Mutational origin of Machado-Joseph disease in the Australian aboriginal communities of Groote Eylandt and Yirrkala

Objective: 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. Design: 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. Setting: 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). Subjects: 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. Results: 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. Conclusion: 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.