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Variants in Genes of Calpain System as Modifiers of Spinocerebellar Ataxia Type 3 Phenotype.

Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. Departamento de Estatística, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Programa de Pós-Graduação em Epidemiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Porto Alegre, 90035-003, Brazil. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. ljardim@hcpa.edu.br. Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. ljardim@hcpa.edu.br. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Porto Alegre, 90035-003, Brazil. ljardim@hcpa.edu.br. Departamento de Medicina Interna, FAMED, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. ljardim@hcpa.edu.br.

Journal of molecular neuroscience : MN. 2021;(9):1906-1913
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Abstract

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 + GGrs1559085 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 Crs27852/Grs1559085 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 Grs1559085 and haplotype Crs27852/Grs1559085 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.