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

Tortajada, Agustín, Yébenes, Hugo, Abarrategui-Garrido, Cynthia, Anter, Jaouad, García-Fernández, Jesús M., Martínez-Barricarte, Rubén, Alba-Domínguez, María, Malik, Talat H., Bedoya, Rafael, Pérez, Rocío Cabrera, Trascasa, Margarita López, Pickering, Matthew C., Harris, Claire Louise, Sánchez-Corral, Pilar, Llorca, Oscar and Rodríguez de Córdoba, Santiago 2013. C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation. The Journal of Clinical Investigation 123 (6) , pp. 2434-2446. 10.1172/JCI68280

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
Additional Information: Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0021-9738/ (accessed 24/02/2014)
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Date of First Compliant Deposit: 30 March 2016
Last Modified: 04 Jun 2017 05:06
URI: http://orca.cf.ac.uk/id/eprint/48491

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