Molecular epidemiology of C9 deficiency heterozygotes with an Arg95Stop mutation of the C9 gene in Japan

Deficiency of the ninth component of human complement (C9) is the most comm on complement deficiency in Japan, with an incidence of approximately one h omozygote in 1000, but is very rare in other countries. Genetic analyses of Japanese C9 deficiency have shown that a C-to-T transition leading to TGA stop codon for Arg95 in exon 4 of the C9 gene (Arg95Stop) is common in Japa nese C9 deficiency. To determine the prevalence of heterozygous carriers of the Arg95Stop mutation in a Japanese population, we collected DNA samples from 300 individuals in two of the four main islands of Japan. Heterozygote detection was performed with an allele-specific polymerase chain reaction (PCR) system designed to detect exclusively only one of the normal and muta nt alleles, followed by confirmation with PCR/single-strand conformation po lymorphism (SSCP) analysis and direct sequencing. Twenty individuals were h eterozygous for the Arg95Stop mutation. None was homozygous. The prevalence of carriers of the Arg95Stop mutation was 6.7% (20/300). An estimated freq uency (0.12%) of complete C9 deficiency due to homozygous Arg95Stop mutatio n was consistent with frequencies determined by serological studies.