Founder SVA retrotransposal insertion in Fukuyama-type congenital muscular dystrophy and its origin in Japanese and Northeast Asian populations.

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal recessive disorders in Japan, is characterized by congenital muscular dystrophy associated with brain malformation due to a defect in neuronal migration. Previously, we identified the gene responsible for FCMD, which encodes the fukutin protein. Most FCMD-bearing chromosomes (87%) are derived from a single ancestral founder, who lived 2,000-2,500 years ago and whose mutation consisted of a 3-kb retrotransposal insertion in the 3' non-coding region of the fukutin gene. Here we show, through detailed sequence analysis, that the founder insertion is derived from the SINE-VNTR-Alu (SVA) retroposon. To enable rapid detection of this insertion, we have developed a PCR-based diagnostic method that uses three primers simultaneously. We used this method to investigate the distribution and origin of the founder insertion, screening a total of 4,718 control DNA samples from Japanese and other Northeast Asian populations. Fifteen founder chromosomes were detected among 2,814 Japanese individuals. Heterozygous carriers were found in various regions throughout Japan, with an averaged ratio of 1 in 188. In Korean populations, we detected one carrier in 935 individuals. However, we were unable to detect any heterozygous alleles in 203 Mongolians and 766 Mainland Chinese populations. These data largely rule out the possibility that a single ancestor bearing an insertion-chromosome immigrated to Japan from Korea or Mainland China and appear to confirm that FCMD carriers are rare outside of Japan. Copyright 2005 Wiley-Liss, Inc