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Spinocerebellar ataxia type 3 (SCA3), also called Machado-Joseph disease (MJD), is one of the most common SCAs worldwide and caused by a CAG repeat expansion located in ATXN3 gene. Based on the CAG repeat numbers, alleles of ATXN3 can be divided into normal alleles (ANs), intermediate alleles (AIs) and expanded alleles (AEs). It was controversial whether the frequency of large normal alleles (large ANs) is related to the prevalence of SCA3 or not. And there were huge chaos in the comprehension of the specific numbers of the range of CAG repeats which is fundamental for genetic analysis of SCA3. To illustrate these issues, we made a novel CAG repeat ladder to detect CAG repeats of ATXN3 in 1003 unrelated Chinese normal individuals and studied haplotypes defined by three single nucleotide polymorphisms (SNPs) closed to ATXN3. We found that the number of CAG repeats ranged from 13 to 49, among them, 14 was the most common number. Positive skew, the highest frequency of large ANs and 4 AIs which had never been reported before were found. Also, AEs and large ANs shared the same haplotypes defined by the SNPs. Based on these data and other related studies, we presumed that de novo mutations of ATXN3 emerging from large ANs are at least one survival mechanisms of mutational ATXN3 and we can redefine the range of CAG repeats as: ANs≤44, 45 ≤AIs ≤49 and AEs≥50.

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.