Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B.

Abstract

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.

• Authors: Tamara Montes, Agustín Tortajada, B Paul Morgan, Santiago Rodríguez de Córdoba, Claire L Harris
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 11 Pg. 4366-71 (Mar 17 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19255449 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Complement C3b
• Complement Activating Enzymes
• Complement Factor B

Topics

• Complement Activating Enzymes
• Complement Activation (genetics)
• Complement C3b (metabolism)
• Complement Factor B (genetics, metabolism)
• Homozygote
• Humans
• Macular Degeneration (prevention & control)
• Polymorphism, Genetic