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The Complement Factor H R1210C Mutation Is Associated With Atypical Hemolytic Uremic Syndrome

Ruben Martinez-Barricarte^*, Gaia Pianetti, Ruxandra Gautard, Joachim Misselwitz, Lisa Strain^||, Veronique Fremeaux-Bacchi^¶, Christine Skerka^**, Peter F. Zipfel^,**, Tim Goodship^||, Marina Noris, Giuseppe Remuzzi, Santiago Rodriguez de Cordoba^* on behalf of the European Working Party on the Genetics of HUS

^* Centro de Investigaciones Biológicas and Centro de Investigacion Biomedica en Enfermedades Raras, Madrid, Spain; Clinical Research for Rare Diseases, Aldo e Cele Dacco, Mario Negri Institute for Pharmacological Research, Ranica, Italy; Nephrology Department, Bretonneau Hospital, Tours, France; Friedrich Schiller University, Jena, Germany; ^|| Institute of Human Genetics, Newcastle upon Tyne University, Central Parkway, Newcastle upon Tyne, United Kingdom; ^¶ Service d'Immunologie Biologique, Hôpital Europeen Georges Pompidou, Paris, France; and ^** Department of Infection Biology, Hans Knöll Institute for Natural Product Research, Jena, Germany

Correspondence: Dr. Santiago Rodríguez de Córdoba, Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. Phone: +34 918373112; Fax: +34 915360432; E-mail: SRdeCordoba{at}cib.csic.es

Received for publication August 21, 2007. Accepted for publication October 19, 2007.

Mutations in the gene encoding complement factor H (CFH) that alter the C3b/polyanions-binding site in the C-terminal region impair the capacity of factor H to protect host cells. These mutations are also strongly associated with atypical hemolytic uremic syndrome (aHUS). Although most of the aHUS-associated CFH mutations seem "unique" to an individual patient or family, the R1210C mutation has been reported in several unrelated aHUS patients from distinct geographic origins. Five aHUS pedigrees and 7 individual aHUS patients were analyzed to identify potential correlations between the R1210C mutation and clinical phenotype and to characterize the origins of this mutation. The clinical phenotype of aHUS patients carrying the R1210C mutation was heterogeneous. Interestingly, 12 of the 13 affected patients carried at least one additional known genetic risk factor for aHUS. These data are in accord with the 30% penetrance of aHUS in R1210C mutation carriers, as it seems that the presence of other genetic or environmental risk factors significantly contribute to the manifestation and severity of aHUS in these subjects. Genotype analysis of CFH and CFHR3 polymorphisms in the 12 unrelated carriers suggested that the R1210C mutation has a single origin. In conclusion, the R1210C mutation of complement factor H is a prototypical aHUS mutation that is present as a rare polymorphism in geographically separated human populations.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673