Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 11, Pages 4366-4371Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0812584106
Keywords
alternative pathway; AMD
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Funding
- Wellcome Trust [068823, 06850]
- Medical Research Council [84908]
- Ministerio de Ciencia e Innovacio [SAF 2008-00226]
- Centro de Investigacion Biome medica en Red de Enfermedades Raras
- Fundacion Renal Inigo Alvarez de Toledo
- Medical Research Council [G0701298] Funding Source: researchfish
- MRC [G0701298] Funding Source: UKRI
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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.
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