title: Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome.
abstract: Membrane cofactor protein (MCP; CD46) is a widely expressed transmembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10-20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237/S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237/S238 deletion had reduced MCP levels and approximately 50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of protein, but demonstrated approximately 50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies.
authors.affiliation: Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle NE1 4LP, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Richards
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Kemp
authors.forename: M Kathryn
authors.initials: MK
authors.lastname: Liszewski
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.forename: Anne K
authors.initials: AK
authors.lastname: Lampe
authors.forename: Ronny
authors.initials: R
authors.lastname: Decorte
authors.forename: M Hamza
authors.initials: MH
authors.lastname: Müslümanoğlu
authors.forename: Salih
authors.initials: S
authors.lastname: Kavukcu
authors.forename: Guido
authors.initials: G
authors.lastname: Filler
authors.forename: Yves
authors.initials: Y
authors.lastname: Pirson
authors.forename: Leana S
authors.initials: LS
authors.lastname: Wen
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001483:Base Sequence; D016466:CHO Cells; D002874:Chromosome Mapping; D003169:Complement Inactivator Proteins / Q000235:genetics*; D006224:Cricetinae; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010375:Pedigree; D017384:Sequence Deletion; D014162:Transfection
chemical_list: D015703:Antigens, CD; C497857:CD46 protein, human; D003169:Complement Inactivator Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins