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J Am Soc Nephrol. 2016 May;27(5):1305-11. doi: 10.1681/ASN.2015050580. Epub 2015 Sep 16.

Molecular Basis of Factor H R1210C Association with Ocular and Renal Diseases.

Author information

1
Department of Ophthalmology, University Clinic of Navarra, Pamplona, Navarra, Spain;
2
Department of Cellular and Molecular Medicine, Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain;
3
Nephrology and Kidney Transplant Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain;
4
Mario Negri Institute for Pharmacology Research, Aldo and Cele Daccò Clinical Research Center for Rare Diseases, Ranica, Bergamo, Italy; and.
5
Institute of Applied Ophthalmology, University of Valladolid, Valladolid, Spain.
6
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.

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.

KEYWORDS:

complement; glomerular disease; hemolytic uremic syndrome

PMID:
26376859
PMCID:
PMC4849834
DOI:
10.1681/ASN.2015050580
[Indexed for MEDLINE]
Free PMC Article

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