Human Molecular Genetics Advance Access originally published online on June 23, 2009
Human Molecular Genetics 2009 18(18):3452-3461; doi:10.1093/hmg/ddp289
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The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity
1 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Centro de Investigación Biomédica en Enfermedades Raras, Instituto Reina Sofía de Investigaciones Nefrológicas, Ramiro de Maeztu 9 28040 Madrid, Spain and 2 Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK
* To whom correspondence should be addressed at: Complement Genetics and Molecular Pathology Unit, Department of Cellular and Molecular Medicine, Centro de Investigaciones Biologicas, Ramiro de Maeztu 9, Madrid 28040, Spain (S.R.C.) and Complement Biology Group, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK (C.L.H.). Tel: +34 917373112 x4432; Fax: +34 915360432; Email: srdecordoba{at}cib.csic.es (S.R.C.) and Tel: +44 2920687012; Fax: +44 2920687079; Email: harriscl{at}cardiff.ac.uk (C.L.H.)
Received May 4, 2009; Revised May 28, 2009; Accepted June 16, 2009
Mutations and polymorphisms in the gene encoding factor H (CFH) have been associated with atypical haemolytic uraemic syndrome, dense deposit disease and age-related macular degeneration. The disease-predisposing CFH variants show a differential association with pathology that has been very useful to unravel critical events in the pathogenesis of one or other disease. In contrast, the factor H (fH)-Ile62 polymorphism confers strong protection to all three diseases. Using ELISA-based methods and surface plasmon resonance analyses, we show here that the protective fH-Ile62 variant binds more efficiently to C3b than fH-Val62 and competes better with factor B in proconvertase formation. Functional analyses demonstrate an increased cofactor activity for fH-Ile62 in the factor I-mediated cleavage of fluid phase and surface-bound C3b; however, the two fH variants show no differences in decay accelerating activity. From these data, we conclude that the protective effect of the fH-Ile62 variant is due to its better capacity to bind C3b, inhibit proconvertase formation and catalyze inactivation of fluid-phase and surface-bound C3b. This demonstration of the functional consequences of the fH-Ile62 polymorphism provides relevant insights into the complement regulatory activities of fH that will be useful in disease prediction and future development of effective therapeutics for disorders caused by complement dysregulation.
The authors wish it to be known that, in their opinion, the last two authors should be regarded as joint Last Authors.