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

A Tortajada, H Yébenes… - The Journal of …, 2013 - Am Soc Clin Investig
A Tortajada, H Yébenes, C Abarrategui-Garrido, J Anter, JM García-Fernández…
The Journal of clinical investigation, 2013Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation