Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 123, Issue 6, Pages 2434-2446Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI68280
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Funding
- Spanish Ministerio de Economia y Competitividad [SAF2011-26583, SAF2011-22988]
- Fundacion Renal Inigo Alvarez de Toledo
- European Union
- Ramon Areces Foundation
- Red Tematica de Investigacion Cooperativa en Cancer (RTICC) [RD06/0020/1001]
- Spanish Ministerio de Economia y Competitividad [P10900268, PS09/00122]
- MRC UK [G0701298]
- Autonomous Region of Madrid [S2010/BMD-2316]
- RTICC
- Fundacion de Investigacion Biomedica del Hospital Universitario La Paz
- MRC [G0701298] Funding Source: UKRI
- Medical Research Council [G0701298] Funding Source: researchfish
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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.
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