753

[0208] Figure 6 Shown is an ROC analysis of the combined model of PDE4D7 & DHX9 and PDE4D7 & DHX9 & CAPRA-S for predicting postoperative metastasis of prostate cancer (data from Taylor BS et al., "Integrative genomic profiling of human prostate cancer", Cancer Cell, Vol. 18, No. 1, pages 11 to 22, 2010). As detailed in Table 28, the calculated metastasis category AUC (area under the curve) was 0.736 for PDE4D7 & DHX9 alone and 0.840 for PDE4D7 & DHX9 & CAPRA-S. The standard errors were 0.0777 (PDE4D7 & DHX9) and 0.0636 (PDE4D7 & DHX9 & CAPRA-S), respectively, with 95% confidence intervals of 0.651-0.809 (PDE4D7 & DHX9) and 0.765-0.899 (PDE4D7 & DHX9 & CAPRA-S), respectively. Table 29 shows a pairwise comparison of ROC curves. As can be seen, the AUCs for the PDE4D7 & DHX9 alone and the PDE4D7 & DHX9 & CAPRA-S combined model were significantly different (p = 0.0323), with an AUC difference of 0.104 (or 10.4%).

[0209] Table 27: Independent variable dataset

[0210] Variable 1 PDE4D7&DHX9 Variable 2 PDE4D7&DHX9&CAPRA-S Categorical variables Transfer Category Sample size 129 <![CDATA[Positive case a > 8(6.20％) <![CDATA[Negative cases b > 121(93.8％) Disease prevalence (%) unknown

[0211] a Transfer Type = 1

[0212] b Transfer Category = 0

[0213] Table 28: ROC curve analysis

[0214] variable AUC <![CDATA[Standard error c > <![CDATA[95%CI d ]]> PDE4D7&DHX9 0.736 0.0777 0.651-0.809 PDE4D7&DHX9&CAPRA-S 0.840 0.0636 0.765-0.899

[0215] c DeLong ERet al.

[0216] d binomial distribution exact

[0217] Table 29: Pairwise comparison of ROC curves

[0218]

[0219] c DeLong ERet al.

[0220] discuss

[0221] Treatment decisions for primary localized prostate cancer are largely determined by a combination of the risk of future disease progression and life expectancy. The data presented suggest that the combined use of PDE4D7 and DHX9 in preoperative risk scoring adds value compared to using PDE4D7 alone as a prognostic marker. Therefore, DHX9 may add prognostic value to PDE4D7 in clinical prediction models for disease-specific outcomes, such as progression to biochemical recurrence or clinical recurrence to metastasis after surgery, as well as for predicting cancer-specific survival to support treatment decision making.

[0222] Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the appended claims.

[0223] In the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality.

[0224] Figure 1One or more steps of the method shown may be implemented in a computer program product that can be executed on a computer. The computer program product may include a permanent computer-readable recording medium, such as a magnetic disk, a hard disk drive, etc., on which a control program is recorded (stored). Common forms of permanent computer-readable media include, for example, floppy disks, flexible disks, hard disks, magnetic tapes or any other magnetic storage media, CD-ROMs, DVDs or any other optical media, RAMs, PROMs, EPROMs, FLASH-EPROMs or other memory chips or cassettes, or any other permanent media that can be read and used by a computer.

[0225] Alternatively, one or more steps of the method may be implemented in a transient medium, such as a transmissible carrier wave, wherein the control program is present as a data signal using a transmission medium such as acoustic or light waves, such as those generated during radio wave and infrared data communications.

[0226] The example methods may be executed on one or more general purpose computers, special purpose computers, programmed microprocessors or microcontrollers and peripheral integrated circuit components, ASICs or other integrated circuits, digital signal processors, hard-wired electronic or logic circuits such as stand-alone component circuits, programmable logic devices such as PLDs, PLAs, FPGAs, graphics card CPUs (GPUs), or PALs. Typically, a finite state machine can be executed and a finite state machine can be executed. Figure 1 Any device of the flowchart shown can be used to perform one or more steps of the risk stratification method for treatment selection of prostate patients. As will be understood, although the steps of the method can be entirely computer-implemented, in some embodiments one or more steps can be at least partially performed manually.

[0227] The computer program instructions may also be loaded onto a computer, other programmable data processing apparatus or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer-implemented process, whereby the instructions executed on the computer or other programmable apparatus provide a program that performs the functions / behaviors specified herein.

