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Ataxin-2 as potential disease modifier in C9ORF72 expansion carriers
Marka van Blitterswijk1, Bianca Mullen1, Michael G Heckman2
1Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Neurobiology of Aging
|May 29, 2014
Summary
Intermediate repeat lengths in ATXN2 may modify disease presentation in C9ORF72 expansion carriers, particularly increasing motor neuron disease risk. Other investigated genes showed no significant modifying effects in this cohort.
Area of Science:
- Neurogenetics
- Molecular Neurology
Background:
- Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are a leading genetic cause of motor neuron disease (MND) and frontotemporal dementia (FTD).
- Phenotypic variability among C9ORF72 expansion carriers suggests the influence of genetic modifiers.
- The role of specific genetic factors in modulating C9ORF72-associated neurodegeneration remains incompletely understood.
Purpose of the Study:
- To investigate potential genetic modifiers of C9ORF72 expansion-associated neurodegenerative diseases.
- To assess the role of ataxin-2 (ATXN2), NIPA1, SMN1, and SMN2 genes in modulating disease presentation in C9ORF72 carriers.
Main Methods:
- Genotyping of ATXN2, NIPA1, SMN1, and SMN2 in a cohort of 331 C9ORF72 expansion carriers and 376 control subjects.
- Analysis of intermediate repeat lengths within these candidate modifier genes.
- Comparison of gene frequencies and clinical phenotypes between C9ORF72 carriers and controls.
Main Results:
- Intermediate repeat lengths in ATXN2 were found to be a potential disease modifier in C9ORF72 expansion carriers.
- The frequency of intermediate ATXN2 repeats was significantly higher in probands with MND or FTD/MND compared to controls (2.1% vs. 0%, p=0.013).
- No evidence supported a modifying role for NIPA1, SMN1, or SMN2 in this cohort.
Conclusions:
- Intermediate ATXN2 repeat lengths may increase susceptibility to motor neuron disease in individuals with C9ORF72 repeat expansions.
- The findings suggest ATXN2 as a potential genetic modifier contributing to phenotypic heterogeneity in C9ORF72-related disorders.
- Further research is warranted to validate the role of ATXN2 in C9ORF72 expansion carriers.
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