Defective targeting of hemojuvelin to plasma membrane is a common pathogenetic mechanism in juvenile hemochromatosis

San Raffaele Scientific Institute, Dibit, Milan, Italy.
Blood (Impact Factor: 10.45). 06/2007; 109(10):4503-10. DOI: 10.1182/blood-2006-08-041004
Source: PubMed


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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    • "). The p.Arg326X truncation mutation in particular lacks the N-terminus of the protein and the GPI anchor, and is not found on the cell surface of hepatocytes [Silvestri et al., 2007]. If the PIGA deletion reduces HJV cell surface expression, this could result in progressive systemic iron overload. "
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    ABSTRACT: Three related males presented with a newly recognized x-linked syndrome associated with neurodegeneration, cutaneous abnormalities, and systemic iron overload. Linkage studies demonstrated that they shared a haplotype on Xp21.3-Xp22.2 and exome sequencing was used to identify candidate variants. Of the segregating variants, only a PIGA mutation segregated with disease in the family. The c.328_330delCCT PIGA variant predicts, p.Leu110del (or c.1030_1032delCTT, p.Leu344del depending on the reference sequence). The unaffected great-grandfather shared his X allele with the proband but he did not have the PIGA mutation, indicating that the mutation arose de novo in his daughter. A single family with a germline PIGA mutation has been reported; affected males had a phenotype characterized by multiple congenital anomalies and severe neurologic impairment resulting in infantile lethality. In contrast, affected boys in the family described here were born without anomalies and were neurologically normal prior to onset of seizures after 6 months of age, with two surviving to the second decade. PIGA encodes an enzyme in the GPI anchor biosynthesis pathway. An affected individual in the family studied here was deficient in GPI anchor proteins on granulocytes but not erythrocytes. In conclusion, the PIGA mutation in this family likely causes a reduction in GPI anchor protein cell surface expression in various cell types, resulting in the observed pleiotropic phenotype involving central nervous system, skin, and iron metabolism. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36189 · 2.16 Impact Factor
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    • "Hemojuvelin is a BMP6 coreceptor on hepatocytes whose presence is required for induction of hepcidin expression by BMP6 [17]. The Gly320Val mutation causes a defect in the proteolytic processing of hemojuvelin that prevents targeting the protein to the plasma membrane and thus abrogates BMP6 signaling [18]. As a consequence, hepcidin expression no longer responds appropriately to iron status and iron overload ensues. "
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    ABSTRACT: Juvenile hemochromatosis is a rare and severe form of hereditary hemochromatosis. We report the case of a 39-year-old female who presented with heart failure and cirrhosis from previously unrecognized juvenile hemochromatosis. This is the latest presentation described in the literature. An important clue to the diagnosis was a history of amenorrhea since the age of 20 that had never been investigated. The patient died of intractable heart failure two months after the initial presentation. Juvenile hemochromatosis should be suspected in a young patient with endocrine or cardiac manifestations. Early diagnosis is crucial since phlebotomy can improve the prognosis and delay or prevent progression to heart failure and cirrhosis.
    Case Reports in Medicine 09/2013; 2013:875093. DOI:10.1155/2013/875093
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    • "To investigate why proteolytically inactive variants suppress hepcidin transcription in the promoter assay, we analyzed the plasma membrane localization of TMPRSS6 artificial variants and HJV by using both cell surface biotinylation and binding assay [Silvestri et al., 2007]. Both TMPRSS6 variants are expressed on the cell surface as the wt protein (Fig. 1C, lower panel). "

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