Molecular basis of Japanese complement C9 deficiency

The ninth component of human complement (C9) is a soluble monomeric glycoprotein of 538 amino acids that acts as the last of the terminal complement components. Deficiency of C9 is the most common complement deficiency in Japan with its incidence between 0.036%-0.095%, but rare in other countries. C9 deficiency is associated with an increased risk of recurrent neisserial infection as well as congenital deficiency of other terminal complement components C5, C6, C7, or C8. We studied the molecular basis of C9 deficiency in four Japanese C9-deficient patients who had suffered from meningococcal meningitis. Direct sequencing of amplified C9 cDNA and DNA from peripheral white blood cells revealed a nonsense substitution (CGA→TGA) at codon 95 in exon 4 in the four C9-deficient individuals. An allele-specific polymerase chain reaction system designed to detect exclusively only one of the normal and mutant alleles indicated that all the four patients were homozygous for the mutation in exon 4 and parents of patient 2 were heterozygous. Since unrelated parents of the four patients were from various places in western Japan, the hot spot at codon 95 in exon 4 might be responsible for most Japanese C9 deficiency.