A familial C3GN secondary to defective C3 regulation by complement receptor 1 and complement factor H

Sophie Chauvet, Lubka T. Roumenina, Sarah Bruneau, Maria Chiara Marinozzi, Tania Rybkine, Elizabeth C. Schramm, Anuja Java, John P. Atkinson, Jean Claude Aldigier, Frank Bridoux, Guy Touchard, Veronique Fremeaux-Bacchi

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

C3 glomerulopathy is a recently described form of CKD. C3GN is a subtype of C3 glomerulopathy characterized by predominant C3 deposits in the glomeruli and is commonly the result of acquired or genetic abnormalities in the alternative pathway (AP) of the complement system. We identified and characterized the first mutation of the C3 gene (p. I734T) in two related individuals diagnosed with C3GN. Immunofluorescence and electron microscopy studies showed C3 deposits in the subendothelial space, associated with unusual deposits located near the complement receptor 1 (CR1)-expressing podocytes. In vitro, this C3 mutation exhibited decreased binding toCR1, resultingin lessCR1-dependent cleavageofC3bby factor 1.Both patients had normal plasma C3 levels, and the mutant C3 interacted with factor B comparably to wild-type (WT) C3 to form a C3 convertase. Binding of mutant C3 to factor H was normal, but mutant C3 was less efficiently cleaved by factor I in the presence of factor H, leading to enhanced C3 fragment deposition on glomerular cells. In conclusion, our results reveal that a CR1 functional deficiency is a mechanism of intraglomerular AP dysregulation and could influence the localization of the glomerular C3 deposits.

Original languageEnglish
Pages (from-to)1665-1677
Number of pages13
JournalJournal of the American Society of Nephrology
Volume27
Issue number6
DOIs
StatePublished - Jun 2016

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