Martins Sandra, Soong Bing-Wen, Wong Virginia C N, Giunti Paola, Stevanin Giovanni, Ranum Laura P W, Sasaki Hidenao, Riess Olaf, Tsuji Shoji, Coutinho Paula, Amorim António, Sequeiros Jorge, Nicholson Garth A
Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
Arch Neurol. 2012 Jun;69(6):746-51. doi: 10.1001/archneurol.2011.2504.
To determine whether the presence of Machado-Joseph disease (MJD, also spinocerebellar ataxia type 3 [SCA3]) among Australian aborigines was caused by a new mutational event or by the introduction of expanded alleles from other populations.
We sequenced a region of 4 kilobases (kb), encompassing the CAG repeat within the ATXN3 gene, in 2 affected Australian aboriginal families and compared them with the Joseph and Machado lineages described before. Full-extended haplotypes (including also more distant single-nucleotide polymorphisms and flanking short tandem repeats) were assessed by segregation and allele-specific amplification. A phylogenetic tree was inferred from genetic distances, and age of the Australasian Joseph-derived lineage was estimated.
The aboriginal communities of Groote Eylandt and Yirrkala, in the Northern Territories, Australia (local ethics institutional permission was granted, and both community and individual informed consent was obtained).
A convenience sample of 19 patients and unaffected relatives, from 2 Australian aboriginal families affected with MJD; 40 families with MJD of multiethnic origins and 50 unrelated Asian control subjects.
The 2 aboriginal families shared the same full haplotype, including 20 single-nucleotide polymorphisms:TTGATCGAGC-(CAG)(Exp)-CACCCAGCGC, that is, the Joseph lineage with a G variant in rs56268847.Among 33 families with the Joseph lineage, this derived haplotype was found only in 5 of 16 Taiwanese, all 3 Indian,and 1 of 3 Japanese families analyzed.
A related-extended MJD haplotype shared by Australian aborigines and some Asian families (a Joseph-derived lineage) suggests a common ancestor for all, dating back more than 7000 years.
确定澳大利亚原住民中马查多-约瑟夫病（MJD，亦称3型脊髓小脑共济失调[SCA3]）的出现是由新的突变事件引起，还是由其他人群引入的扩展等位基因所致。
我们对2个受影响的澳大利亚原住民家庭中包含ATXN3基因内CAG重复序列的4千碱基（kb）区域进行了测序，并将其与之前描述的约瑟夫和马查多谱系进行比较。通过分离和等位基因特异性扩增评估完整扩展单倍型（还包括更远距离的单核苷酸多态性和侧翼短串联重复序列）。从遗传距离推断系统发育树，并估计澳大拉西亚约瑟夫衍生谱系的年龄。
澳大利亚北领地的格鲁特艾兰岛和伊尔卡拉的原住民社区（已获得当地伦理机构许可，并获得社区和个人知情同意）。
从2个受MJD影响的澳大利亚原住民家庭中选取的19名患者及未受影响亲属的便利样本；40个多民族起源的MJD家庭和50名无关的亚洲对照个体。
这2个原住民家庭共享相同的完整单倍型，包括20个单核苷酸多态性：TTGATCGAGC-(CAG)(Exp)-CACCCAGCGC，即rs56268847中有G变体的约瑟夫谱系。在33个具有约瑟夫谱系的家庭中，这种衍生单倍型仅在16个台湾家庭中的5个、所有3个印度家庭以及分析的3个日本家庭中的1个中发现。
澳大利亚原住民和一些亚洲家庭（约瑟夫衍生谱系）共享的相关扩展MJD单倍型表明，所有这些家庭有一个共同祖先，可追溯到7000多年前。
