title: Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome.
abstract: Mutations in the plasma complement regulator factor H (CFH) and the transmembrane complement regulator membrane co-factor protein (MCP) have been shown to predispose to atypical hemolytic uremic syndrome (HUS). Both of these proteins act as co-factors for complement factor I (IF). IF is a highly specific serine protease that cleaves the alpha-chains of C3b and C4b and thus downregulates activation of both the classical and the alternative complement pathways. This study looked for IF mutations in a panel of 76 patients with HUS. Mutations were detected in two patients, both of whom had reduced serum IF levels. A heterozygous bp change, c.463 G>A, which results in a premature stop codon (W127X), was found in one, and in the other, a heterozygous single base pair deletion in exon 7 (del 922C) was detected. Both patients had a history of recurrent HUS after transplantation. This is in accordance with the high rate of recurrence in patients with CFH mutations. Patients who are reported to have mutations in MCP, by contrast, do not have recurrence after transplantation. As with CFH- and MCP-associated HUS, there was incomplete penetrance in the family of one of the affected individuals. This study provides further evidence that atypical HUS is a disease of complement dysregulation.
authors.affiliation: Institute of Human Genetics, University of Newcastle upon Tyne, Tyne and Wear NE1 3BZ, UK.
authors.forename: David
authors.initials: D
authors.lastname: Kavanagh
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Kemp
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Mayland
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Winney
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
authors.forename: Graham
authors.initials: G
authors.lastname: Warwick
authors.forename: Anna
authors.initials: A
authors.lastname: Richards
authors.forename: Roy
authors.initials: R
authors.lastname: Ward
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
mesh_terms: D000328:Adult; D002648:Child; D017244:Complement Factor I / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree
chemical_list: D017244:Complement Factor I