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.
Neuromolecular Med. 2020 Mar;22(1):133-138. doi: 10.1007/s12017-019-08572-4. Epub 2019 Oct 5.
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.
脊髓小脑性共济失调 3 型，又称 Machado-Joseph 病（SCA3/MJD），是由 CAG 重复扩展引起的，其与症状发病年龄（AO）呈负相关。然而，平均而言，AO 的变化只有 55.2%可以用扩展长度来解释。其他调节剂，如 ATXN2 基因中的多态性 CAG 片段，可以将 AO 的变化提高到 63.0%。先前已经表明，FAN1 基因中的序列变异（rs3512）与亨廷顿病和与共济失调相关的多聚谷氨酰胺病的晚发性 AO 有关。在本研究中，对来自巴西南部的 SCA3/MJD 患者队列进行了 rs3512 基因型频率的研究，并将这些数据与 AO 相关联。与携带相同 ATXN3 基因 CAGexp 长度和其他基因型（C/G 和 C/C）的个体相比，携带 G/G 基因型的个体的疾病发病年龄提前了 2.44 年。将 rs3512 基因型数据与 ATXN2 中的 CAG 片段数据放在一起，G/G 基因型患者的 AO 提前了 2.58 年，而携带短 ATXN2 等位基因的患者则延迟了 4.25 年。这里提供的数据进一步说明了除了致病突变之外，其他因素对 SCA3/MJD 的 AO 贡献。因此，众所周知的调节剂可以帮助揭示新的调节剂，并且总体上可以更好地阐明疾病发作背后的机制。
