title: Type I human complement C2 deficiency. A 28-base pair gene deletion causes skipping of exon 6 during RNA splicing.
abstract: Two variants of a genetic deficiency of complement protein C2 (C2D) have been previously identified. No C2 protein translation is detected in type I deficiency, while type II deficiency is characterized by a selective block in C2 secretion. Type I C2 deficiency was described in a family in which the C2 null allele (C2Q0) is associated with the major histocompatibility haplotype/complotype HLA-A25,B18,C2Q0,BfS,C4A4, C4B2,Drw2; this extended haplotype occurs in over 90% of C2-deficient individuals (common complotype/haplotype). To determine the molecular basis of type I C2 deficiency, the C2 gene and cDNA were characterized from a homozygous type I C2-deficient individual with the common associated haplotype/complotype. We found a 28-base pair deletion in the type I C2Q0 gene, beginning 9 base pairs upstream of the 3'-end of exon 6, that generates a C2 transcript with a complete deletion of exon 6 (134 base pair) and a premature termination codon. In studies of eight kindred, the 28-base pair deletion was observed in all C2Q0 alleles associated with the common type I deficient complotype/haplotype; this deletion was not present in normal C2 nor in type II C2-deficient genes. These data demonstrate that: 1) type I human complement C2 deficiency is caused by a 28-base pair genomic deletion that causes skipping of exon 6 during RNA splicing, resulting in generation of a premature termination codon, 2) the 28-base pair deletion in the type I C2Q0 gene is strongly associated with the HLA haplotype/complotype A25,B18,C2Q0,BfS,C4A4,C4B2,Drw2, suggesting that all C2-deficient individuals with this haplotype/complotype will harbor the 28-base pair C2 gene deletion, and 3) type II C2 deficiency is caused by a different, as yet uncharacterized, molecular genetic defect.
authors.affiliation: Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: C A
authors.initials: CA
authors.lastname: Johnson
authors.forename: P
authors.initials: P
authors.lastname: Densen
authors.forename: R K
authors.initials: RK
authors.lastname: Hurford
authors.forename: H R
authors.initials: HR
authors.lastname: Colten
authors.forename: R A
authors.initials: RA
authors.lastname: Wetsel
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015139:Blotting, Southern; D002872:Chromosome Deletion; D003175:Complement C2 / Q000172:deficiency* / Q000235:genetics; D004247:DNA / Q000235:genetics; D005091:Exons; D005260:Female; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D003175:Complement C2; D012333:RNA, Messenger; D004247:DNA