RT Journal Article
T1 Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B
A1 Montes, Tamara
A1 Tortajada, Agustin
A1 Tortajada Alonso, Agustín
A1 Morgan, B. Paul
A1 Rodriguez de Cordoba, Santiago
A1 Harris, Claire L.
AB 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 (fB32R), Gln (fB32Q), or Trp (fB32W) at position 32 in the Ba domain. The fB32Q 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 fB32Q had decreased activity compared with fB32R. Biacore comparison revealed markedly different proenzyme formation; fB32R bound C3b with 4-fold higher affinity, and formation of activated convertase was enhanced. Binding and functional differences were confirmed with recombinant fB32R and fB32Q; an intermediate affinity was revealed for fB32W. To confirm contribution of Ba to binding, affinity of Ba for C3b was determined. Ba-fB32R had 3-fold higher affinity compared with Ba-fB32Q. We demonstrate that the disease-protective effect of fB32Q 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.
PB National Academy of Sciences
YR 2009
FD 2009-03-17
LK https://hdl.handle.net/20.500.14352/114368
UL https://hdl.handle.net/20.500.14352/114368
LA eng
NO Montes, T., Tortajada, A., Morgan, B. P., Rodríguez De Córdoba, S., & Harris, C. L. (2009). Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proceedings of the National Academy of Sciences, 106(11), 4366-4371. https://doi.org/10.1073/pnas.0812584106
DS Docta Complutense
RD 18 abr 2025