Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B.
Mutations and polymorphisms in complement genes have been linked with numerous rare and prevalent disorders, implicating dysregulation of complement in pathogenesis. The 3 common alleles of factor B (fB) encode Arg (fB(32R)), Gln (fB(32Q)), or Trp (fB(32W)) at position 32 in the Ba domain. The fB(32Q) allele is protective for age-related macular degeneration, the commonest cause of blindness in developed countries. Factor B variants were purified from plasma of homozygous individuals and were tested in hemolysis assays. The protective variant fB(32Q) had decreased activity compared with fB(32R). Biacore comparison revealed markedly different proenzyme formation; fB(32R) bound C3b with 4-fold higher affinity, and formation of activated convertase was enhanced. Binding and functional differences were confirmed with recombinant fB(32R) and fB(32Q); an intermediate affinity was revealed for fB(32W). To confirm contribution of Ba to binding, affinity of Ba for C3b was determined. Ba-fB(32R) had 3-fold higher affinity compared with Ba-fB(32Q). We demonstrate that the disease-protective effect of fB(32Q) is consequent on decreased potential to form convertase and amplify complement activation. Knowledge of the functional consequences of polymorphisms in complement activators and regulators will aid disease prediction and inform targeting of diagnostics and therapeutics.
Montes
Tamara
T
Consejo Superior de Investigaciones Cientificas, Centro de Investigación Biomédica en Red de Enfermedades Raras and Fundación Renal Iñigo Alvarez de Toledo, Ramiro de Maeztu 9, 28040 Madrid, Spain.
Tortajada
Agustín
A
Morgan
B Paul
BP
Rodríguez de Córdoba
Santiago
S
Harris
Claire L
CL
D003166:Complement Activating Enzymes; D003167:Complement Activation / Q000235:genetics; D003179:Complement C3b / Q000378:metabolism; D011415:Complement Factor B / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D008268:Macular Degeneration / Q000517:prevention & control*; D011110:Polymorphism, Genetic
D003179:Complement C3b; D003166:Complement Activating Enzymes; D011415:Complement Factor B