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Neurofibromin/dopamine signaling as a biomarker for cognitive and behavioral problems in children with neurofibromatosis type 1 (NF1)

a neurofibromatosis and neurofibromatosis technology, applied in the field of neurofibromatosis type 1, can solve the problems of deficits in visual perception or response inhibition, lack of predictive markers to identify individuals, and difficulty in identifying individuals

Inactive Publication Date: 2016-12-22
WASHINGTON UNIV IN SAINT LOUIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present patent text is directed to methods for detecting behavioral disorders, cognitive impairment, and altered brain neurofibromin-dependent dopaminergic signaling in individuals with neurofibromatosis type-1 (NF1). These methods involve measuring the expression level of neurofibromin in a sample obtained from the individual and comparing it to a reference level of neurofibromin from a healthy subject. If there is a difference between the two, it indicates a memory defect or a cognitive impairment in the individual. The invention helps in early diagnosis and timely treatment of neurofibromatosis type-1, which can improve the overall quality of life of individuals with the disorder.

Problems solved by technology

Some children with NF1 can have problems with reading or mathematic achievement, while others exhibit deficits in visual perception or response inhibition.
A challenge to the management of children with NF1 is the lack of predictive markers to identify individuals with a risk for specific morbidities.
Cognitive problems in neurological disorders can be difficult to identify, especially in non-verbal or young children.

Method used

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  • Neurofibromin/dopamine signaling as a biomarker for cognitive and behavioral problems in children with neurofibromatosis type 1 (NF1)
  • Neurofibromin/dopamine signaling as a biomarker for cognitive and behavioral problems in children with neurofibromatosis type 1 (NF1)
  • Neurofibromin/dopamine signaling as a biomarker for cognitive and behavioral problems in children with neurofibromatosis type 1 (NF1)

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0076]In this Example, the effect of specific Nf1 germline mutations on optic glioma formation was analyzed.

[0077]C57 / B16 mice that harbor germline point mutations in exons 21 (sp21) and 18 (st18) were generated. Employing the GFAP-Cre driver line, we generated two new conditional knockout (CKO) mice that have a single germline mutation in all cells and an additional somatic inactivating mutation in neuroglial cells: 2542G>C (exon 21; Nf1 flox / 21 GFAP-Cre; F21C) and 2041C>T (exon 18; Nf1 flox / 18 GFAP-Cre; F18C) (FIG. 1A). Direct volume measurements of optic nerves revealed a 43% increase in optic nerve volumes of F18C mice, similar to Nf1flox / − GFAP-Cre (FMC; Bajenaru et al, 2003 PMID: 14695164) mice (48% increase), whereas there was no significant increase in optic nerve volume of F21C mice compared to FF controls (FIG. 1B). Additionally, hematoxylin and eosin staining revealed hypercellularity (1.6 fold increase in cell number), mitotic figures and atypical cells in F18C optic ner...

example 2

[0080]In this Example, the effect of Nf1 germline mutation on microglial infiltration and signaling was analyzed.

[0081]Non-neoplastic cells in the optic glioma microenvironment, such as Nf1+ / − microglia, contribute to tumor formation, growth and maintenance by promoting astrocyte proliferation. In accordance with these findings, an increase in F18C optic nerve microglia (97%±7) was found, but not in F21C optic nerves compared to FMC mice (FIG. 1D) indicating that the specific Nf1 germline mutation contributes to microglia activation and infiltration. Since inactivation of the second Nf1 allele promoted higher proliferation in all astrocyte cultures irrespective if the Nf1 germline mutation (FIG. 6), whether optic nerve tumor formation in FMC and F18C mice is dependent on microglial infiltration and activation rather than astrocyte proliferation was analyzed. Previous studies have revealed that JNK pathway activation (phospho JNK) in microglia is critical for optic nerve formation an...

example 3

[0083]In this Example, the dependence of Nf1 germline mutation on Neurofibromin expression levels were analyzed.

[0084]Similarly to microglia, neurons are highly sensitive to Nf1 germline mutation. As such, NF1 germline mutation impacts neuronal signaling both in human NPCs and mouse hippocampal neurons. To determine the effect of specific Nf1 germline mutations on mouse neurons, neurofibromin expression levels were assayed in hippocampi of Nf1+ / sp21, Nf1+ / − and Nf1+ / st18 animals (FIG. 3A). Western blotting revealed that neurofibromin expression was decreased by 39% in Nf1+ / −sp21, 50% in Nf1+ / − and 76% in Nf1+ / st18 hippocampi.

[0085]To further assess whether the specific germline mutation differentially impacted neurofibromin GAP activity in the three Nf1 models RAS activity (RAS-GTP) in adult mouse hippocampi were assayed. RAS activity was increased by 1.8-fold in Nf1+ / sp21, 1.7-fold in Nf1+ / − and 1.7-fold in Nf1+ / st18 hippocampi (FIG. 3B). Since RAS negatively regulates cAMP in Nf1-...

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Abstract

The present disclosure is generally related to neurofibromatosis type 1. More particularly, disclosed herein are methods for detecting behavioral disorders, methods for detecting cognitive impairment, and methods for detecting brain neurofibromin-dependent dopaminergic signaling associated with neurofibromatosis type 1.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 62 / 181,949, filed on Jun. 19, 2015, the disclosure of which is incorporated by reference in its entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]This invention was made with government support under 5-T32-EY13360, 5-T32-NS007205-33, and 1R01-CA195692-01 awarded by The National Institutes of Health. The Government has certain rights in the invention.INCORPORATION OF SEQUENCE LISTING[0003]A paper copy of the Sequence Listing and a computer readable form of the Sequence Listing containing the file named “WUSTL015422_ST25.txt”, which is 82,262 bytes in size (as measured in MICROSOFT WINDOWS® EXPLORER), are provided herein and are herein incorporated by reference. This Sequence Listing consists of SEQ ID NO:1-4.BACKGROUND OF THE DISCLOSURE[0004]The present disclosure relates generally to neurofibromatosis type 1. More particularly, the present dis...

Claims

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Application Information

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IPC IPC(8): G01N33/68C12Q1/68
CPCG01N33/6893C12Q1/6883G01N2800/30G01N2440/14C12Q2600/158G01N2333/4704C12Q2600/156
Inventor GUTMANN, DAVID H.ANASTASAKI, CORINA
Owner WASHINGTON UNIV IN SAINT LOUIS
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