title: Molecular basis of subtotal complement C6 deficiency. A carboxy-terminally truncated but functionally active C6.
abstract: Individuals with subtotal complement C6 deficiency possess a C6 molecule that is 14% shorter than normal C6 and present in low but detectable concentrations (1-2% of the normal mean). We now show that this dysmorphic C6 is bactericidally active and lacks an epitope that was mapped to the most carboxy-terminal part of C6 using C6 cDNA fragments expressed as fusion proteins in the pUEX expression system. We thus predicted that the abnormal C6 molecule might be carboxy-terminally truncated and sought a mutation in an area approximately 14% from the carboxy-terminal end of the coding sequence. By sequencing PCR-amplified products from this region, we found, in three individuals from two families, a mutation that might plausibly be responsible for the defect. All three have an abnormal 5' splice donor site of intron 15, which would probably prevent splicing. An in-frame stop codon is found 17 codons downstream from the intron boundary, which would lead to a truncated polypeptide 13.5% smaller than normal C6. This result was unexpected, as earlier studies mapped the C5b binding site, or a putative enzymatic region, to this part of C6. Interestingly, all three subjects were probably heterozygous for both subtotal C6 and complete C6 deficiency.
authors.affiliation: Molecular Immunopathology Unit, Medical Research Council Centre, Cambridge, United Kingdom.
authors.forename: R
authors.initials: R
authors.lastname: Würzner
authors.forename: M J
authors.initials: MJ
authors.lastname: Hobart
authors.forename: B A
authors.initials: BA
authors.lastname: Fernie
authors.forename: D
authors.initials: D
authors.lastname: Mewar
authors.forename: P C
authors.initials: PC
authors.lastname: Potter
authors.forename: A
authors.initials: A
authors.lastname: Orren
authors.forename: P J
authors.initials: PJ
authors.lastname: Lachmann
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001770:Blood Bactericidal Activity; D002648:Child; D003183:Complement C6 / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D015938:Complement Membrane Attack Complex; D000939:Epitopes; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D015151:Immunoblotting; D008297:Male; D008589:Meningococcal Infections / Q000276:immunology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D017422:Sequence Analysis, DNA
chemical_list: D003183:Complement C6; D015938:Complement Membrane Attack Complex; D000939:Epitopes