title: A novel C3 mutation causing increased formation of the C3 convertase in familial atypical hemolytic uremic syndrome.
abstract: Atypical hemolytic uremic syndrome has been associated with dysregulation of the alternative complement pathway. In this study, a novel heterozygous C3 mutation was identified in a factor B-binding region in exon 41, V1636A (4973 T > C). The mutation was found in three family members affected with late-onset atypical hemolytic uremic syndrome and symptoms of glomerulonephritis. All three patients exhibited increased complement activation detected by decreased C3 levels and glomerular C3 deposits. Platelets from two of the patients had C3 and C9 deposits on the cell surface. Patient sera exhibited more C3 cleavage and higher levels of C3a. The C3 mutation resulted in increased C3 binding to factor B and increased net formation of the C3 convertase, even after decay induced by decay-accelerating factor and factor H, as assayed by surface plasmon resonance. Patient sera incubated with washed human platelets induced more C3 and C9 deposition on the cell surface in comparison with normal sera. More C3a was released into serum over time when washed platelets were exposed to patient sera. Results regarding C3 and C9 deposition on washed platelets were confirmed using purified patient C3 in C3-depleted serum. The results indicated enhanced convertase formation leading to increased complement activation on cell surfaces. Previously described C3 mutations showed loss of function with regard to C3 binding to complement regulators. To our knowledge, this study presents the first known C3 mutation inducing increased formation of the C3 convertase, thus explaining enhanced activation of the alternative pathway of complement.
authors.affiliation: Department of Pediatrics, Clinical Sciences Lund, Lund University, Lund 22184, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Sartz
authors.forename: Anders I
authors.initials: AI
authors.lastname: Olin
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Kristoffersson
authors.forename: Anne-lie
authors.initials: AL
authors.lastname: Ståhl
authors.forename: Martin E
authors.initials: ME
authors.lastname: Johansson
authors.forename: Kerstin
authors.initials: K
authors.lastname: Westman
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.forename: Kristina
authors.initials: K
authors.lastname: Nilsson-Ekdahl
authors.forename: Diana
authors.initials: D
authors.lastname: Karpman
mesh_terms: D000818:Animals; D065766:Atypical Hemolytic Uremic Syndrome; D019556:COS Cells; D002522:Chlorocebus aethiops; D003167:Complement Activation; D050577:Complement C3-C5 Convertases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015926:Complement C3a / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D003179:Complement C3b / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D003186:Complement C9 / Q000096:biosynthesis / Q000378:metabolism; D011415:Complement Factor B / Q000378:metabolism; D017242:Complement Factor H / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics; D005921:Glomerulonephritis / Q000235:genetics; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D003186:Complement C9; D015926:Complement C3a; D003179:Complement C3b; D017242:Complement Factor H; D050577:Complement C3-C5 Convertases; D011415:Complement Factor B