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¹ Molecular Genetics and Rheumatology Section and ² Department of Histopathology, Faculty of Medicine, Imperial College, London W12 0NN, England, UK
³ Departamento de Fisiopatologia Celular y Molecular, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Red de Enfermedades Raras–Instituto de Salud Carlos III, 28040 Madrid, Spain
⁴ Department of Ophthalmology, University Clinic of Navarra University, 31080 Pamplona, Spain

CORRESPONDENCE Matthew Pickering: matthew.pickering{at}imperial.ac.uk OR Santiago Rodríguez de Córdoba: SRdeCordoba{at}cib.csic.es

Factor H (FH) is an abundant serum glycoprotein that regulates the alternative pathway of complement-preventing uncontrolled plasma C3 activation and nonspecific damage to host tissues. Age-related macular degeneration (AMD), atypical hemolytic uremic syndrome (aHUS), and membranoproliferative glomerulonephritis type II (MPGN2) are associated with polymorphisms or mutations in the FH gene (Cfh), suggesting the existence of a genotype–phenotype relationship. Although AMD and MPGN2 share pathological similarities with the accumulation of complement-containing debris within the eye and kidney, respectively, aHUS is characterized by renal endothelial injury. This pathological distinction was reflected in our Cfh association analysis, which demonstrated that although AMD and MPGN2 share a Cfh at-risk haplotype, the haplotype for aHUS was unique. FH-deficient mice have uncontrolled plasma C3 activation and spontaneously develop MPGN2 but not aHUS. We show that these mice, transgenically expressing a mouse FH protein functionally equivalent to aHUS-associated human FH mutants, regulate C3 activation in plasma and spontaneously develop aHUS but not MPGN2. These animals represent the first model of aHUS and provide in vivo evidence that effective plasma C3 regulation and the defective control of complement activation on renal endothelium are the critical events in the molecular pathogenesis of FH-associated aHUS.

S. Rodriguez de Córdoba and M. Botto contributed equally to this work.

M.J. Walport's present address is the Wellcome Trust, London NW1 2BE, England, UK.

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