C3 glomerulopathy–associated CFHR1 mutation alters FHR oligomerization and complement regulation
Agustín Tortajada, … , Oscar Llorca, Santiago Rodríguez de Córdoba
Agustín Tortajada, … , Oscar Llorca, Santiago Rodríguez de Córdoba
Published May 24, 2013
Citation Information: J Clin Invest. 2013;123(6):2434-2446. https://doi.org/10.1172/JCI68280.
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Research Article

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

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.

Authors

Agustín Tortajada, Hugo Yébenes, Cynthia Abarrategui-Garrido, Jaouad Anter, Jesús M. García-Fernández, Rubén Martínez-Barricarte, María Alba-Domínguez, Talat H. Malik, Rafael Bedoya, Rocío Cabrera Pérez, Margarita López Trascasa, Matthew C. Pickering, Claire L. Harris, Pilar Sánchez-Corral, Oscar Llorca, Santiago Rodríguez de Córdoba

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Figure 1

Histology, immunofluorescence, and EM findings.

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Histology, immunofluorescence, and EM findings. Kidney biopsies from pro...
Kidney biopsies from probate GN29 (A–G) and his mother, GN29M (H–O), showed remarkably similar light, immunofluorescence, and ultrastructural findings. The characteristic histological lesion consisted of mesangial hypercellularity with thickened, eosinophil-rich segments of GBM (A and H). The affected glomerular segments were PAS positive and reacted to trichrome and Jones methenamine-silver stain (B, C, and I–K). The main immunofluorescence findings were prominent and diffuse C3 deposits, which were granular in some glomerular areas (D and L). IgG was absent from these deposits (F and M), although local deposits of IgM were observed in GN29 (E). Both biopsies showed similar ultrastructural alterations (G, N, and O) consisting of the presence of ribbon-like, osmiophilic deposits in the GBM (arrows); these electron-dense deposits were also evident in the mesangial matrix (asterisks). Original magnification, ×400 (A–C, H, and I); ×200 (D–F); ×1,600 (G); ×600 (J and K); ×100 (L and M); ×2,950 (N); ×8,900 (O).