ABSTRACT
A nonsense mutation at codon 95 (R95X) in the C9 gene is responsible for most Japanese C9 deficiency (C9D) cases, with a carrier frequency of 6.7%. Upon analysis of microsatellite markers and newly identified dinucleotide repeat number polymorphisms in the 3' flanking region of the C9 gene, a founder effect was demonstrated for the R95X mutation of the C9 gene in Japanese. Screening for the R95X mutation in Korean and Chinese individuals showed that the R95X carrier frequencies in Koreans and Chinese were 2.0% and 1.0%, respectively. Although homozygotes for the R95X mutation were not found in Korea or China, the shared haplotype of the dinucleotide repeat number polymorphisms appeared to be associated with the R95X mutation in the heterozygotes in Korea and China. The founder effect found in East Asians (Japanese, Koreans and Chinese) but not in Caucasians, as well as the haplotype sharing in only a small chromosomal interval, suggested that the R95X mutation of C9 gene was ancient and had occurred after the divergence of East Asians and Caucasians, and before migration of the Yayoi people to Japan. Since the mortality of meningococcal infections in complement-deficient patients is lower than that in normal individuals, a founder effect and a selective advantage in isolation might be the main reasons for the high frequency of the R95X mutation in Japan.
