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Variation in DNA Repair System Gene as an Additional Modifier of Age at Onset in Spinocerebellar Ataxia Type 3/Machado–Joseph Disease


Spinocerebellar ataxia type 3, or Machado–Joseph disease (SCA3/MJD), is caused by an expansion of CAG repeats, which is inversely correlated to age at onset (AO) of symptoms. However, on average, just 55.2% of variation in AO can be explained by expansion length. Additional modulators, such as polymorphic CAG tract in ATXN2 gene, can raise to 63.0% of the variation in AO. A sequence variation (rs3512) in FAN1 gene has previously been shown to be associated with late AO in Huntington’s disease and polyglutaminopathies associated to ataxia. In the present study, genotype frequency of rs3512 was demonstrated in a cohort of SCA3/MJD patients from South Brazil, and these data were correlated to AO. The disease started 2.44 years earlier in subjects with the G/G genotype when compared to those subjects carrying the same CAGexp length at the ATXN3 gene and other genotypes (C/G and C/C) at rs3512. Placing together data on rs3512 genotype with data on CAG tract in ATXN2, AO of patients with G/G genotype was 2.58 years earlier, and a delay of 4.25 years was observed in patients that carry a short ATXN2 allele. Data presented here add further insights on the contribution of other factors in AO of SCA3/MJD beyond the causal mutation. Thus, well-known modifiers can help to unveil new ones and, as a whole, to better elucidate the mechanisms behind disease onset.

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The authors thank the individuals who agreed to participate in this study. This work was supported by the following Brazilian agencies: Coordenação de aperfeiçoamento de pessoal de Nível superior (CAPES), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Grant Nos. 142057/2013-4 and 313132/2018-6), and Fundo de Incentivo à Pesquisa do Hospital de Clínicas de Porto Alegre (FIPE/HCPA) (Grant No. 20080395).

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Correspondence to Maria Luiza Saraiva-Pereira.

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The study was performed as per the revised Helsinki declaration following approval of ethics committee of the hospital from where samples were collected.

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Mergener, R., Furtado, G.V., de Mattos, E.P. et al. Variation in DNA Repair System Gene as an Additional Modifier of Age at Onset in Spinocerebellar Ataxia Type 3/Machado–Joseph Disease. Neuromol Med 22, 133–138 (2020). https://doi.org/10.1007/s12017-019-08572-4

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  • Spinocerebellar ataxia type 3
  • Machado–Joseph disease
  • PolyQ
  • Genetic modifiers
  • FAN1 gene
  • rs3512