title: Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome.
abstract: The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies demonstrate that heterozygous mutations of membrane cofactor protein (MCP;CD46) predispose to atypical HUS (aHUS), which is not associated with exposure to Shiga toxin (Stx). Among the initial 25 MCP mutations in patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control protein module 2, while A304V is in the hydrophobic transmembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated proteins were complement "challenged," and membrane control of C3 fragment deposition was monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transmembrane proteins in situ.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Celia J
authors.initials: CJ
authors.lastname: Fang
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.forename: M Kathryn
authors.initials: MK
authors.lastname: Liszewski
authors.forename: Gaia
authors.initials: G
authors.lastname: Pianetti
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: D019943:Amino Acid Substitution; D003167:Complement Activation / Q000235:genetics*; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005921:Glomerulonephritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017359:HELLP Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006461:Hemolysis / Q000235:genetics; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D020125:Mutation, Missense; D011247:Pregnancy; D017434:Protein Structure, Tertiary / Q000235:genetics; D022621:Shiga Toxin
chemical_list: C497857:CD46 protein, human; D003176:Complement C3; D051916:Membrane Cofactor Protein; D022621:Shiga Toxin