Abstract
Machado-Joseph disease (MJD) is an inherited neurodegenerative disease caused by an expanded CAG repeat in the ATXN3 gene. Although the principal genetic determinant of the age at onset (AAO) is the length of the expanded CAG repeat, the additional genetic contribution of MJD toward the AAO has mostly not yet been clarified. It was recently suggested in two independent studies that apolipoprotein E (APOE) might be associated with AAO variability in MJD patients. To identify the potential modifier effect of APOE polymorphisms on the AAO of MJD patients, 403 patients with MJD (confirmed by molecular tests) from eastern and southeastern China were enrolled in the present study. CAG repeats in the ATXN3 and APOE polymorphisms were genotyped. Data were analyzed using a statistical package. No contribution of APOE polymorphisms to the variance in disease onset was observed using ANCOVA (F = 0.183, P = 0.947). However, significant effects on the AAO of MJD were found for the normal ATXN3 allele and for the interaction of mutant and normal ATXN3 alleles in a multiple linear regression model (P = 0.043 and P = 0.035, respectively). Our study does not support a role for APOE as a genetic modifier of the AAO of MJD. Additionally, our study presents evidence that the normal ATXN3 allele and its interaction with mutant alleles contribute toward AAO variance in MJD patients.
Highlights
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia associated with marked phenotypic heterogeneity [1]
MJD is caused by a CAG repeat expansion in exon 10 of the ATXN3 gene that translates to an elongated polyglutamine tract in the ataxin-3 protein [3]
Patients carrying different apolipoprotein E (APOE) genotypes showed no differences in the age at onset (AAO) adjusted for the expanded ATXN3 allele (ANCOVA, F = 0.18, p = 0.9474)
Summary
Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder characterized by cerebellar ataxia associated with marked phenotypic heterogeneity [1]. MJD is caused by a CAG repeat expansion in exon 10 of the ATXN3 gene that translates to an elongated polyglutamine tract in the ataxin-3 protein [3]. Similar to several other polyglutamine disorders, the AAO for MJD patients is not completely determined by the expanded CAG repeat. Previous studies have demonstrated that the length of the mutant CAG repeat explains approximately 45–87% of the total AAO variance of MJD [4,5,6]. Familial factors are responsible for some of the residual variance [5,7], indicating that modifier genes may play a role in the AAO variance. The identification and characterization of these modifiers offer an important opportunity to better understand the biological mechanisms involved in the disease, improving consultation services for pre-symptomatic individuals
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