Calpain-mediated proteolysis has been proposed to modulate the pathogenesis of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), a disorder due to a CAG repeat expansion (CAGexp) at ATXN3. We aimed to investigate if single-nucleotide polymorphisms (SNPs) at calpain gene CAPN2 and at calpastatin gene CAST modulate the age at onset (AO) and disease progression in SCA3/MJD. A total of 287 SCA3/MJD symptomatic subjects (151 families) were included. AO was analyzed and controlled by the CAG repeat length of expanded allele and family. Candidate polymorphisms were chosen based on the literature and on a priori criteria. The CAG repeat length and SNPs were genotyped according to standard methods. AO of carriers of AA and AG + GG^rs1559085 genotypes in CAST and with the median value of 75 repeats at the expanded allele were 34.23 (33.07–35.38) and 36.42 years (34.50–38.34), respectively (p = 0.049, mixed model treating the expanded CAG repeat size as fixed effect and family as random effect). Carriers of haplotype C^rs27852/G^rs1559085 had mean AO of 37.23 (12.76) and 33.42 years (12.20) (p = 0.047, Student’s t test). Our data suggest an association between allele G^rs1559085 and haplotype C^rs27852/G^rs1559085 at CAST and variations in the AO of SCA3/MJD subjects, independent from the effects of the CAGexp and family. The present results support the potential role of calpain cleavage pathway over modulation of SCA3/MJD phenotype.

钙蛋白酶介导的蛋白水解已被提议调节脊髓小脑共济失调 3 型的发病机制，也称为 Machado-Joseph 病 (SCA3/MJD)，这是一种由于 ATXN3 处的 CAG 重复扩增 (CAGexp)引起的疾病。我们旨在研究钙蛋白酶基因CAPN2和钙蛋白酶抑制剂基因CAST的单核苷酸多态性 (SNP) 是否调节 SCA3/MJD 的发病年龄 (AO) 和疾病进展。共纳入 287 名 SCA3/MJD 症状受试者（151 个家庭）。AO通过扩展等位基因和家族的CAG重复长度进行分析和控制。基于文献和先验标准选择候选多态性。根据标准方法对 CAG 重复长度和 SNP 进行基因分型。AA 和 AG + GG 携带者的 AOCAST中的^rs1559085基因型和扩展等位基因中 75 个重复的中值分别为 34.23（33.07-35.38）和 36.42 年（34.50-38.34）（p = 0.049，混合模型将扩展的 CAG 重复大小视为固定效应和家庭作为随机效应）。单倍型 C ^rs27852 /G ^rs1559085的携带者的平均 AO 为 37.23 (12.76) 和 33.42 年 (12.20)（p = 0.047，学生 t 检验）。我们的数据表明等位基因 G ^rs1559085与CAST单倍型 C ^rs27852 /G ^rs1559085之间存在关联SCA3/MJD 受试者的 AO 和变化，独立于 CAGexp 和家庭的影响。目前的结果支持钙蛋白酶裂解途径对调节 SCA3/MJD 表型的潜在作用。