title: Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome.
abstract: The hemolytic uremic syndrome is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. There are two general types. One occurs in epidemic form and is diarrheal associated (D+HUS). It has a good prognosis. The second is a rare form known as atypical (aHUS), which may be familial or sporadic, and has a poor prognosis. aHUS is increasingly recognized to be a disease of defective complement regulation, particularly cofactor activity. Mutations in membrane cofactor protein (MCP; CD46) that predispose to the development of aHUS were first identified in 2003. MCP is a membrane-bound complement regulator that acts as a cofactor for the factor I-mediated cleavage of C3b and C4b deposited on host cells. More than 20 different mutations in MCP have now been identified in patients with aHUS. Many of these mutants have been functionally characterized and have helped to define the pathogenic mechanisms leading to aHUS development. Over 75% of the reported mutations cause a reduction in MCP expression, due to homozygous, compound heterozygous or heterozygous mutations. This deficiency of MCP leads to inadequate control of complement activation on endothelial cells after an initiating injury. The remaining MCP mutants are expressed, but demonstrate reduced ligand (C3b/C4b) binding capacity and cofactor activity of MCP. MCP mutations in aHUS demonstrate incomplete penetrance, indicating that additional genetic and environmental factors are required to manifest disease. MCP mutants as a cause of aHUS have a favorable clinical outcome in comparison to patients with factor H (CFH) or factor I (IF) mutations. In 90% of the renal transplants performed in patients with MCP-HUS, there has been no recurrence of the primary disease, whilst >50% of factor I or factor H deficient patients have had a prompt recurrence. This highlights the importance of defining and characterizing the underlying genetic defects in patients with aHUS.
authors.affiliation: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Campus Box 8045, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Richards
authors.forename: M
authors.initials: M
authors.lastname: Kathryn Liszewski
authors.forename: David
authors.initials: D
authors.lastname: Kavanagh
authors.forename: Celia J
authors.initials: CJ
authors.lastname: Fang
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Moulton
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
mesh_terms: D006239:Haplotypes; D006463:Hemolytic-Uremic Syndrome / Q000145:classification / Q000209:etiology* / Q000235:genetics; D006801:Humans; D016030:Kidney Transplantation; D051916:Membrane Cofactor Protein / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D009154:Mutation
chemical_list: D051916:Membrane Cofactor Protein