Age and origin of the FCMD 3 '-untranslated-region retrotransposal insertion mutation causing Fukuyama-type congenital muscular dystrophy in the Japanese population

Fukuyama-type congenital muscular dystrophy (FCMD), an autosomal recessive disorder with a high prevalence in the Japanese population, is characterise d by severe muscular dystrophy associated with brain malformation (cortical dysgenesis) and mental retardation. In Japan, 87% of FCMD-bearing chromoso mes carry a 3-kb retrotransposal insertion of tandemly repeated sequences w ithin the disease gene recently identified on chromosome 9q31, and most of them share a common founder haplotype. FCMD is the first human disease know n to be caused primarily by an ancient retrotransposal integration. By appl ying two methods for the study of linkage disequilibrium between flanking p olymorphic markers and the disease locus, and of its decay over time, the a ge of the insertion mutation causing FCMD in Japanese patients is calculate d to be approximately 102 generations (95% confidence interval: 86-117 g), or slightly less. The estimated age dates the most recent common ancestor o f the mutation-bearing chromosomes back to the time (or a few centuries bef ore) the Yayoi people started migrating to Japan from the Korean peninsula. This finding makes the molecular population genetics of FCMD understandabl e in the context of Japan's history and the founder effect consistent with the prevalent theory on the origins of the modem Japanese population.