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.
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11 June 2007
Brief Definitive Report|
May 21 2007
Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains
Matthew C. Pickering,
Matthew C. Pickering
1Molecular Genetics and Rheumatology Section
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Elena Goicoechea de Jorge,
Elena Goicoechea de Jorge
3Departamento 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
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Rubén Martinez-Barricarte,
Rubén Martinez-Barricarte
3Departamento 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
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Sergio Recalde,
Sergio Recalde
4Department of Ophthalmology, University Clinic of Navarra University, 31080 Pamplona, Spain
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Alfredo Garcia-Layana,
Alfredo Garcia-Layana
4Department of Ophthalmology, University Clinic of Navarra University, 31080 Pamplona, Spain
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Kirsten L. Rose,
Kirsten L. Rose
1Molecular Genetics and Rheumatology Section
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Jill Moss,
Jill Moss
2Department of Histopathology, Faculty of Medicine, Imperial College, London W12 0NN, England, UK
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Mark J. Walport,
Mark J. Walport
1Molecular Genetics and Rheumatology Section
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H. Terence Cook,
H. Terence Cook
2Department of Histopathology, Faculty of Medicine, Imperial College, London W12 0NN, England, UK
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Santiago Rodriguez de Córdoba,
Santiago Rodriguez de Córdoba
3Departamento 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
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Marina Botto
Marina Botto
1Molecular Genetics and Rheumatology Section
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Matthew C. Pickering
1Molecular Genetics and Rheumatology Section
Elena Goicoechea de Jorge
3Departamento 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
Rubén Martinez-Barricarte
3Departamento 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
Sergio Recalde
4Department of Ophthalmology, University Clinic of Navarra University, 31080 Pamplona, Spain
Alfredo Garcia-Layana
4Department of Ophthalmology, University Clinic of Navarra University, 31080 Pamplona, Spain
Kirsten L. Rose
1Molecular Genetics and Rheumatology Section
Jill Moss
2Department of Histopathology, Faculty of Medicine, Imperial College, London W12 0NN, England, UK
Mark J. Walport
1Molecular Genetics and Rheumatology Section
H. Terence Cook
2Department of Histopathology, Faculty of Medicine, Imperial College, London W12 0NN, England, UK
Santiago Rodriguez de Córdoba
3Departamento 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
Marina Botto
1Molecular Genetics and Rheumatology Section
CORRESPONDENCE Matthew Pickering: [email protected] OR Santiago Rodríguez de Córdoba: [email protected]
M.C. Pickering and E. Goicoechea de Jorge contributed equally to this work.
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.
Received:
February 08 2007
Accepted:
April 13 2007
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2007
J Exp Med (2007) 204 (6): 1249–1256.
Article history
Received:
February 08 2007
Accepted:
April 13 2007
Connected Content
Citation
Matthew C. Pickering, Elena Goicoechea de Jorge, Rubén Martinez-Barricarte, Sergio Recalde, Alfredo Garcia-Layana, Kirsten L. Rose, Jill Moss, Mark J. Walport, H. Terence Cook, Santiago Rodriguez de Córdoba, Marina Botto; Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains . J Exp Med 11 June 2007; 204 (6): 1249–1256. doi: https://doi.org/10.1084/jem.20070301
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