The ancient mutational event for Machado-Joseph disease (MJD/SCA3) is older in Japan than in Europe: what more has Asia to tell us about MJD mutational origins?
MJD (also SCA3) is a late-onset neurodegenerative disorder, originally described in families of Portuguese-Azorean ancestry. It is known now to be the most frequent dominant ataxia, representing more than 40% among all SCAs in Portugal, China, Japan, Germany, Netherlands and Brazil. MJD is mainly characterised by ataxia, spasticity, limitation of eye movements, dystonia, and peripheral amyotrophies. The ATXN3 gene contains a (CAG)n within the coding region, which is expanded in patients. Pathogenic alleles are very unstable, but de novo expansions are rare. A worldwide study disclosed only four MJD haplotypes, two (ACA and GGC) being present in the vast majority of families. We proposed to trace back in history the two MJD independent mutations, through haplotype analysis, including six intragenic SNPs and four flanking STRs, in 270 families of 24 ethnic origins (in five continents). We (1) compared gene diversity among MJD populations, (2) calculated the variation accumulated from the ancestral haplotype, (3) constructed phylogenetic networks reflecting the STR-based haplotypes’ evolution within each lineage, and (4) estimated evolutionary distances between expanded and different-size normal alleles. For the worldwide spread lineage (TTACAC), the highest diversity was found in Japan, where we identified the ancestral haplotype and the normal (CAG)n alleles potentially involved in the mutational process. Variability accumulated from this background suggested a post-neolithic mutation, about 5774±1116 yrs old; recent introductions occurred, progressively, in North America, France, Germany, Portugal and Brazil. As to the second mutational event, in the GTGGCA lineage, only six families did not share a Portuguese ancestry, although gene diversity was smaller among Portuguese (0.44) than non-Portuguese families (0.93). It occurred about 1416±434 yrs ago. In conclusion, de novo mutations are extremely rare events in MJD: the worldwide spread mutation seems to have occurred in Asia, being later diffused throughout Europe, where a founder effect accounted for its high prevalence in Portugal; the other MJD lineage occurred more recently, and its current dispersion may be explained by recent Portuguese emigration.