title: Modeling how CD46 deficiency predisposes to atypical hemolytic uremic syndrome.
abstract: Mutations in complement regulatory proteins predispose to the development of aHUS. Approximately 50% of patients bear a mutation in one of three complement control proteins, factor H, factor I, or membrane cofactor protein (MCP; CD46). Another membrane regulator that is closely related to MCP, decay accelerating factor (DAF; CD55) thus far has shown no association with aHUS and continues to be investigated. The goal of this study was to compare the regulatory profile of MCP and DAF and to assess how alterations in MCP predispose to complement dysregulation. We employed a model system of complement activation on Chinese hamster ovary (CHO) cell transfectants. The four regularly expressed isoforms of MCP and DAF inhibited C3b deposition by the alternative pathway. DAF, but not MCP, inhibited the classical pathway. Most patients with MCP-aHUS are heterozygous and express only 25-50% of the wild-type protein. We, therefore, analyzed the effect of reduced levels of wild-type MCP and found that cells with lowered expression levels were less efficient in inhibiting alternative pathway activation. Further, a dysfunctional MCP mutant, expressed at normal levels and identified in five patients with aHUS (S206P), failed to protect against C3b amplification on CHO cells, even if expression levels were increased 10-fold. Our results add new information relative to the necessity for appropriate expression levels of MCP and further implicate the alternative pathway in disease processes such as aHUS.
authors.affiliation: Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8045, St. Louis, MO 63110, USA.
authors.forename: M Kathryn
authors.initials: MK
authors.lastname: Liszewski
authors.forename: Marilyn K
authors.initials: MK
authors.lastname: Leung
authors.forename: Barbara
authors.initials: B
authors.lastname: Schraml
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
mesh_terms: D000818:Animals; D018958:CD55 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002478:Cells, Cultured; D003179:Complement C3b / Q000378:metabolism*; D017242:Complement Factor H / Q000378:metabolism; D003171:Complement Pathway, Classical; D006224:Cricetinae; D003412:Cricetulus; D020022:Genetic Predisposition to Disease; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics / Q000276:immunology*; D006801:Humans; D051916:Membrane Cofactor Protein / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D008954:Models, Biological; D009154:Mutation; D011487:Protein Conformation; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D018958:CD55 Antigens; D051916:Membrane Cofactor Protein; D020033:Protein Isoforms; D003179:Complement C3b; D017242:Complement Factor H