Horiuchi et al. (1998) found that 8 of 10 unrelated Japanese subjects with C9 deficiency (613825) were homozygous for a C-to-T transition at nucleotide 343, which converted codon 95 from CGA (arg) to TGA (stop). Two other patients were heterozygous for the R95X mutation; one of these had a C507Y (120940.0005) substitution, while the genetic defect in the other allele of the second heterozygote remained unknown. Kira et al. (1998) likewise found that all 4 Japanese C9-deficient patients who had suffered from meningococcal meningitis had this CGA (arg)-to-TGA (stop) mutation.
Ichikawa et al. (2001) found this mutation in a 28-year-old Japanese woman with C9 deficiency and dermatomyositis. Whereas levels of serum hemolytic complement (CH50) are characteristically normal or elevated in patients with dermatomyositis, this patient showed markedly depressed levels of CH50. This case demonstrated that the muscle lesions of dermatomyositis can occur in the presence of a complement defect that would prevent the formation of the C5b-9 membrane attack complex.
The R95X mutation is responsible for most Japanese C9 deficiency cases, with a carrier frequency of 6.7%. Khajoee et al. (2003) showed that in Koreans and Chinese, the R95X carrier frequencies were 2.0% and 1.0%, respectively. 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 region, suggested that the R95X mutation is ancient and occurred after the divergence of East Asians and Caucasians, and before migration of the Yayoi people to Japan. Because 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.
