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

J Clin Invest. 2013 Jun;123(6):2434-46. doi: 10.1172/JCI68280.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Complement C3 / chemistry
  • Complement C3 / metabolism*
  • Complement C3b Inactivator Proteins / chemistry
  • Complement C3b Inactivator Proteins / genetics*
  • Complement C3b Inactivator Proteins / metabolism
  • Complement System Proteins / isolation & purification
  • Complement System Proteins / metabolism
  • Female
  • Gene Duplication
  • Hemolysis
  • Humans
  • Immobilized Proteins / chemistry
  • Immobilized Proteins / metabolism
  • Kidney / pathology
  • Kidney Diseases / genetics*
  • Male
  • Middle Aged
  • Mutagenesis, Insertional
  • Pedigree
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Quaternary
  • Sequence Analysis, DNA

Substances

  • CFHR1 protein, human
  • Complement C3
  • Complement C3b Inactivator Proteins
  • FHR5 protein, human
  • Immobilized Proteins
  • Complement System Proteins