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Human Molecular Genetics Advance Access published online on June 23, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp289
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The disease-protective complement factor H allotypic variant Ile62 shows increased binding affinity for C3b and enhanced cofactor activity

Agustín Tortajada1, Tamara Montes1, Ruben Martinez-Barricarte1, B. Paul Morgan2, Claire L. Harris2,* and Santiago Rodríguez de Córdoba1,*

1 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Centro de Investigación Biomédica en Enfermedades Raras and Instituto Reina Sofía de Investigaciones Nefrológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain 2 Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK

Corresponding authors: Dr. Santiago Rodríguez de Córdoba, Complement Genetics and Molecular Pathology Unit, Depart. of Cellular and Molecular Physiopathology, Centro de Investigaciones Biologicas, Ramiro de Maeztu 9, Madrid 28040, Spain. Tel: (+34) 91 7373112 x4432, Fax: (+34) 91 5360432, E-mail: srdecordoba{at}cib.csic.es Dr. Claire L Harris, Complement Biology Group, Depart. of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff, CF14 4XN, UK. Tel: (+44) 29 20687012, Fax: (+44) 29 20687079, E-mail: HarrisCL{at}cardiff.ac.uk

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 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 catalyse 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.

* These two authors contributed equally to this work.


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