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C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation

发布于：2013年8月5日    文字：【大】【中】【小】

J Clin Invest. 2013 Jun 3;123(6):2434-46.

C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation.

Tortajada A, Yébenes H, Abarrategui-Garrido C, Anter J, García-Fernández JM, Martínez-Barricarte R, Alba-Domínguez M, Malik TH, Bedoya R, Cabrera Pérez R,López Trascasa M, Pickering MC, Harris CL, Sánchez-Corral P, Llorca O, Rodríguez de Córdoba S.

Source

Centro de InvestigacionesBiológicas, Consejo Superior de InvestigacionesCientíficas, Madrid, Spain.

Abstract

C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H–related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain.In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G.

C3肾小球病是一组严重的肾脏疾病，以特殊的肾炎及C3沉积为特点，病因为补体系统失调。这里我们报道了一种新发现的家族性的C3肾小球病，这种疾病是由编码FHR1的CFHR1基因突变引起的。这种突变可造成保守的FHR2和FHR5N端SCR段的重复编码。我们已经发现原始的FHR1，FHR2和FHR5在人体血液循环中以纯合或杂合的形式形成二聚体，这种二聚体的形成可能源于保守的N端结构域。突变的FHR1分子由于N端结构域的重叠，可导致FHR1多聚体的形成。在表面等离子共振中发现这种多聚体对C3b, iC3b和 C3dg的亲和力增强，并可以与H因子竞争结合这些分子。这些数据提示，FHR1，FHR2和FHR5可以形成各种形式的低聚体，这些低聚体结构的改变可能影响补体系统的调节。总之，我们发现了一种特殊的CFHR1的基因突变，对这种突变引起的分子功能改变的研究对FHR蛋白的生物学机制有所提示，对C3肾病潜在的发病机制的研究也作出了贡献。