title: Combined heterozygous deficiency of the classical complement pathway proteins C2 and C4.
abstract: Genetic deficiencies of components of the classical pathway of complement activation are associated with an increased risk for the development of autoimmune and immune complex-mediated diseases. In the present study we report on the molecular and clinical features associated with combined heterozygous C4 and C2 deficiency in 15 individuals investigated within six families. Approximately 30% of the individuals manifested SLE or another autoimmune condition. Heterozygous C2 deficiency was related to a 28-bp deletion in the C2 gene (C2 deficiency type I), in most cases within the HLA-A25 B18 C2Q0 BfS C4A4B2 DR2 haplotype. Among 13 partial C4-deficient haplotypes transmitted, 8 carried C4A*Q0 alleles and 5 C4B*Q0 alleles. In seven cases the C4A*Q0 alleles were associated with a deletion of the C4A/CYP21P genes within the HLA-B8 C2C BfS C4AQ0B1 DR3 haplotype. In three cases, the C4B*Q0 allele was associated with a deletion of the C4B/CYP21P genes within the HLA-B18 C2C BfF1 C4A3BQ0 DR3 haplotype. In the other cases, C4A*Q0 or C4B*Q0 was dependent on as yet uncharacterized defects in the C4 gene or in C4 gene expression. In view of the relatively high frequency of heterozygous C4 deficiency in the normal Caucasian population, the expected frequency of the combined deficiency should approximate 0.001.
authors.affiliation: Laboratoire de Recherches en Immunologie, Université Louis Pasteur, Strasbourg, France.
authors.forename: D
authors.initials: D
authors.lastname: Hartmann
authors.forename: V
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.forename: L
authors.initials: L
authors.lastname: Weiss
authors.forename: A
authors.initials: A
authors.lastname: Meyer
authors.forename: J
authors.initials: J
authors.lastname: Blouin
authors.forename: G
authors.initials: G
authors.lastname: Hauptmann
authors.forename: M
authors.initials: M
authors.lastname: Kazatchkine
authors.forename: B
authors.initials: B
authors.lastname: Uring-Lambert
mesh_terms: D000328:Adult; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D002648:Child; D003175:Complement C2 / Q000172:deficiency* / Q000235:genetics; D003181:Complement C4 / Q000172:deficiency* / Q000235:genetics; D003171:Complement Pathway, Classical / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D006239:Haplotypes; D006801:Humans; D007105:Immune Complex Diseases / Q000276:immunology* / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D003175:Complement C2; D003181:Complement C4; D017931:DNA Primers