Association of Long ATXN2 CAG Repeat Sizes With Increased Risk of Amyotrophic Lateral Sclerosis

Centre for Excellence in Neuromics, CHUM Research Center, Université de Montréal, 2099 Alexandre De-Seve St, Montreal, QC H2L 2W5, Canada.
Archives of neurology (Impact Factor: 7.01). 06/2011; 68(6):739-42. DOI: 10.1001/archneurol.2011.111
Source: PubMed

ABSTRACT To analyze the ataxin 2 (ATXN2) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG)(n) alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS.
Case-control study.
France and Quebec, Canada.
A total of 556 case patients with ALS and 471 healthy controls; both groups of participants are of French or French-Canadian origin.
We observed a significant association between ATXN2 high-length alleles (≥29 CAG repeats) and ALS in French and French-Canadian ALS populations. Furthermore, we identified spinocerebellar ataxia type 2-pathogenic polyglutamine expansions (≥32 CAG repeats) in both familial and sporadic ALS cases.
Altogether, our findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS.

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Available from: Veronique V Belzil, Nov 11, 2014
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    • "Single-nucleotide polymorphisms (SNPs) have an important function in the development of neurodegenerative disorders (Ramanan and Saykin, 2013). For example, polymorphisms in the promoter Rep1 of alpha-synuclein (SNCA), polyglutamine repeats in ATXN2, and Val343Ala in coenzyme Q2 4-hydroxybenzoate polyprenyltransferase increase the risk for PD (Mata et al., 2010), ALS (Daoud et al., 2011), and MSA (Collaboration, 2013), respectively. SNCA, which is encoded by the SNCA gene, is the major component of Lewy bodies and neurites, which are the pathologic hallmarks of PD (Mollenhauer et al., 2011). "
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    Neurobiology of Aging 07/2014; 35(12). DOI:10.1016/j.neurobiolaging.2014.07.014 · 4.85 Impact Factor
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    • "Further, an increase in ataxin-2 polyglutamine length is a risk factor for ALS demonstrating the clinical relevance of these findings [Elden et al., 2010; Daoud et al., 2011]. "
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    ABSTRACT: Mutations in the TAR DNA Binding Protein gene (TARDBP), encoding the protein TDP-43, were identified in amyotrophic lateral sclerosis (ALS) patients. Interestingly, TDP-43 positive inclusion bodies were first discovered in ubiquitin-positive, tau negative ALS and frontotemporal dementia (FTD) inclusion bodies, and subsequently observed in the majority of neurodegenerative disorders. To date, 47 missense and one truncating mutations have been described in a large number of familial (FALS) and sporadic (SALS) patients. Fused in Sarcoma (FUS) was found to be responsible for a previously identified ALS6 locus, being mutated in both FALS and SALS patients. TARDBP and FUS have a structural and functional similarity and most of mutations in both genes are also clustered in the C-terminus of the proteins. The molecular mechanisms through which mutant TDP-43 and FUS may cause motor neuron degeneration are not well understood. Both proteins play an important role in mRNA transport, axonal maintenance and motor neuron development. Functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs. This report summarizes the biological and clinical relevance of TARDBP and FUS mutations in ALS. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database(LOVD) and is accessible online at,
    Human Mutation 06/2013; 34(6). DOI:10.1002/humu.22319 · 5.05 Impact Factor
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    • "A trinucleotide repeat in ATXN2 exon 1, which codes for a polyglutamine (polyQ) domain, was found to expand from usually 22 U to 32 or more CAG units and thus cause this multisystem atrophy of the central nervous system through a gain-of-function mechanism (Auburger 2011). Intermediate and large expansions of 27–37 trinucleotide units, usually CAG repeats with CAA interruptions, were recently shown to contribute to the risk of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of the Parkinson plus syndrome Progressive Supranuclear Palsy (PSP) (Elden et al. 2010; Chen et al. 2011; Daoud et al. 2011; Gispert et al. 2011; Lee et al. 2011a, b; Ross et al. 2011; Soraru et al. 2011; Van Damme et al. 2011). In animal models, overexpression of ATXN2 potentiates toxicity from neurodegenerative disease proteins ATXN1, ATXN3, TDP-43, and MAPT, which are responsible for different variants of spinocerebellar ataxia, ALS, frontotemporal dementia, and PSP (Shulman and Feany 2003; Al-Ramahi et al. 2007; Lessing and Bonini 2008; Elden et al. 2010). "
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