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

Arch Neurol. 2012 Jun;69(6):746-51. 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: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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asia / epidemiology
  • Ataxin-3
  • Australia / ethnology
  • Family Health
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Haplotypes
  • Humans
  • Machado-Joseph Disease / ethnology*
  • Machado-Joseph Disease / genetics*
  • Male
  • Mutation / genetics*
  • Native Hawaiian or Other Pacific Islander / genetics
  • Nerve Tissue Proteins / genetics*
  • Northern Territory / epidemiology
  • Northern Territory / ethnology
  • Nuclear Proteins / genetics*
  • Phylogeny
  • Polymorphism, Single Nucleotide / genetics
  • Repressor Proteins / genetics*
  • Terminal Repeat Sequences / genetics


  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Repressor Proteins
  • ATXN3 protein, human
  • Ataxin-3