Genetic basis of human complement C8α-γ deficiency

Deficiency of the α-γ subunit of the eighth component of complement (C8α-γD) is frequently associated with recurrent neisserial infections, especially meningitis caused by Neisseria meningitidis. We here report the molecular basis of C8α-γD in two unrelated Japanese subjects. Screening all 11 exons of the C8α gene and all 7 exons of the C8γ gene and their boundaries by exon-specific PCR/single-strand conformation polymorphism demonstrated aberrant single-stranded DNA fragments in exon 2 of C8α gene in case 1 and in exons 2 and 9 of C8α gene in case 2. Nucleotide sequencing of the amplified DNA fragments in case 1 revealed a homozygous single-point mutation at the second exon-intron boundary, inactivating the universally conserved 5' splice site consensus sequence of the second intron (IVS2+IG→T). Case 2 was a compound heterozygote for the splice junction mutation, IVS2+IG→T, and a nonsense mutation at Arg³⁹⁴ (R394x). R394X was caused by a C to T transition at nucleotide 1407, the first nucleotide of the codon CGA for Arg³⁹⁴, leading to a stop codon TGA. No mutations were detected in the C8γ gene by our method. Our results indicate that the pathogenesis of C8α-γD might be caused by heterogeneous molecular defects in the C8α gene.