title: Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases.
abstract: The complement factor H (FH) mutation R1210C, which was described in association with atypical hemolytic uremic syndrome (aHUS), also confers high risk of age-related macular degeneration (AMD) and associates with C3 glomerulopathy (C3G). To reveal the molecular basis of these associations and to provide insight into what determines the disease phenotype in FH-R1210C carriers, we identified FH-R1210C carriers in our aHUS, C3G, and AMD cohorts. Disease status, determined in patients and relatives, revealed an absence of AMD phenotypes in the aHUS cohort and, vice versa, a lack of renal disease in the AMD cohort. These findings were consistent with differences in the R1210C-independent overall risk for aHUS and AMD between mutation carriers developing one pathology or the other. R1210C is an unusual mutation that generates covalent complexes between FH and HSA. Using purified FH proteins and surface plasmon resonance analyses, we demonstrated that formation of these FH-HSA complexes impairs accessibility to all FH functional domains. These data suggest that R1210C is a unique C-terminal FH mutation that behaves as a partial FH deficiency, predisposing individuals to diverse pathologies with distinct underlying pathogenic mechanisms; the final disease outcome is then determined by R1210C-independent genetic risk factors.
authors.affiliation: Department of Ophthalmology, University Clinic of Navarra, Pamplona, Navarra, Spain;
authors.forename: Sergio
authors.initials: S
authors.lastname: Recalde
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain;
authors.forename: Agustin
authors.initials: A
authors.lastname: Tortajada
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain;
authors.forename: Marta
authors.initials: M
authors.lastname: Subias
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain;
authors.forename: Jaouad
authors.initials: J
authors.lastname: Anter
authors.affiliation: Nephrology and Kidney Transplant Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain;
authors.forename: Miquel
authors.initials: M
authors.lastname: Blasco
authors.affiliation: Mario Negri Institute for Pharmacology Research, Aldo and Cele Daccò Clinical Research Center for Rare Diseases, Ranica, Bergamo, Italy; and.
authors.forename: Ramona
authors.initials: R
authors.lastname: Maranta
authors.affiliation: Institute of Applied Ophthalmology, University of Valladolid, Valladolid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Coco
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain;
authors.forename: Sheila
authors.initials: S
authors.lastname: Pinto
authors.affiliation: Mario Negri Institute for Pharmacology Research, Aldo and Cele Daccò Clinical Research Center for Rare Diseases, Ranica, Bergamo, Italy; and.
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.affiliation: Department of Ophthalmology, University Clinic of Navarra, Pamplona, Navarra, Spain;
authors.forename: Alfredo
authors.initials: A
authors.lastname: García-Layana
authors.affiliation: Department of Cellular and Molecular Medicine, Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain; srdecordoba@cib.csic.es.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez de Córdoba
mesh_terms: D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics*; D003176:Complement C3; D017242:Complement Factor H / Q000235:genetics; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D007678:Kidney Glomerulus; D008268:Macular Degeneration / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree
chemical_list: C493495:CFH protein, human; D003176:Complement C3; D017242:Complement Factor H
keywords: complement; glomerular disease; hemolytic uremic syndrome