title: Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome.
abstract: Recent studies have identified mutations in the complement regulatory gene factor I (CFI) that predispose to atypical hemolytic uremic syndrome (aHUS). CFI is a two-chain serine protease in which the light chain carries the catalytic domain while the heavy chain's function is unclear. It downregulates the alternative and classical complement pathways by cleaving the alpha' chains of C3b and C4b in the presence of cofactor proteins (known as cofactor activity). Many CFI mutations in aHUS result in low CFI levels with a consequent quantitative defect in complement regulation. In others, the mutant protein is present in normal amounts but the presumed functional deficiency has not yet been defined. In this report we examine the nature of the functional defect in aHUS-associated CFI mutations. The I322T, D501N and D506V mutations reside in the serine protease domain of CFI and result in secreted proteins that lack C3b and C4b cofactor activity. The delTTCAC (1446-1450) mutant leads to a protein that is not secreted. The R299W mutant lies in a region of the CFI heavy chain of no known function. Our assessments demonstrate decreased C3b and C4b cofactor activity, providing evidence that this region is important for cofactor activity. In two other heavy chain mutants and one probable polymorphic variant, no functional deficiency was identified. These defective mutant proteins will result in an inability to appropriately control the complement cascade at sites of endothelial cell injury. The excessive complement activation for a given degree of damage may result in generation of a procoagulant state and aHUS.
authors.affiliation: Division of Rheumatology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kavanagh
authors.forename: Anna
authors.initials: A
authors.lastname: Richards
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Richard
authors.initials: R
authors.lastname: Hauhart
authors.forename: M Kathryn
authors.initials: MK
authors.lastname: Liszewski
authors.forename: Diana
authors.initials: D
authors.lastname: Karpman
authors.forename: Judith A
authors.initials: JA
authors.lastname: Goodship
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
mesh_terms: D000328:Adult; D002460:Cell Line; D002675:Child, Preschool; D003179:Complement C3b / Q000378:metabolism; D015935:Complement C4b / Q000378:metabolism; D017244:Complement Factor I / Q000737:chemistry / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D011994:Recombinant Proteins; D003179:Complement C3b; D015935:Complement C4b; D017244:Complement Factor I