C3 glomerulopathy–associated CFHR1 mutation alters FHR oligomerization and complement regulation
Agustín Tortajada, … , Oscar Llorca, Santiago Rodríguez de Córdoba
Agustín Tortajada, … , Oscar Llorca, Santiago Rodríguez de Córdoba
Published May 24, 2013
Citation Information: J Clin Invest. 2013;123(6):2434-2446. https://doi.org/10.1172/JCI68280.
View: Text | PDF
Research Article

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

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.

Authors

Agustín Tortajada, Hugo Yébenes, Cynthia Abarrategui-Garrido, Jaouad Anter, Jesús M. García-Fernández, Rubén Martínez-Barricarte, María Alba-Domínguez, Talat H. Malik, Rafael Bedoya, Rocío Cabrera Pérez, Margarita López Trascasa, Matthew C. Pickering, Claire L. Harris, Pilar Sánchez-Corral, Oscar Llorca, Santiago Rodríguez de Córdoba

×

Figure 9

Proposed model for a novel pathogenic mechanism in C3G.

Options: View larger image (or click on image) Download as PowerPoint
Proposed model for a novel pathogenic mechanism in C3G. FH is an elongat...
FH is an elongated glycoprotein of 155 kDa composed of 20 SCRs (small circles). FH presents C3b binding sites at each end of the molecule. The N-terminal C3b binding site mediates the accelerated decay of the AP C3 convertase (C3bBb) and the cofactor activity for the FI-dependent proteolytic inactivation of C3b. The C-terminal region binds both C3b and polyanions normally present in the cell surfaces (e.g., sialic acid, heparan sulfates, and glycosaminoglycans). This region is essential for the complement regulatory activity of FH on surfaces and to discriminate between self and pathogens, which normally lack these polyanions on their surfaces. Extensive experimental data generated during the last 10 years has provided conclusive evidence that mutations disrupting the functional activity of the C-terminal region, like those associated with aHUS, decrease the avidity of FH for cell surfaces and impair complement regulation (34–36). The data reported here suggest similarities between the established model for the aHUS-associated FH mutations and the FHR1 mutant described here. We therefore propose that multimerization of the FHRs as a consequence of duplication of the oligomerization domain in mutant FHR1, FHR2, or FHR5 proteins increases binding to surface-bound C3b, iC3b, C3dg, and carbohydrates, resulting in enhanced competition with FH that decreases its complement regulatory capacity and causes different degrees of cell surface complement dysregulation.