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Title: | C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation |
Authors: | Tortajada, Agustín ![]() ![]() ![]() ![]() |
Keywords: | Complement C3 CFHR1 Factor H-related Glomerulopathy |
Issue Date: | Jun-2013 |
Publisher: | American Society for Clinical Investigation |
Citation: | Journal of Clinical Investigation 123 (6):2434–2446 (2013) |
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. Copyright © 2013, American Society for Clinical Investigation. |
Description: | Tortajada, Agustín et alt. |
Publisher version (URL): | http://dx.doi.org/10.1172/JCI68280 |
URI: | http://hdl.handle.net/10261/96650 |
DOI: | 10.1172/JCI68280 |
ISSN: | 0021-9738 |
Appears in Collections: | (CIB) Artículos |
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JCI 123 (6) 2013-Óscar Llorca.pdf | 4,07 MB | Adobe PDF | ![]() View/Open |
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