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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 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 Citation Map 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 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. Related Collections Hemostasis, Thrombosis, and Vascular Biology Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome Celia J. Fang1, Veronique Fremeaux-Bacchi2, M. Kathryn Liszewski1, Gaia Pianetti3, Marina Noris3, Timothy H. J. Goodship4, and John P. Atkinson1 1 Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO; 2 Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique, Paris, France; 3 Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Bergamo, Italy; and 4 Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom 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 patients with aHUS were 2, R69W and A304V, that were expressed normally and for which no dysfunction was found. The R69W mutation is in complement control protein module 2, while A304V is in the hydrophobic transmembrane domain. In addition to 3 patients with aHUS, the A304V mutation was identified in 1 patient each with fatal Stx-HUS, the HELLP (hemolysis, elevated liver enzymes, and low platelets) 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 was 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?

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