GENETIC-BASIS OF HUMAN-COMPLEMENT C8-BETA DEFICIENCY

The eighth component of human complement (C8) is a serum protein consi sting of three chains (alpha, beta, and gamma) and encoded by three di fferent genes, C8A, C8B, and C8G. C8A and C8B are closely linked on ch romosome 1p, whereas C8G is located on chromosome 9q. In the serum the beta subunit is non-covalently bound to the disulfide-linked alpha-ga mma subunit. Patients with C8beta deficiency suffer from recurrent nei sserial infections such as meningitis. Exon-specific polymerase chain reaction (PCR) amplification with primer pairs from the flanking intro n sequences was used to amplify all 12 C8B exons separately. No differ ence regarding the exon sizes was observed in a C8beta-deficient patie nt compared with a normal person. Therefore, direct sequence analysis of all exon-specific PCR products from normal and C8beta-deficient ind ividuals was carried out. As a cause for C8beta deficiency, we found a single C-T exchange in exon 9 leading to a stop codon. An allele-spec ific PCR system was designed to detect the normal and the deficiency a llele simultaneously. Using this approach as well as PCR typing of the TaqI polymorphism located in intron 11, five families with 7 C8beta-d eficient members were investigated. The mutation was not found to be r estricted to one of the two TaqI RFLP alleles. The mutant allele was o bserved in all families investigated and can therefore be regarded as a major cause of C8beta deficiency in the Caucasian population. In add ition, two C8beta-deficient patients were found to be heterozygous for the C-T exchange. The molecular basis of the alleles without this poi nt mutation also causing deficiency has not yet been defined.