[0228] Although the present invention has been described so far based on the gene expression profile of PDE4D7, which may include expression levels (e.g., values) of PDE4D7, which may be normalized using the values ​​for each gene of a set of reference genes, the gene expression profile may further include expression information from other PDE4D variants. For example, the other PDE4D variants may include one or more of PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D8, and PDE4D9. The diagnostic kit may then additionally comprise at least one primer and / or probe for determining the gene expression profile of each of the other PDE4D variants in a biological sample obtained from a prostate cancer subject. However, it is preferred to use only the gene expression profile of PDE4D7, in particular the expression levels (e.g., values) of PDE4D7 normalized using the values ​​for each gene of a set of reference genes.

[0229] The term "phosphodiesterase 4D1" or "PDE4D1" relates to splice variant 1 of the human phosphodiesterase PDE4D, i.e., the human phosphodiesterase PDE4D1 gene, such as the sequence defined in the NCBI Reference Sequence: NM_001197222.1, in particular the nucleotide sequence set forth in SEQ ID NO: 1, which corresponds to the sequence of the NCBI Reference Sequence for the PDE4D1 transcript, and the corresponding amino acid sequence, such as that set forth in SEQ ID NO: 2, which corresponds to the protein sequence encoding the PDE4D1 polypeptide defined in the NCBI Protein Accession Reference Sequence NP_001184151.1. The term "phosphodiesterase 4D1" or "PDE4D1" also relates to an amplicon that can be generated by the primer pair PDE1D1D2_Forward (SEQ ID NO: 3) and PDE1D1D2_Reverse (SEQ ID NO: 4) and that can be detected by the probe SEQ ID NO: 5.

[0230] The term "phosphodiesterase 4D2" or "PDE4D2" refers to splice variant 2 of human phosphodiesterase PDE4D, i.e., the human phosphodiesterase PDE4D2 gene, such as the sequence defined in the NCBI reference sequence: NM_001197221.1, in particular the nucleotide sequence shown in SEQ ID NO: 6, which corresponds to the sequence of the NCBI reference sequence of the PDE4D2 transcript mentioned above, and also relates to the corresponding amino acid sequence shown in, for example, SEQ ID NO: 7, which corresponds to the protein sequence encoding the PDE4D2 polypeptide defined in the NCBI protein accession reference sequence NP_001184150.1.

[0231] The term "phosphodiesterase 4D3" or "PDE4D3" refers to splice variant 3 of human phosphodiesterase PDE4D, i.e., the human phosphodiesterase PDE4D3 gene, such as the sequence defined in the NCBI reference sequence: NM_006203.4, in particular the nucleotide 0 sequence shown in SEQ ID NO: 8, which corresponds to the sequence of the NCBI reference sequence of the above-mentioned PDE4D3 transcript, and also relates to the corresponding amino acid sequence shown in, for example, SEQ ID NO: 9, which corresponds to the protein sequence encoding the PDE4D3 polypeptide defined in the NCBI protein accession reference sequence NP_006194.2.

[0232] The term "phosphodiesterase 4D4" or "PDE4D4" refers to splice variant 4 of human phosphodiesterase PDE4D, i.e., the human phosphodiesterase PDE4D4 gene, such as the sequence defined in the NCBI reference sequence: NM_001104631.1, in particular the nucleotide sequence shown in SEQ ID NO: 10, which corresponds to the sequence of the NCBI reference sequence of the above-mentioned PDE4D4 transcript, and also relates to the corresponding amino acid sequence shown in, for example, SEQ ID NO: 11, which corresponds to the protein sequence encoding the PDE4D4 polypeptide defined in the NCBI protein accession reference sequence NP_001098101.1.

[0233] The term "phosphodiesterase 4D5" or "PDE4D5" refers to splice variant 5 of the human phosphodiesterase PDE4D, i.e., the human phosphodiesterase PDE4D5 gene, such as the sequence defined in the NCBI Reference Sequence: NM_001197218.1, in particular the nucleotide sequence set forth in SEQ ID NO: 12, which corresponds to the sequence of the NCBI Reference Sequence for the PDE4D5 transcript, and also relates to the corresponding amino acid sequence, such as that set forth in SEQ ID NO: 13, which corresponds to the protein sequence encoding the PDE4D5 polypeptide defined in the NCBI Protein Accession Reference Sequence NP_001184147.1. The term "phosphodiesterase 4D5" or "PDE4D5" also relates to an amplicon that can be generated by the primer pair PDE4D5_Forward (SEQ ID NO: 14) and PDE4D5_Reverse (SEQ ID NO: 15) and that can be detected by the probe SEQ ID NO: 16.

