Genetic basis of human complement C8 alpha-gamma deficiency.
Deficiency of the alpha-gamma subunit of the eighth component of complement (C8alpha-gammaD) is frequently associated with recurrent neisserial infections, especially meningitis caused by Neisseria meningitidis. We here report the molecular basis of C8alpha-gammaD in two unrelated Japanese subjects. Screening all 11 exons of the C8alpha gene and all 7 exons of the C8gamma gene and their boundaries by exon-specific PCR/single-strand conformation polymorphism demonstrated aberrant single-stranded DNA fragments in exon 2 of C8alpha gene in case 1 and in exons 2 and 9 of C8alpha 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+1G-->T). Case 2 was a compound heterozygote for the splice junction mutation, IVS2+1G-->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 C8gamma gene by our method. Our results indicate that the pathogenesis of C8alpha-gammaD might be caused by heterogeneous molecular defects in the C8alpha gene.
First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
T
T
Kojima
T
T
Horiuchi
H
H
Nishizaka
Y
Y
Fukumori
T
T
Amano
K
K
Nagasawa
Y
Y
Niho
K
K
Hayashi
D000328:Adult; D017398:Alternative Splicing / Q000235:genetics / Q000276:immunology; D003185:Complement C8 / Q000172:deficiency* / Q000235:genetics*; D005091:Exons / Q000235:genetics / Q000276:immunology; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D017354:Point Mutation / Q000276:immunology; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational
D003185:Complement C8