Asian origin for the worldwide-spread mutational event in Machado-Joseph disease.

Sandra Martins, Francesc Calafell, Claudia Gaspar, Virginia C. N. Wong, Isabel Silveira, Garth A. Nicholson, Ewout R. Brunt, Lisbeth Tranebjaerg, Giovanni Stevanin, Mingli Hsieh, Bing-wen Soong, Leal Loureiro, Alexandra Dürr, Shoji Tsuji, Mitsunori Watanabe, Laura B. Jardim, Paola Giunti, Olaf Riess, Laura P. W. Ranum, Alexis Brice, Guy A. Rouleau, Paula Coutinho, António Amorim, Jorge Sequeiros
Arch Neurol. 2007-10-01; 64(10): 1502
DOI: 10.1001/archneur.64.10.1502

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1. Arch Neurol. 2007 Oct;64(10):1502-8.

Asian origin for the worldwide-spread mutational event in Machado-Joseph disease.

Martins S(1), Calafell F, Gaspar C, Wong VC, Silveira I, Nicholson GA, Brunt ER,
Tranebjaerg L, Stevanin G, Hsieh M, Soong BW, Loureiro L, Dürr A, Tsuji S,
Watanabe M, Jardim LB, Giunti P, Riess O, Ranum LP, Brice A, Rouleau GA, Coutinho
P, Amorim A, Sequeiros J.

Author information:
(1)Instituto de Patologia e Imunologia Molecular da Universidade do Porto and
Faculdade de Ciências, University of Porto, Porto, Portugal.

BACKGROUND: Machado-Joseph disease is the most frequent dominant ataxia
worldwide. Despite its frequency and presence in many populations, only 2 founder
mutations have been suggested to explain its current geographic distribution.
OBJECTIVES: To trace back in history the main mutational events in Machado-Joseph
disease, we aimed to assess ancestral haplotypes and population backgrounds, to
date the mutations, and to trace the routes and time of introduction of the
founder haplotypes in different populations.
DESIGN, SETTING, AND PARTICIPANTS: We studied 264 families with Machado-Joseph
disease from 20 different populations. Six intragenic single-nucleotide
polymorphisms were used to determine ancestral mutational events; 4 flanking
short tandem repeats were used to construct extended haplotypes and measure
accumulation of genetic diversity over time within each lineage.
RESULTS: The worldwide-spread lineage, TTACAC, had its highest diversity in the
Japanese population, where we identified the ancestral short tandem repeat-based
haplotype. Accumulated variability suggested a postneolithic mutation, about 5774
+/- 1116 years old, with more recent introductions in North America, Germany,
France, Portugal, and Brazil. As to the second mutational event, in the GTGGCA
lineage, only 7 families (of 71 families) did not have Portuguese ancestry,
although gene diversity was again smaller in Portuguese families (0.44) than in
non-Portuguese families (0.93).
CONCLUSIONS: The worldwide-spread mutation may have first occurred in Asia and
later been diffused throughout Europe, with a founder effect accounting for its
high prevalence in Portugal; the other Machado-Joseph disease lineage is more
recent, about 1416 +/- 434 years old, and its dispersion may be explained mainly
by recent Portuguese emigration.

DOI: 10.1001/archneur.64.10.1502
PMID: 17923634 [Indexed for MEDLINE]

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