SEARCH:   Advanced

Blood, 15 May 2007, Vol. 109, No. 10, pp. 4503-4510. Prepublished online as a Blood First Edition Paper on January 30, 2007; DOI 10.1182/blood-2006-08-041004. This Article Full Text Full Text (PDF) Supplemental Methods, Table, and Figures All Versions of this Article: blood-2006-08-041004v1 109/10/4503    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Silvestri, L. Articles by Camaschella, C. Search for Related Content PubMed PubMed Citation Articles by Silvestri, L. Articles by Camaschella, C. Related Collections Red Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis Laura Silvestri1, Alessia Pagani2, Claudia Fazi2, Gianmario Gerardi3, Sonia Levi1,2, Paolo Arosio3, and Clara Camaschella1,2 1 San Raffaele Scientific Institute, Dibit, Milan, Italy; 2 University Vita-Salute San Raffaele, Milan, Italy; 3 Dipartimento Materno Infantile e Tecnologie Biomediche University of Brescia, Italy Hemojuvelin (HJV) positively modulates the iron regulator hepcidin, and its mutations are the major cause of juvenile hemochromatosis (JH), a recessive disease leading to iron overload. Defective HJV reduces hepcidin up-regulation both in humans and in Hjv-deficient mice. To investigate the JH pathogenesis and the functional properties of human HJV we studied the biosynthesis and maturation of 6 HJV pathogenic mutants in HeLa and HepG2 cells. We show that proteolytic processing is defective in mutants F170S, W191C, and G320V, but not in G99V and C119F. Moreover, we show that mutants G99V and C119F are targeted to the cell surface, while F170S, W191C, G320V, and R326X (lacking the glycosilphosphatidylinositol [GPI] anchor) are mainly retained in the endoplasmic reticulum, although all mutants are released as soluble forms (s-HJV) in a proportion that is modulated by iron supplementation. Membrane HJV (m-HJV) is mainly composed of the cleaved protein, and its level is increased by iron in wild-type (WT) mice but not in the mutants. Altogether, the data demonstrate that the loss of HJV membrane export is central to the pathogenesis of JH, and that HJV cleavage is essential for the export. The results support a dual function for s- and m-HJV in iron deficiency and overload, respectively. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Y. Lok, A. T. Merryweather-Clarke, V. Viprakasit, Y. Chinthammitr, S. Srichairatanakool, C. Limwongse, D. Oleesky, A. J. Robins, J. Hudson, P. Wai, et al. Iron overload in the Asian community Blood, July 2, 2009; 114(1): 20 - 25. [Abstract] [Full Text] [PDF] J. E. Maxson, C. A. Enns, and A.-S. Zhang Processing of hemojuvelin requires retrograde trafficking to the Golgi in HepG2 cells Blood, February 19, 2009; 113(8): 1786 - 1793. [Abstract] [Full Text] [PDF] S. A. Browne and D. Reddan Potential role of bone morphogenetic protein (BMP) signalling as a potential therapeutic target for modification of iron balance Nephrol. Dial. Transplant., January 1, 2009; 24(1): 28 - 30. [Full Text] [PDF] Y. Nagayoshi, M. Nakayama, S. Suzuki, J. Hokamaki, H. Shimomura, K. Tsujita, M. Fukuda, T. Yamashita, Y. Nakamura, S. Sugiyama, et al. A Q312X mutation in the hemojuvelin gene is associated with cardiomyopathy due to juvenile haemochromatosis Eur J Heart Fail, October 1, 2008; 10(10): 1001 - 1006. [Abstract] [Full Text] [PDF] A.-S. Zhang, F. Yang, K. Meyer, C. Hernandez, T. Chapman-Arvedson, P. J. Bjorkman, and C. A. Enns Neogenin-mediated Hemojuvelin Shedding Occurs after Hemojuvelin Traffics to the Plasma Membrane J. Biol. Chem., June 20, 2008; 283(25): 17494 - 17502. [Abstract] [Full Text] [PDF] R. Kuns-Hashimoto, D. Kuninger, M. Nili, and P. Rotwein Selective binding of RGMc/hemojuvelin, a key protein in systemic iron metabolism, to BMP-2 and neogenin Am J Physiol Cell Physiol, April 1, 2008; 294(4): C994 - C1003. [Abstract] [Full Text] [PDF] L. Silvestri, A. Pagani, and C. Camaschella Furin-mediated release of soluble hemojuvelin: a new link between hypoxia and iron homeostasis Blood, January 15, 2008; 111(2): 924 - 931. [Abstract] [Full Text] [PDF] C. Ka, G. Le Gac, E. Letocart, I. Gourlaouen, B. Martin, and C. Ferec Phenotypic and functional data confirm causality of the recently identified hemojuvelin p.r176c missense mutation Haematologica, September 1, 2007; 92(9): 1262 - 1263. [Abstract] [Full Text] [PDF] B. A. C. van Dijk, E. H. J. M. Kemna, H. Tjalsma, S. M. Klaver, E. T. G. Wiegerinck, J.-P. Goossens, P. H. Th. J. Slee, M. H. Breuning, and D. W. Swinkels Effect of the new HJV-L165X mutation on penetrance of HFE Blood, June 15, 2007; 109(12): 5525 - 5526. [Full Text] [PDF]

	Copyright © 2007 by American Society of Hematology         Online ISSN: 1528-0020