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

• Type: Article in International Scientific Journal
• Date: 2007

Authors

Sandra Martins (Author) Other; Francesc Calafell (Author) Other; Claudia Gaspar (Author) Other; Virginia C N Wong (Author) Other; Isabel Silveira (Author) Other; Garth A Nicholson (Author) Other; Ewout R Brunt (Author) Other; Lisbeth Tranebjaerg (Author) Other; Giovanni Stevanin (Author) Other; Mingli Hsieh (Author) Other; Bing Wen Soong (Author) Other; Leal Loureiro (Author) Other; Alexandra Duerr (Author) Other; Shoji Tsuji (Author) Other; Mitsunori Watanabe (Author) Other; Laura B Jardim (Author) Other; Paola Giunti (Author) Other; Olaf Riess (Author) Other; Laura P W Ranum (Author) Other; Alexis Brice (Author) Other; Guy A Rouleau (Author) Other; Paula Coutinho (Author) Other; Antonio Amorim (Author) FCUP; Jorge Sequeiros (Author) ICBAS

Journal

Title: Archives of Neurology

Vol. 64

Pages: 1502-1509

ISSN: 0003-9942

Publisher: American Medical Association

Indexing

ISI Web of Knowledge - 48 Citations

Scopus - 59 Citations

Scientific classification

FOS: Medical and Health sciences > Clinical medicine

Other information

Authenticus ID: P-004-6X4

DOI: 10.1001/archneur.64.10.1502

Abstract (EN): 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, about5774 +/- 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8