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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.
Mergener, Rafaella; Furtado, Gabriel Vasata; de Mattos, Eduardo Preusser; Leotti, Vanessa Bielefeldt; Jardim, Laura Bannach; Saraiva-Pereira, Maria Luiza.
Affiliation
  • Mergener R; Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
  • Furtado GV; Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  • de Mattos EP; Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
  • Leotti VB; Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  • Jardim LB; Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
  • Saraiva-Pereira ML; Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
Neuromolecular Med ; 22(1): 133-138, 2020 03.
Article in En | MEDLINE | ID: mdl-31587151
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.
Subject(s)
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Repressor Proteins / Machado-Joseph Disease / Age of Onset / Polymorphism, Single Nucleotide / DNA Repair / Endodeoxyribonucleases / Exodeoxyribonucleases / Multifunctional Enzymes / Ataxin-3 / Ataxin-2 Limits: Adolescent / Adult / Child / Child, preschool / Female / Humans / Male / Middle aged Language: En Journal: Neuromolecular Med Journal subject: BIOLOGIA MOLECULAR / NEUROLOGIA Year: 2020 Document type: Article Affiliation country: Brazil Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Repressor Proteins / Machado-Joseph Disease / Age of Onset / Polymorphism, Single Nucleotide / DNA Repair / Endodeoxyribonucleases / Exodeoxyribonucleases / Multifunctional Enzymes / Ataxin-3 / Ataxin-2 Limits: Adolescent / Adult / Child / Child, preschool / Female / Humans / Male / Middle aged Language: En Journal: Neuromolecular Med Journal subject: BIOLOGIA MOLECULAR / NEUROLOGIA Year: 2020 Document type: Article Affiliation country: Brazil Country of publication: United States