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Blood, 15 January 2008, Vol. 111, No. 2, pp. 624-632. Prepublished online as a Blood First Edition Paper on October 3, 2007; DOI 10.1182/blood-2007-04-084533. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-04-084533v1 111/2/624    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fang, C. J. Articles by Atkinson, J. P. Search for Related Content PubMed PubMed Citation Articles by Fang, C. J. Articles by Atkinson, J. P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 10, 2007 Accepted September 19, 2007 Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis and the HELLP syndrome Celia J. Fang, Veronique Fremeaux-Bacchi, M. Kathryn Liszewski, Gaia Pianetti, Marina Noris, Timothy H.J. Goodship, and John P. Atkinson* Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, United States Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Service d'Immunologie Biologique & INSERM Unite 255, Paris, France Clinical Research Center for Rare Diseases, Mario Negri Institute for Pharmacological Research, Bergamo, Italy Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom * Corresponding author; email: jatkinso{at}im.wustl.edu. The hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia and renal impairment. Genetic studies demonstrate that heterozygous mutations of membrane cofactor protein (MCP;CD46) predispose to atypical HUS (aHUS) which is not associated with exposure to Shiga-toxin (Stx). Among the initial 25 MCP mutations in aHUS patients, were two, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control protein module two while A304V is in the hydrophobic transmembrane domain. In addition to three patients with aHUS, the A304V mutation was identified in one patient each with fatal Stx-HUS, the HELLP syndrome, and glomerulonephritis with C3 deposits. A major goal was to assess if these putative mutations lead to defective complement regulation. Permanent cell lines expressing the mutated proteins were complement "challenged" and membrane control of C3 fragment deposition monitored. Both the R69W and A304V MCP mutations were deficient in their ability to control the alternative pathway of complement activation on a cell surface, illustrating the importance of modeling transmembrane proteins in situ. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Noris and G. Remuzzi Atypical Hemolytic-Uremic Syndrome N. Engl. J. Med., October 22, 2009; 361(17): 1676 - 1687. [Full Text] [PDF] F. Fakhouri, M. Jablonski, J. Lepercq, J. Blouin, A. Benachi, M. Hourmant, Y. Pirson, A. Durrbach, J.-P. Grunfeld, B. Knebelmann, et al. Factor H, membrane cofactor protein, and factor I mutations in patients with hemolysis, elevated liver enzymes, and low platelet count syndrome Blood, December 1, 2008; 112(12): 4542 - 4545. [Abstract] [Full Text] [PDF] M. K. Liszewski, P. Bertram, M. K. Leung, R. Hauhart, L. Zhang, and J. P. Atkinson Smallpox Inhibitor of Complement Enzymes (SPICE): Regulation of Complement Activation on Cells and Mechanism of Its Cellular Attachment J. Immunol., September 15, 2008; 181(6): 4199 - 4207. [Abstract] [Full Text] [PDF]

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