Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome.
Hemolytic uremic syndrome (HUS) is an important cause of acute renal failure in children. Mutations in one or more genes encoding complement-regulatory proteins have been reported in approximately one-third of nondiarrheal, atypical HUS (aHUS) patients, suggesting a defect in the protection of cell surfaces against complement activation in susceptible individuals. Here, we identified a subgroup of aHUS patients showing persistent activation of the complement alternative pathway and found within this subgroup two families with mutations in the gene encoding factor B (BF), a zymogen that carries the catalytic site of the complement alternative pathway convertase (C3bBb). Functional analyses demonstrated that F286L and K323E aHUS-associated BF mutations are gain-of-function mutations that result in enhanced formation of the C3bBb convertase or increased resistance to inactivation by complement regulators. These data expand our understanding of the genetic factors conferring predisposition to aHUS, demonstrate the critical role of the alternative complement pathway in the pathogenesis of aHUS, and provide support for the use of complement-inhibition therapies to prevent or reduce tissue damage caused by dysregulated complement activation.
Goicoechea de Jorge
Elena
E
Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Harris
Claire L
CL
Esparza-Gordillo
Jorge
J
Carreras
Luis
L
Arranz
Elena Aller
EA
Garrido
Cynthia Abarrategui
CA
López-Trascasa
Margarita
M
Sánchez-Corral
Pilar
P
Morgan
B Paul
BP
Rodríguez de Córdoba
Santiago
S
D018958:CD55 Antigens / Q000494:pharmacology; D011415:Complement Factor B / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D017242:Complement Factor H / Q000494:pharmacology; D003170:Complement Pathway, Alternative; D006463:Hemolytic-Uremic Syndrome / Q000209:etiology / Q000235:genetics* / Q000276:immunology; D006801:Humans; D009154:Mutation; D013329:Structure-Activity Relationship
D018958:CD55 Antigens; D017242:Complement Factor H; D011415:Complement Factor B