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Original Contribution
June 2012

Mutational Origin of Machado-Joseph Disease in the Australian Aboriginal Communities of Groote Eylandt and Yirrkala

Author Affiliations

Author Affiliations: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal (Drs Martins and Amorim); Department of Neurology, National Yang-Ming University School of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (Dr Soong); Department of Pediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China (Dr Wong); Department of Molecular Neuroscience, University College of London Institute of Neurology, University of London, London, United Kingdom (Dr Giunti); Institut du Cerveau et de la Moelle Épinière Hôpital Pitié-Salpêtrière, Paris, France (Dr Stevanin); Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and Genetics Institute, College of Medicine, University of Florida, Gainesville (Dr Ranum); Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan (Dr Sasaki); Department of Medical Genetics, University of Tübingen, Tübingen, Germany (Dr Riess); Department of Neurology, University of Tokyo, Tokyo, Japan (Dr Tsuji); Serviço Neurologia, Hospital S. Sebastião, Feira, Portugal (Dr Coutinho); Faculdade de Ciências (Dr Amorim), Institute for Molecular and Cell Biology (Dr Sequeiros) and Instituto de Ciências Biomédicas Abel Salazar (Dr Sequeiros), University of Porto, Porto, Portugal; and University of Sydney, Department of Medicine, Concord Hospital, Australia (Dr Nicholson).

Arch Neurol. 2012;69(6):746-751. doi:10.1001/archneurol.2011.2504

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: TT GA TC GAGC-(CAG)Exp- CAC CCAGCGC, 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.