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Title

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

AuthorsTortajada, Agustín ; Yébenes, Hugo; Anter, Jauoad; García-Fernández, Jesús; Martínez-Barricarte, Rubén ; Llorca, Óscar ; Rodríguez de Córdoba, Santiago
KeywordsComplement
C3
CFHR1
Factor H-related
Glomerulopathy
Issue DateJun-2013
PublisherAmerican Society for Clinical Investigation
CitationJournal of Clinical Investigation 123 (6):2434–2446 (2013)
AbstractC3 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. Copyright © 2013, American Society for Clinical Investigation.
DescriptionTortajada, Agustín et alt.
Publisher version (URL)http://dx.doi.org/10.1172/JCI68280
URIhttp://hdl.handle.net/10261/96650
DOI10.1172/JCI68280
ISSN0021-9738
Appears in Collections:(CIB) Artículos
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