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

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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.

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Acknowledgements

The authors thank all the subjects who agreed to participate in this study.

Funding

This study was supported by Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE-HCPA), grant number 18–0294. ACM, MLSP, and LBJ were supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Ana Carolina Martins, Maria Luiza Saraiva-Pereira & Laura Bannach Jardim

  2. Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

    Ana Carolina Martins, Mariana Rieck, Maria Luiza Saraiva-Pereira & Laura Bannach Jardim

  3. Departamento de Estatística, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Vanessa Bielefeldt Leotti

  4. Programa de Pós-Graduação em Epidemiologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Vanessa Bielefeldt Leotti

  5. Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Porto Alegre, 90035-003, Brazil

    Maria Luiza Saraiva-Pereira & Laura Bannach Jardim

  6. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Maria Luiza Saraiva-Pereira

  7. Departamento de Medicina Interna, FAMED, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Laura Bannach Jardim

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  1. Ana Carolina Martins
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  2. Mariana Rieck
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  3. Vanessa Bielefeldt Leotti
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  4. Maria Luiza Saraiva-Pereira
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  5. Laura Bannach Jardim
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Contributions

ACM, MR, and LBJ contributed to the conception and design of the study; ACM, MR, VBL, MLSP, and LBJ contributed to the acquisition and analysis of data; ACM, MR, VBL, MLSP, and LBJ contributed to the drafting of the text and preparing the figures.

Corresponding author

Correspondence to Laura Bannach Jardim.

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Ethics Approval

The study was approved by the Institutional Ethics Committee (Comissão de Ética em Pesquisa do Hospital de Clínicas de Porto Alegre) by the number CAAE 81,431,517,100,005,327, GPPG 2018–0294.

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Consent to participate was obtained from subjects or from the family of dead patients.

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The authors declare no competing interests.

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Martins, A.C., Rieck, M., Leotti, V.B. et al. Variants in Genes of Calpain System as Modifiers of Spinocerebellar Ataxia Type 3 Phenotype. J Mol Neurosci 71, 1906–1913 (2021). https://doi.org/10.1007/s12031-021-01877-9

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