title: Mutational origin of Machado-Joseph disease in the Australian Aboriginal communities of Groote Eylandt and Yirrkala.
abstract: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Martins
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
authors.forename: Virginia C N
authors.initials: VC
authors.lastname: Wong
authors.forename: Paola
authors.initials: P
authors.lastname: Giunti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Laura P W
authors.initials: LP
authors.lastname: Ranum
authors.forename: Hidenao
authors.initials: H
authors.lastname: Sasaki
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
authors.forename: Paula
authors.initials: P
authors.lastname: Coutinho
authors.forename: António
authors.initials: A
authors.lastname: Amorim
authors.forename: Jorge
authors.initials: J
authors.lastname: Sequeiros
authors.forename: Garth A
authors.initials: GA
authors.lastname: Nicholson
mesh_terms: D001208:Asia / Q000453:epidemiology; D000067699:Ataxin-3; D001315:Australia / Q000208:ethnology; D005192:Family Health; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D017827:Machado-Joseph Disease / Q000208:ethnology* / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D015876:Northern Territory / Q000453:epidemiology / Q000208:ethnology; D009687:Nuclear Proteins / Q000235:genetics*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics*; D020079:Terminal Repeat Sequences / Q000235:genetics; D000095283:Australian Aboriginal and Torres Strait Islander Peoples
chemical_list: D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3