Normal ATXN3 Allele but Not CHIP Polymorphisms Modulates Age at Onset in Machado–Joseph Disease

Marcondes C França,Laura Bannach Jardim,Anelyssa D’Abreu,Rodrigo Secolin,Cláudia V Maurer-Morelli,Vanessa E Emmel,Maria Luiza Saraiva-Pereira,Anamarli Nucci,Wilson Marques,Luciana Cardoso Bonadia,Marilza Santos Da Silva,Iscia Lopes-Cendes,Henry Paulson

doi:10.3389/fneur.2012.00164

Abstract

Background: Age at onset (AO) in Machado–Joseph disease (MJD) is closely associated with the length of the CAG repeat at the mutant ATXN3 allele, but there are other intervening factors. Experimental evidence indicates that the normal ATXN3 allele and the C-terminal heat shock protein 70 (Hsp70)-interacting protein (CHIP) may be genetic modifiers of AO in MJD. Methods: To investigate this hypothesis, we determined the length of normal and expanded CAG repeats at the ATXN3 gene in 210 unrelated patients with MJD. In addition, we genotyped five single nucleotide polymorphisms (SNPs) within the CHIP gene. We first compared the frequencies of the different genotypes in two subgroups of patients who were highly discordant for AO after correction for the length of the expanded CAG allele. The possible modifier effect of each gene was then evaluated in a stepwise multiple linear regression model. Results: AO was associated with the length of the expanded CAG allele (r2 = 0.596, p < 0.001). Frequencies of the normal CAG repeats at the ATXN3 gene and of CHIP polymorphisms did not differ significantly between groups with highly discordant ages at onset. However, addition of the normal allele improved the model fit for prediction of AO (r2 = 0.604, p = 0.014). Indeed, we found that the normal CAG allele at ATXN3 had a positive independent effect on AO. Conclusion: The normal CAG repeat at the ATXN3 gene has a small but significant influence on AO of MJD.

Highlights

Machado–Joseph disease [MJD, named spinocerebellar ataxia (SCA) type 3 (SCA3)], is the most common autosomal dominant SCA worldwide (Schols et al, 2004)
Our results confirm the close association of at onset (AO) and length of ATXN3 (CAG) expansion in MJD, which is evident among patients with large expansions
Much of the AO variance cannot be explained by the (CAG) repeat expansion in the ATXN3 gene, and other intervening factors, either environmental or genetic, must contribute

Summary

Introduction

Machado–Joseph disease [MJD, named spinocerebellar ataxia (SCA) type 3 (SCA3)], is the most common autosomal dominant SCA worldwide (Schols et al, 2004) It is caused by an unstable trinucleotide (CAG) repeat expansion in exon 10 of the ATXN3 gene, which leads to an elongated polyglutamine (PolyQ) tract in the encoded protein, ataxin-3 (ATXN3; Kawaguchi et al, 1994). In other polyQ disorders, some modifier loci and genes have already been identified (Rubinsztein et al, 1997; Hayes et al, 2000; Pulst et al, 2005; Metzger et al, 2008) This motivated us to investigate two possible genetic modifiers of AO in a large sample of unrelated Brazilian patients with MJD, C-terminal heat shock protein 70 (Hsp70)interacting protein (CHIP), and the normal ATXN3 allele. Conclusion: The normal CAG repeat at the ATXN3 gene has a small but significant influence on AO of MJD

Methods

Results

Conclusion