[0234] The term "phosphodiesterase 4D6" or "PDE4D6" refers to splice variant 6 of human phosphodiesterase PDE4D, i.e., the human phosphodiesterase PDE4D6 gene, such as the sequence defined in the NCBI reference sequence: NM_001197223.1, in particular the nucleotide sequence shown in SEQ ID NO: 17, which corresponds to the sequence of the NCBI reference sequence of the above-mentioned PDE4D6 transcript, and also relates to the corresponding amino acid sequence shown in, for example, SEQ ID NO: 18, which corresponds to the protein sequence encoding the PDE4D6 polypeptide defined in the NCBI protein accession reference sequence NP_001184152.1.

[0235] The term "phosphodiesterase 4D8" or "PDE4D8" relates to splice variant 8 of human phosphodiesterase PDE4D, i.e., the human phosphodiesterase PDE4D8 gene, such as the sequence defined in the NCBI reference sequence: NM_001197219.1, in particular the nucleotide sequence shown in SEQ ID NO: 27, which corresponds to the sequence of the NCBI reference sequence of the above-mentioned PDE4D8 transcript, and also relates to the corresponding amino acid sequence shown in, for example, SEQ ID NO: 28, which corresponds to the protein sequence encoding the PDE4D8 polypeptide defined in the NCBI protein accession reference sequence NP_001184148.1.

[0236] The term "phosphodiesterase 4D9" or "PDE4D9" refers to splice variant 9 of the human phosphodiesterase PDE4D, i.e., the human phosphodiesterase PDE4D9 gene, such as the sequence defined in the NCBI Reference Sequence: NM_001197220.1, in particular the nucleotide sequence shown in SEQ ID NO: 29, which corresponds to the sequence of the NCBI Reference Sequence for the PDE4D9 transcript, and also to the corresponding amino acid sequence, such as that shown in SEQ ID NO: 30, which corresponds to the protein sequence encoding the PDE4D9 polypeptide defined in the NCBI Protein Accession Reference Sequence NP_001184149.1. The term "phosphodiesterase 4D9" or "PDE4D9" also refers to an amplicon that can be generated by the primer pair PDE4D9_Forward (SEQ ID NO: 31) and PDE4D9_Reverse (SEQ ID NO: 32) and that can be detected by the probe SEQ ID NO: 33.

[0237] The terms "PDE4D1", "PDE4D2", "PDE4D3", "PDE4D4", "PDE4D5", "PDE4D6", "PDE4D8" and "PDE4D9" also encompass nucleotide sequences that show a high degree of homology to PDE4D1, PDE4D2, PDE4D3, PDE4D4, PDE4D5, PDE4D6, PDE4D8 and PDE4D9, respectively, such as nucleic acid sequences that are at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequences shown in SEQ ID NO: 1, 6, 8, 10, 12, 17, 27 or 29, respectively, or to SEQ ID NO: 2, 3 or 4, respectively. NO:2, 7, 9, 11, 13, 18, 28 or 30 has an amino acid sequence that is at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO:2, 7, 9, 11, 13, 13, 18, 28 or 30, or a nucleic acid sequence that encodes an amino acid sequence that is at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO:2, 7, 9, 11, 13, 13, 18, 28 or 30, or a nucleic acid sequence that encodes an amino acid sequence that is at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the sequence of SEQ ID NO:2, The amino acid sequence encoded by the nucleic acid sequence shown in NO:1, 6, 8, 10, 12, 17, 27 or 29 has at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity.

[0238] Any reference signs in the claims should not be construed as limiting the scope.

[0239] The present invention relates to a method for preoperative risk stratification of prostate cancer subjects, comprising determining a gene expression profile of phosphodiesterase 4D variant 7 (PDE4D7) in a biological sample obtained from the subject, determining a gene expression profile of DExH-box helicase 9 (DHX9) in the same or another biological sample obtained from the subject, and determining a preoperative prognostic risk score for the subject based on the gene expression profile of PDE4D7 and the gene expression profile of DHX9. This can improve the stratification of subjects in the preoperative setting and can lead to better primary treatment decisions. For example, for certain subpopulations of prostate cancer patients, a preoperative prognostic risk score can provide better advice on whether to choose active surveillance or active intervention, such as radical prostatectomy.

