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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.
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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.
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