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

Sandra Martins, Bing Wen Soong, Virginia C.N. Wong, Paola Giunti, Giovanni Stevanin, Laura P.W. Ranum, Hidenao Sasaki, Olaf Riess, Shoji Tsuji, Paula Coutinho, António Amorim, Jorge Sequeiros*, Garth A. Nicholson

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)746-751
Number of pages6
JournalArchives of Neurology
Issue number6
Publication statusPublished - 2012
Externally publishedYes

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