[0240] The accompanying sequence listing entitled 2018PF00399_SEQUENCE LISTING_ST25 is incorporated herein by reference in its entirety.

Claims

1. A diagnostic kit comprising: at least one primer and / or probe for determining a gene expression profile of phosphodiesterase 4D variant 7 in a biological sample obtained from a subject with prostate cancer; at least one primer and / or probe for determining the gene expression profile of DExH-box helicase 9 in the same or another biological sample obtained from the subject; and at least one primer and / or probe for determining a gene expression profile of one or more reference genes selected from the group consisting of: Homo sapiens hypoxanthine phosphoribosyltransferase 1, tubulin alpha-1b, Homo sapiens pumilio RNA-binding family member, and Homo sapiens TATA box binding protein; The diagnostic kit further comprises instructions for calculating a preoperative prognostic risk score based on the gene expression profile of phosphodiesterase 4D variant 7 and the gene expression profile of DExH-box helicase 9, wherein the instructions are stored on a computer program product, and when executed by a computer, it performs a method comprising: - determining a preoperative prognostic risk score for the subject based on the gene expression profile of phosphodiesterase 4D variant 7 and the gene expression profile of DExH-box helicase 9, The method comprises: - normalizing the gene expression profile of phosphodiesterase 4D variant 7 and the gene expression profile of DExH-box helicase 9 relative to said one or more reference genes, wherein the preoperative prognostic risk score is determined based on a standardized gene expression profile, and wherein the instructions for calculating the preoperative prognostic risk score comprise instructions for combining the gene expression profile of phosphodiesterase 4D variant 7 and the gene expression profile of DExH-box helicase 9 with a regression function obtained from a group of prostate cancer subjects.

2. The diagnostic kit of claim 1, wherein the normalized gene expression profiles of phosphodiesterase 4D variant 7 and DExH-box helicase 9 are converted into a predetermined value range.

3. The diagnostic kit of claim 2, wherein the conversion function is a linear conversion that converts the normalized gene expression profile to a predetermined range of values.

4. The diagnostic kit of claim 2, wherein the standardized gene expression profile is converted as follows: TNGEP = (((GENE_norm + A)*B)+1), (1) where "TNGEP" is the transformed normalized gene expression profile, "GENE_norm" is the normalized phosphodiesterase 4D variant 7 or DExH-box helicase 9 gene expression profile value, and A and B are variables and are appropriately selected to map "GENE_norm" to the desired value range.

5. Use of at least one primer and / or probe for determining the gene expression profile of phosphodiesterase 4D variant 7 and at least one primer and / or probe for determining the gene expression profile of DExH-box helicase 9 in a biological sample obtained from a prostate cancer subject in the preparation of a kit for preoperative risk stratification of a prostate cancer subject, The kit further comprises at least one primer and / or probe for determining the gene expression profile of one or more reference genes, the reference genes being selected from the group consisting of: Homo sapiens hypoxanthine phosphoribosyltransferase 1, tubulin alpha-1b, Homo sapiens pumilioRNA-binding family member, and Homo sapiens TATA box binding protein, The kit further comprises instructions for calculating a preoperative prognostic risk score based on the gene expression profile of phosphodiesterase 4D variant 7 and the gene expression profile of DExH-box helicase 9, wherein the instructions are stored on a computer program product, and when executed by a computer, it performs a method comprising: - determining a preoperative prognostic risk score for the subject based on the gene expression profile of phosphodiesterase 4D variant 7 and the gene expression profile of DExH-box helicase 9, - normalizing the gene expression profile of phosphodiesterase 4D variant 7 and / or the gene expression profile of DExH-box helicase 9 relative to said one or more reference genes, Wherein the preoperative prognostic risk score is determined based on a standardized gene expression profile.

6. A computer program product comprising instructions which, when executed by a computer, cause the computer to perform a method comprising: - determining a preoperative prognostic risk score for prostate cancer subjects based on the gene expression profile of phosphodiesterase 4D variant 7 and the gene expression profile of DExH-box helicase 9, wherein the gene expression profile of phosphodiesterase 4D variant 7 has been determined in a biological sample obtained from the subject and the gene expression profile of DExH-box helicase 9 has been determined in the same or another biological sample obtained from the subject, wherein the gene expression profile of phosphodiesterase 4D variant 7 and the gene expression profile of DExH-box helicase 9 are combined with a regression function obtained from a group of prostate cancer subjects.

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