title: Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome.
abstract: Hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The non-Shiga toxin-associated HUS (atypical HUS [aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma complement regulators factor H and factor I and the widely expressed membrane cofactor protein (MCP; CD46) have been described recently. This study looked for MCP mutations in a panel of 120 patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS. The majority of patients have a mutation that causes reduced MCP surface expression. A small proportion expressed normal levels of a dysfunctional protein. As in other studies, incomplete penetrance is shown, suggesting that MCP is a predisposing factor rather than a direct causal factor. The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed, and the first MCP null individuals are described. This study confirms the association between MCP deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.
authors.affiliation: Assitance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique, Paris cedex 15, France. veronique.fremeaux-bacchi@hop.egp.ap-hop-paris.fr
authors.forename: Véronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Moulton
authors.forename: David
authors.initials: D
authors.lastname: Kavanagh
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Dragon-Durey
authors.forename: Jacques
authors.initials: J
authors.lastname: Blouin
authors.forename: Amy
authors.initials: A
authors.lastname: Caudy
authors.forename: Nadia
authors.initials: N
authors.lastname: Arzouk
authors.forename: Roxanna
authors.initials: R
authors.lastname: Cleper
authors.forename: Maud
authors.initials: M
authors.lastname: Francois
authors.forename: Genevieve
authors.initials: G
authors.lastname: Guest
authors.forename: Jacques
authors.initials: J
authors.lastname: Pourrat
authors.forename: Roland
authors.initials: R
authors.lastname: Seligman
authors.forename: Wolf Herman
authors.initials: WH
authors.lastname: Fridman
authors.forename: Chantal
authors.initials: C
authors.lastname: Loirat
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
mesh_terms: D000293:Adolescent; D000328:Adult; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003167:Complement Activation; D003165:Complement System Proteins / Q000032:analysis; D005091:Exons; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D051916:Membrane Cofactor Protein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051916:Membrane Cofactor Protein; D003165:Complement System Proteins