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Rare neurodegenerative disease genetic screening kit, application and screening system

A technology of neurodegenerative diseases and kits, applied in the field of genetic screening

Pending Publication Date: 2022-05-27
WUHAN CHILDRENS HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are no reports of ADPRS gene mutations in rare neurodegenerative diseases

Method used

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  • Rare neurodegenerative disease genetic screening kit, application and screening system
  • Rare neurodegenerative disease genetic screening kit, application and screening system
  • Rare neurodegenerative disease genetic screening kit, application and screening system

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Example 1 WES results of cerebellar ataxia-related ADPRS gene in patients

[0053] Genomic DNA in peripheral blood samples was extracted by "QIAamp Blood Genomic DNA Extraction Kit (CatNo. / ID:51104)", and the concentration and purity of DNA were detected by NanoDrop2000. The DNA was fragmented to a length range of 150-300 bp using a Covaris M220 DNA sonicator. The fragmented DNA is subjected to end repair and A reaction, and then amplified after ligation of adapters. The amplified library was subjected to targeted capture using the xGen Exome Research Panel v1.0 kit (IDT). PE150 sequencing was performed using an IlluminaNovaseq 6000 with the following results:

[0054] Whole exome sequencing (WES) results showed that the patient's ADPRS gene contained two compound heterozygous variants c.580C>T (p.Gln194Ter) and c.803-1G>A in the ADPRS gene (first reported in 2018). ).

[0055] c.580C>T(p.Gln194Ter) analysis: the father of the child is wild type, while his mother ca...

Embodiment 2

[0058] Example 2 RNA-Seq results of ADPRS gene related to cerebellar ataxia in children

[0059] RNA-Seq analysis was performed on the patient's ADPRS gene (mutant type) in the above Example 1, and the results of c.580C>T (p.Gln194Ter) were shown in image 3 -4, see c.803-1G>A result Figure 5 -6.

[0060] Depend on image 3 It can be seen: c.580C>T (p.Gln194Ter) is a frameshift deletion variant, the 580th nucleotide C is replaced by T, therefore, the 194th amino acid glutamine (Gln) is converted into a stop codon, Final translation process terminated early. The mutation of c.580C>T (p.Gln194Ter) leads to the early appearance of stop codons, partial amino acid deletion, and incomplete structure of the encoded protein, which eventually leads to the reduction or loss of ADP-ribosyl hydrolase activity, which cannot eliminate excess PAR accumulation.

[0061] It can be seen from Figure 4: After RNA-Seq analysis, we analyzed the c.580C>T (p.Gln194Ter) variation at the trans pos...

Embodiment 3

[0064] Example 3 Evaluation of the conservation of residues in ADPRS gene after mutation (c.580C>T (p.Gln194Ter) and c.803-1G>A mutant)

[0065] ConSurf was used to evaluate the conservation of ADPRS gene residues, and the UCSC genome browser was used to detect the conserved nature of this region. The results are shown in Figure 7. The three-dimensional protein structures constructed using the wild-type and mutant SWISS models are as follows: Figure 8 shown.

[0066] It can be seen from Fig. 7 that Gln at position 194 is highly conserved, indicating that the C base is highly conserved in primates.

[0067] Depend on Figure 8 It can be seen that the three-dimensional structure of the ADPRS-encoded protein constructed by the SWISS model is as follows: Figure 8 As shown in A, the three-dimensional structure of the remaining part after amino acid deletion is as follows Figure 8 shown in B. According to the modeling results, glutamine 194 (based on a classical template (PDB...

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Abstract

The invention discloses a genetic screening kit for rare neurodegenerative diseases, application of the genetic screening kit and a screening system. The genetic screening kit for the rare neurodegenerative diseases contains a mutation site screening reagent at the c.580 and / or c.803-1 position of the ADPRS gene. The compound is applied to preparation of a neurodegenerative disease screening reagent, and is preferably applied to preparation of a hereditary child epilepsy cerebellar ataxia screening reagent. The screening system comprises a gene sequence acquisition module and a judgment module, the gene sequence acquisition module is used for acquiring data of single nucleotide polymorphism containing ADPRS alleles c.580 and c.803-1; the judging module is used for judging whether the ADPRS gene contains the composite heterozygous variation c.580Cgt or not; t, and / or c.803-1 Ggt; and judging the genetic risk of the hereditary child epilepsy cerebellar ataxia disease according to the A variation. It is proved that the complex heterozygote is c.580Cgt; t and c.803-1 Ggt; the ADPRS gene variant of A causes a rare neurodegenerative disease, which indicates that the screening reagent provided by the invention has screening significance on the disease.

Description

technical field [0001] The invention belongs to the technical field of genetic screening, and more particularly, relates to a genetic screening kit for rare neurodegenerative diseases, its application and a screening system. Background technique [0002] Stress-induced childhood neurodegeneration with ataxia and epilepsy (OMIM code: 618170) is an autosomal recessive disorder. Patients usually develop disease before the age of 1 year and in childhood. The main clinical phenotypes of the disease have been reported to be neurodegeneration, epilepsy, nystagmus, ophthalmoplegia, strabismus, ptosis, atrophy of the lingual fasciculus, muscle fiber size, retrograde development, ataxia, joint disorders, Tremor, joint disorders, cerebellar and spinal cord atrophy, autism, and deafness in some patients. [0003] ADP-ribosylation is an important post-translational modification that is involved in several important physiological and pathological processes, such as DNA repair, transcrip...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6883G16B20/20G16B20/40G16B20/50G16B30/10
CPCC12Q1/6883G16B20/20G16B20/40G16B20/50G16B30/10C12Q2600/156
Inventor 孙丹
Owner WUHAN CHILDRENS HOSPITAL
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