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 Tortajada^1,2, Hugo Yébenes¹, Cynthia Abarrategui-Garrido^2,3, Jaouad Anter^1,2, Jesús M. García-Fernández^1,2, Rubén Martínez-Barricarte^1,2, María Alba-Domínguez^2,3, Talat H. Malik⁴, Rafael Bedoya⁵, Rocío Cabrera Pérez⁵, Margarita López Trascasa^2,6, Matthew C. Pickering⁴, Claire L. Harris⁷, Pilar Sánchez-Corral^2,3, Oscar Llorca¹ and Santiago Rodríguez de Córdoba^1,2

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.