title: 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.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Tortajada
authors.forename: Hugo
authors.initials: H
authors.lastname: Yébenes
authors.forename: Cynthia
authors.initials: C
authors.lastname: Abarrategui-Garrido
authors.forename: Jaouad
authors.initials: J
authors.lastname: Anter
authors.forename: Jesús M
authors.initials: JM
authors.lastname: García-Fernández
authors.forename: Rubén
authors.initials: R
authors.lastname: Martínez-Barricarte
authors.forename: María
authors.initials: M
authors.lastname: Alba-Domínguez
authors.forename: Talat H
authors.initials: TH
authors.lastname: Malik
authors.forename: Rafael
authors.initials: R
authors.lastname: Bedoya
authors.forename: Rocío
authors.initials: R
authors.lastname: Cabrera Pérez
authors.forename: Margarita
authors.initials: M
authors.lastname: López Trascasa
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
authors.forename: Claire L
authors.initials: CL
authors.lastname: Harris
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Corral
authors.forename: Oscar
authors.initials: O
authors.lastname: Llorca
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez de Córdoba
mesh_terms: D002648:Child; D003176:Complement C3 / Q000737:chemistry / Q000378:metabolism*; D003180:Complement C3b Inactivator Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003165:Complement System Proteins / Q000302:isolation & purification / Q000378:metabolism; D005260:Female; D020440:Gene Duplication; D006461:Hemolysis; D006801:Humans; D055767:Immobilized Proteins / Q000737:chemistry / Q000378:metabolism; D007668:Kidney / Q000473:pathology; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D010375:Pedigree; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017422:Sequence Analysis, DNA
chemical_list: C517621:CFHR1 protein, human; C432223:CFHR5 protein, human; D003176:Complement C3; D003180:Complement C3b Inactivator Proteins; D055767:Immobilized Proteins; D003165:Complement System Proteins