Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B
Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B
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DOI：
10.1073/pnas.0812584106
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发表时间：
2009-03-17
影响因子：
11.1
通讯作者：
Harris, Claire L.
中科院分区：
文献类型：
--
作者：
Montes, Tamara;Tortajada, Agustin;Harris, Claire L.
补体基因的突变和多态性与许多罕见和流行的疾病有关，在发病机制中涉及补体调节异常。因子B（fB）的3种常见等位基因编码Ba结构域中第32位的Arg（fB（32 R））、Gln（fB（32 Q））或Trp（fB（32 W））。fB（32 Q）等位基因对年龄相关性黄斑变性具有保护作用，这是发达国家最常见的致盲原因。从纯合个体的血浆中纯化因子B变体，并在溶血测定中进行测试。与fB（32 R）相比，保护性变体fB（32 Q）具有降低的活性。Biacore比较显示明显不同的酶原形成; fB（32 R）以4倍更高的亲和力结合C3 b，并且活化转化酶的形成增强。用重组fB（32 R）和fB（32 Q）证实了结合和功能差异;揭示了对fB（32 W）的中间亲和力。为了确认Ba对结合的贡献，测定了Ba对C3 b的亲和力。与Ba-fB（32 Q）相比，Ba-fB（32 R）具有3倍更高的亲和力。我们证明，fB（32 Q）的疾病保护作用是由于形成转化酶和放大补体激活的潜力降低。了解补体激活剂和调节剂中多态性的功能后果将有助于疾病预测，并为诊断和治疗提供信息。
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.