Ancestral Origin of the ATTCT Repeat Expansion in Spinocerebellar Ataxia Type 10 (SCA10)

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disease characterized by cerebellar ataxia and seizures. The disease is caused by a large ATTCT repeat expansion in the ATXN10 gene. The first families reported with SCA10 were of Mexican origin, but the disease was soon after described in Brazilian families of mixed Portuguese and Amerindian ancestry. The origin of the SCA10 expansion and a possible founder effect that would account for its geographical distribution have been the source of speculation over the last years. To unravel the mutational origin and spread of the SCA10 expansion, we performed an extensive haplotype study, using closely linked STR markers and intragenic SNPs, in families from Brazil and Mexico. Our results showed (1) a shared disease haplotype for all Brazilian and one of the Mexican families, and (2) closely-related haplotypes for the additional SCA10 Mexican families; (3) little or null genetic distance in small normal alleles of different repeat sizes, from the same SNP lineage, indicating that they are being originated by a single step mechanism; and (4) a shared haplotype for pure and interrupted expanded alleles, pointing to a gene conversion model for its generation. In conclusion, we show evidence for an ancestral common origin for SCA10 in Latin America, which might have arisen in an ancestral Amerindian population and later have been spread into the mixed populations of Mexico and Brazil.

10型脊髓小脑共济失调（Spinocerebellar ataxia type 10, SCA10）是一种常染色体显性神经退行性疾病，以小脑共济失调与癫痫发作为核心临床特征。该病由ATXN10基因（ATXN10 gene）内大片段ATTCT重复扩增引发。首批被报道的SCA10家系源自墨西哥人群，但此后不久，在葡萄牙裔与美洲原住民混血的巴西家系中也发现了该疾病。多年来，关于SCA10扩增的起源以及可解释其地理分布的潜在奠基者效应（founder effect），一直是学界持续探讨的研究热点。为阐明SCA10扩增的突变起源与传播路径，本研究针对巴西与墨西哥的SCA10家系，采用紧密连锁的短串联重复序列（short tandem repeat, STR）标记与基因内单核苷酸多态性（single nucleotide polymorphism, SNPs）开展了大规模单倍型分析。研究结果显示：（1）所有巴西家系与其中1个墨西哥家系共享疾病相关单倍型；（2）其余SCA10阳性墨西哥家系的单倍型亲缘关系较近；（3）来自同一单核苷酸多态性谱系、重复数不同的小型正常等位基因间仅存在极小甚至无遗传距离，提示此类等位基因通过单步突变机制产生；（4）纯重复扩增等位基因与间断性扩增等位基因共享同一单倍型，表明其生成符合基因转换（gene conversion）模型。综上，本研究证实SCA10在拉丁美洲存在共同祖先起源，该突变最初可能出现于美洲原住民群体，后续扩散至墨西哥与巴西的混血人群中。