jueves, 6 de junio de 2013

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

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

Research Article

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

Agustín Tortajada1,2, Hugo Yébenes1, Cynthia Abarrategui-Garrido2,3, Jaouad Anter1,2, Jesús M. García-Fernández1,2, Rubén Martínez-Barricarte1,2, María Alba-Domínguez2,3, Talat H. Malik4, Rafael Bedoya5, Rocío Cabrera Pérez5, Margarita López Trascasa2,6, Matthew C. Pickering4, Claire L. Harris7, Pilar Sánchez-Corral2,3, Oscar Llorca1 and Santiago Rodríguez de Córdoba1,2
1Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
2Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain.
3Unidad de Investigación, Hospital Universitario de La Paz/IdiPAZ, Madrid, Spain.
4Centre for Complement and Inflammation Research, Imperial College, London, United Kingdom.
5Servicios de Nefrología Pediátrica y Anatomía Patológica, Hospital Virgen de Rocío, Sevilla, Spain.
6Unidad de Inmunología, Hospital Universitario de La Paz/IdiPAZ, Madrid, Spain.
7Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Address correspondence to: Santiago Rodríguez de Córdoba, Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. Phone: 34.918373112; Fax: 34.915360432; E-mail: SRdeCordoba@cib.csic.es.
Authorship note: Agustín Tortajada, Hugo Yébenes, and Cynthia Abarrategui-Garrido contributed equally to this work.
First published May 24, 2013
Received for publication December 18, 2012, and accepted in revised form March 6, 2013.
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.
See the related Commentary beginning on page 2357.

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