Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study.

C. Gaspar, I. Lopes-Cendes, S. Hayes, J. Goto, K. Arvidsson, A. Dias, I. Silveira, P. Maciel, P. Coutinho, M. Lima, Y.-X. Zhou, B.-W. Soong, M. Watanabe, P. Giunti, G. Stevanin, O. Riess, H. Sasaki, M. Hsieh, G.A. Nicholson, E. Brunt, J.J. Higgins, M. Lauritzen, L. Tranebjaerg, V. Volpini, N. Wood, L. Ranum, S. Tsuji, A. Brice, J. Sequeiros, G.A. Rouleau
The American Journal of Human Genetics. 2001-02-01; 68(2): 523-528
DOI: 10.1086/318184

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1. Am J Hum Genet. 2001 Feb;68(2):523-8. Epub 2000 Dec 20.

Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype

Gaspar C(1), Lopes-Cendes I, Hayes S, Goto J, Arvidsson K, Dias A, Silveira I,
Maciel P, Coutinho P, Lima M, Zhou YX, Soong BW, Watanabe M, Giunti P, Stevanin
G, Riess O, Sasaki H, Hsieh M, Nicholson GA, Brunt E, Higgins JJ, Lauritzen M,
Tranebjaerg L, Volpini V, Wood N, Ranum L, Tsuji S, Brice A, Sequeiros J, Rouleau

Author information:
(1)Centre for Research in Neuroscience, McGill University and The Montreal
General Hospital Research Institute, Montreal,Québec, Canada.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder
originally described in families of Portuguese-Azorean ancestry. The cloning of
the MJD1 gene allowed identification of the disease in many other populations,
and MJD is now known to be the most common cause of dominant spinocerebellar
ataxia. The hypothesis that its present world distribution could result from the
spread of an original founder mutation has been raised, both at historical and
molecular levels. In the present study, we tested this hypothesis by
linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype
comparison, in 249 families from different countries. We typed five
microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973,
D14S1016, and D14S977), and three intragenic single-base-pair polymorphisms
(A(669)TG/G(669)TG, C(987)GG/G(987)GG, and TAA(1118)/TAC(1118)). The results show
two different haplotypes, specific to the island of origin, in families of
Azorean extraction. In families from mainland Portugal, both Azorean haplotypes
can be found. The majority of the non-Portuguese families also share the same
intragenic haplotype seen in the families coming from the island of Flores, but
at least three other haplotypes were seen. These findings suggest two
introductions of the mutation into the Portuguese population. Worldwide, the
sharing of one intragenic haplotype by the majority of the families studied
implies a founder mutation in MJD.

DOI: 10.1086/318184
PMCID: PMC1235286
PMID: 11133357 [Indexed for MEDLINE]

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