C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation
C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation
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DOI：
10.1172/jci68280
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发表时间：
2013-06-01
影响因子：
15.9
通讯作者：
Rodriguez de Cordoba, Santiago
中科院分区：
文献类型：
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作者：
Tortajada, Agustin;Yebenes, Hugo;Rodriguez de Cordoba, Santiago
C3肾小球病（C3 glomerulopathies，C3 G）是一组严重的肾脏疾病，具有由补体失调引起的肾小球炎症和C3沉积的独特模式。在这里，我们报告的基因补体因子H相关1（CFHR 1），它编码FHR 1的家族性C3 G相关基因组突变的鉴定。该突变导致在FHR 2和FHR 5中保守的N-末端短共有重复序列（SCR）的重复。我们确定，天然FHR 1，FHR 2和FHR 5在血浆中循环的同源和异源寡聚复合物，其形成可能是由保守的N-末端结构域介导的。在突变型FHR 1中，N-末端结构域的复制导致形成异常大的多聚体FHR复合物，其在表面等离子体共振（SPR）研究和溶血测定中表现出对FHR 1配体C3 b、iC 3b和C3 dg的亲和力增加，并增强与补体因子H（FH）的竞争。这些数据揭示了FHR 1、FHR 2和FHR 5组织寡聚复合物的组合库，并证明了FHR寡聚化的变化影响补体激活的调节。总之，我们对独特CFHR 1突变的鉴定和表征提供了对FHRs生物学的深入了解，并有助于我们理解C3 G的致病机制。
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.