title: A Familial C3GN Secondary to Defective C3 Regulation by Complement Receptor 1 and Complement Factor H.
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 to CR1, resulting in less CR1-dependent cleavage of C3b by 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1138, Complément et Maladies, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France; sophie.chauvet@egp.aphp.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Chauvet
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1138, Complément et Maladies, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France;
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1064, Institut de Transplantation Urologie-Nephrologie, Centre Hospitalier Universitaire de Nantes, Université de Nantes, Nantes, France;
authors.forename: Sarah
authors.initials: S
authors.lastname: Bruneau
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1138, Complément et Maladies, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France; Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital européen Georges Pompidou, Paris, France;
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Marinozzi
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1138, Complément et Maladies, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes Sorbonne Paris-Cité, Paris, France; Université Pierre et Marie Curie (UPMC-Paris-6), Paris, France;
authors.forename: Tania
authors.initials: T
authors.lastname: Rybkine
authors.affiliation: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, Missouri;
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Schramm
authors.affiliation: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, Missouri;
authors.forename: Anuja
authors.initials: A
authors.lastname: Java
authors.affiliation: Department of Medicine, Division of Rheumatology, Washington University School of Medicine, Saint Louis, Missouri;
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.affiliation: Service de Nephrologie, Hôpital de Limoges, Limoges, France;
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Aldigier
authors.affiliation: Service de Nephrologie, and.
authors.forename: Frank
authors.initials: F
authors.lastname: Bridoux
authors.affiliation: Service de Nephrologie, and Service d'Anatomo-Pathologie et Pathologie ultrastructurale, Hôpital de Poitiers, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Touchard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S1138, Complément et Maladies, Centre de Recherche des Cordeliers, Paris, France; Assistance Publique-Hôpitaux de Paris, Service d'Immunologie Biologique, Hôpital européen Georges Pompidou, Paris, France;
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
mesh_terms: D000328:Adult; D003176:Complement C3 / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics; D005786:Gene Expression Regulation; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017463:Receptors, Complement 3b / Q000235:genetics*
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D017463:Receptors, Complement 3b; D017242:Complement Factor H
keywords: C; glomerular disease; immunology and pathology