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Blood, 9 July 2009, Vol. 114, No. 2, pp. 437-443. Prepublished online as a Blood First Edition Paper on April 21, 2009; DOI 10.1182/blood-2008-03-146134. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-03-146134v1 114/2/437    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 Fernandes, A. Articles by Nemeth, E. Search for Related Content PubMed PubMed Citation Articles by Fernandes, A. Articles by Nemeth, E. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 24, 2008 Accepted April 13, 2009 The molecular basis of hepcidin-resistant hereditary hemochromatosis Augustine Fernandes, Gloria C. Preza, Yen Phung, Ivana De Domenico, Jerry Kaplan, Tomas Ganz, and Elizabeta Nemeth* Departments of Medicine and Pathology, David Geffen School of Medicine, University of California, Los Angeles, CA, United States Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT, United States * Corresponding author; email: enemeth{at}mednet.ucla.edu. The interaction between the hormone hepcidin and the iron exporter ferroportin (Fpn) regulates plasma iron concentrations. Hepcidin binds to Fpn and induces its internalization and degradation, resulting in decreased iron efflux from cells into plasma. Fpn mutations in N144, Y64N and C326 residue cause autosomal dominant disease with parenchymal iron overload, apparently due to the resistance of mutant Fpn to hepcidin-mediated internalization. To define the mechanism of resistance, we generated human Fpn constructs bearing the pathogenic mutations. The mutants localized to the cell surface and exported iron normally but were partially or completely resistant to hepcidin-mediated internalization and continued to export iron despite the presence of hepcidin. The primary defect with exofacial C326 substitutions was the loss of hepcidin binding which resulted in the most severe phenotype. The thiol form of C326 was essential for interaction with hepcidin suggesting that C326-SH is located in or near the binding site of hepcidin. In contrast, N144 and Y64 residues were not required for hepcidin binding, but their mutations impaired the subsequent internalization of the ligand-receptor complex. Our observations explain why the mutations in C326 Fpn residue produce a severe form of hemochromatosis with iron overload at an early age. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Hereditary hemochromatosis due to resistance to hepcidin: high hepcidin concentrations in a family with C326S ferroportin mutation Ronald L. Sham, Pradyumna D. Phatak, Elizabeta Nemeth, and Tomas Ganz Blood 2009 114: 493-494. [Full Text] [PDF] This article has been cited by other articles: J. B. Jordan, L. Poppe, M. Haniu, T. Arvedson, R. Syed, V. Li, H. Kohno, H. Kim, P. D. Schnier, T. S. Harvey, et al. Hepcidin Revisited, Disulfide Connectivity, Dynamics, and Structure J. Biol. Chem., September 4, 2009; 284(36): 24155 - 24167. [Abstract] [Full Text] [PDF] R. L. Sham, P. D. Phatak, E. Nemeth, and T. Ganz Hereditary hemochromatosis due to resistance to hepcidin: high hepcidin concentrations in a family with C326S ferroportin mutation Blood, July 9, 2009; 114(2): 493 - 494. [Full Text] [PDF]

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