MOLECULAR-BASES FOR INHERITED HUMAN-COMPLEMENT COMPONENT C6 DEFICIENCY IN 2 UNRELATED INDIVIDUALS

Deficiency of the sixth component of complement (C6D) is frequently as sociated with recurrent neisserial infections, especially meningitis c aused by Neisseria meningitidis, We here report the molecular bases of C6D in two unrelated subjects, one African American (case 1) and the other Japanese (case 2), Screening all 17 exons of the C6 gene and the ir boundaries by exon-specific PCR/single strand conformation polymorp hism demonstrated aberrant single stranded DNA fragments in exon 12 of case! and exon 2 of case 2, Nucleotide sequencing of the amplified DN A fragments revealed a homozygous single-base deletion (C-1936) in exo n 12 of case 1 and a heterozygous single base deletion (C-291/C-292/C- 293/C-294) in exon 2 of case 2, Both mutations resulted in frame shift s and premature termination of the C6 polypeptide, Sequence-specific o ligonucleotide probe hybridization and direct sequencing of exon 12 am plified from genomic DNA further supported the homozygosity of the mut ation in case 1, Case 2 is apparently compound heterozygote, but the p utative mutation in the other allele of the C6 gene remains unknown, B oth case 1 and case 2 were homozygous for the C6A allotype, These data indicate that at least three distinct mutational events can cause C6D , single nucleotide deletions in exons 2 and 12, and a mutation as yet unidentified, Thus, similar to other complement protein deficiencies, the pathogenesis of C6D appears to be heterogeneous.