Publication

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

Mergener, R., Furtado, G. V., de Mattos, E. P., Leotti, V. B., Jardim, L. B. & Saraiva-Pereira, M. L., 5-Oct-2019, In : Neuromolecular medicine. 6 p.

Research output: Contribution to journalArticleAcademicpeer-review

Copy link to clipboard

Documents

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

    Final publisher's version, 778 KB, PDF document

    Request copy

DOI

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.

Original languageEnglish
Number of pages6
JournalNeuromolecular medicine
Publication statusE-pub ahead of print - 5-Oct-2019
Externally publishedYes

ID: 99094379