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Blood, 1 August 2005, Vol. 106, No. 3, pp. 1092-1097. Prepublished online as a Blood First Edition Paper on April 14, 2005; DOI 10.1182/blood-2005-02-0561. This Article Full Text (PDF) All Versions of this Article: 2005-02-0561v1 106/3/1092    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 Drakesmith, H. Articles by Townsend, A. R Search for Related Content PubMed PubMed Citation Articles by Drakesmith, H. Articles by Townsend, A. R Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 9, 2005 Accepted April 1, 2005 Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin Hal Drakesmith*, Lisa M Schimanski, Emma Ormerod, Alison T Merryweather-Clarke, Vip Viprakasit, Jon P Edwards, Emma Sweetland, Judy M Bastin, Diana Cowley, Yingyong Chinthammitr, Kathryn J Robson, and Alain R Townsend Weatherall Institute of Molecular Medicine, Oxford, United Kingdom MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom; Department of Paediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand * Corresponding author; email: hdrakes{at}hammer.imm.ox.ac.uk. Ferroportin mediates iron export from cells; ferroportin mutations are associated with the iron overloading disorder hemochromatosis. We previously found that the A77D, V162del and G490D mutations inhibited ferroportin activity, but that other disease-associated ferroportin variants retained full iron export capability. The peptide hormone hepcidin inhibits ferroportin as part of a homeostatic negative feedback loop. We measured surface expression and function of wild-type ferroportin and fully active ferroportin mutants in the presence of hepcidin. We found that the Y64N and C326Y mutants of ferroportin are completely resistant to hepcidin inhibition, and N144D and N144H are partially resistant. Hemochromatosis associated ferroportin mutations therefore have two distinct effects on protein function; they either reduce iron export ability or produce a ferroportin variant that is hepcidin insensitive. The former mutation type is associated with Kupffer cell iron deposition and normal transferrin saturation in vivo, while patients with the latter category of FPN mutation have high transferrin saturation and tend to deposit iron throughout the liver parenchyma. Ferroportin-linked hemochromatosis may have a variable pathogenesis depending on the causative ferroportin mutant. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. Chung, T. Chaston, J. Marks, S. K. Srai, and P. A. Sharp Hepcidin Decreases Iron Transporter Expression in Vivo in Mouse Duodenum and Spleen and in Vitro in THP-1 Macrophages and Intestinal Caco-2 Cells J. Nutr., August 1, 2009; 139(8): 1457 - 1462. [Abstract] [Full Text] [PDF] R. L. Sham, P. D. Phatak, E. Nemeth, and T. 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