title: Characterization of non-expressed C4 genes in a case of complete C4 deficiency: identification of a novel point mutation leading to a premature stop codon.
abstract: The genetic basis of complete C4 deficiency in a patient with SLE was investigated. Previous studies have demonstrated that this patient has two different major histocompatibility complex (MHC) haplotypes that each contain a major deletion and a non-expressed C4 gene. In the present study, non-expression of the C4 genes was explained by the finding of two distinct C4 gene mutations. A previously described two base pair insertion in exon 29 of the C4 gene was detected in the paternal MHC haplotype [HLA-A2, B40, SC00, DR6]. The maternal haplotype [HLA-A30, B18, F1C00, DR3] carried a C4 gene with a one base pair deletion in exon 20 generating a premature stop codon. This mutation was neither found in 10 individuals with known non-expressed C4 genes nor in 9 individuals homozygous for the complotype F1C30. The isotype and allotype specific regions of the patient's C4 genes were sequenced, and both contained C4A3a sequence. In conclusion, two different MHC haplotypes resembling the extended haplotypes [HLA-A2, B40, SC02, DR6] and [HLA-A30, B18, F1C30, DR3] both contained a non-expressed C4A gene that was due to either of two distinct mutations, demonstrating the heterogeneous genetic background of C4 deficiency.
authors.affiliation: Department of Medical Microbiology, Lund University, Sweden.
authors.forename: G N
authors.initials: GN
authors.lastname: Fredrikson
authors.forename: B
authors.initials: B
authors.lastname: Gullstrand
authors.forename: P M
authors.initials: PM
authors.lastname: Schneider
authors.forename: K
authors.initials: K
authors.lastname: Witzel-Schlömp
authors.forename: A G
authors.initials: AG
authors.lastname: Sjöholm
authors.forename: C A
authors.initials: CA
authors.lastname: Alper
authors.forename: Z
authors.initials: Z
authors.lastname: Awdeh
authors.forename: L
authors.initials: L
authors.lastname: Truedsson
mesh_terms: D000328:Adult; D002460:Cell Line; D018388:Codon, Terminator / Q000235:genetics*; D003181:Complement C4 / Q000172:deficiency* / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA
chemical_list: D018388:Codon, Terminator; D003181:Complement C4