<i>HJV</i> gene mutations in European patients with juvenile hemochromatosis

Gehrke, S; Pietrangelo, Antonello; M, Kascák; Braner, Axel; Eisold, Michael; Kulaksiz, Hasan; Herrmann, Thomas; Hebling, Ulrike; Bents, Karin; Gugler, R; Stremmel, Wolfgang

doi:10.1111/j.1399-0004.2005.00413.x

Cited by 58 publications

(40 citation statements)

References 19 publications

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“…This finding was supported by subsequent studies by several other groups showing numerous additional mutations of HJV in JH patients (11)(12)(13)(14)(15)(16). In this study, we characterized the processing of HJV expressed in HEK293 cells and identified a binding interaction with neogenin that increases iron accumulation in HEK293 cells.…”

Section: Discussionsupporting

confidence: 71%

“…The proposal that HJV-induced changes in iron homeostasis require interaction with neogenin is supported by the observation that the HJV G320V mutation, the most common mutation in Type 2A HH (6,14), neither interacted with neogenin nor altered intracellular iron levels. Notably, expression of HJV overlapped with that of neogenin in muscles and liver, but not with expression of two other RGM family members, RGMa and RGMb (22)(23)(24)30).…”

Section: Discussionmentioning

confidence: 99%

“…Numerous mutations in HJV that cause Type 2A HH have been identified. These include missense, frameshift, and nonsense mutations in either homozygous or compound heterozygous individuals (6,(11)(12)(13)(14)(15)(16). Although the amino acid substitution G320V accounts for about two-thirds of Type 2A HH (6), the sporadic distribution of these mutations hints that Type 2A HH is due to the loss of HJV function.…”

Section: Hereditary Hemochromatosis (Hh)mentioning

confidence: 99%

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Interaction of Hemojuvelin with Neogenin Results in Iron Accumulation in Human Embryonic Kidney 293 Cells

Zhang

West

Wyman

et al. 2005

Journal of Biological Chemistry

132

149

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Hereditary Hemochromatosis (Hh)mentioning

confidence: 99%

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Interaction of Hemojuvelin with Neogenin Results in Iron Accumulation in Human Embryonic Kidney 293 Cells

Zhang

West

Wyman

et al. 2005

Journal of Biological Chemistry

132

149

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“…There were no hematologic abnormalities suggestive of the presence of a secondary, anemia-induced iron overload phenotype in mice with liverspecific Alk2 or Alk3 deficiency (supplemental Figure 3). Moreover, hepatic expression of hereditary hemochromatosis diseasecausing genes, including transferrin receptor-2 (Tfr2), 30 Hfe, 31,32 hemojuvelin (Hjv), 9,13,14,33 and ferroportin 1 (Fpn1), 34 did not differ between genotypes (supplemental Figure 4). These results demonstrate a mild iron overload phenotype in Alk2 fl/fl ; Alb-Cre mice and a severe iron overload phenotype in Alk3 fl/fl ; Alb-Cre mice and indicate that both Alk2 and Alk3 have roles in the regulation of systemic iron homeostasis.…”

Section: Liver-specific Deletion Of Alk2 and Alk3 Leads To Iron Overlmentioning

confidence: 99%

Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice

Steinbicker

Bartnikas

Lohmeyer

et al. 2011

Blood

160

170

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Bone morphogenetic protein (BMP) signaling induces hepatic expression of the peptide hormone hepcidin. Hepcidin reduces serum iron levels by promoting degradation of the iron exporter ferroportin. A relative deficiency of hepcidin underlies the pathophysiology of many of the genetically distinct iron overload disorders, collectively termed hereditary hemochromatosis. Conversely, chronic inflammatory conditions and neoplastic diseases can induce high hepcidin levels, leading to impaired mobilization of iron stores and the anemia of chronic disease. Two BMP type I receptors, Alk2 (Acvr1) and Alk3 (Bmpr1a), are expressed in murine hepatocytes. We report that liver-specific deletion of either Alk2 or Alk3 causes iron overload in mice. The iron overload phenotype was more marked in Alk3-than in Alk2-deficient mice, and Alk3 deficiency was associated with a nearly complete ablation of basal BMP signaling and hepci- IntroductionThe hepatic hormone hepcidin regulates serum iron levels in mice and humans by inducing degradation of the iron exporter, ferroportin. 1,2 Low ferroportin levels reduce intestinal iron absorption and the release of iron from macrophage stores. Human hereditary hemochromatosis is characterized by low hepcidin levels, leading to iron accumulation in liver, heart, and endocrine organs. 1,3 Similarly, hepcidin deficiency causes hepatic iron overload in mice. 2,4 In contrast, high hepcidin levels contribute to the anemia of chronic disease (ACD) by reducing iron bioavailability for erythropoiesis. 5,6 Recent studies have demonstrated a critical role for bone morphogenetic protein (BMP) signaling in the regulation of hepcidin expression by iron. [7][8][9][10][11] Binding of BMP ligands to type I and type II BMP receptors induces the type II receptor to phosphorylate and activate the type I receptor. The activated type I receptor, in turn, phosphorylates intracellular signaling molecules, including SMADs 1, 5, and 8. Phosphorylated SMADs 1, 5, and 8 bind SMAD4 and together translocate to the nucleus, where they activate the expression of genes, including hepcidin and the Id family of transcription factors. 12 Deficiency of Smad4, 10 the BMP coreceptor hemojuvelin, 13,14 or BMP6 15,16 in hepatocytes reduces expression of hepcidin 17,18 and induces iron overload. In addition, BMP signaling appears to have an important role in the induction of hepcidin expression by inflammatory mediators that are involved in ACD. 11,19,20 There are 4 type I BMP receptors: Alk1, Alk2, Alk3, and Alk6. The identity of the type I BMP receptor(s) responsible for iron-dependent signaling and the regulation of hepcidin expression in hepatocytes are unknown. Alk1 is predominantly expressed in the endothelium. Alk6 is expressed at low levels in murine liver, 21 and global Alk6 deficiency does not induce iron overload in mice (D. R. Campagna, P. J. Schmidt, and M.D.F., unpublished observations, January 2011). In contrast, Alk2 and Alk3 are abundantly expressed in hepatocytes. 21 To identify the type I BMP receptor required for th...

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“…14 About 30 distinct missense or nonsense point mutations have been identified in the HJV gene leading to JH. 3,15,16 In order to gain insights into the pathogenesis of this disorder and to characterize the functional properties of human HJV, we have studied the biosynthesis and maturation of 5 missense (G99V, 3 C119F, 16 F170S, 17 W191C, 17 and G320V 3 ) and 1 nonsense (R326X 3 ) allelic variants associated with JH. We demonstrate that mutants with defective autoproteolytic processing (F170S, W191C, and G320V) are not correctly targeted to the plasma membrane (PM) but are mainly retained in the endoplasmic reticulum (ER), as observed for the truncated R326X variant.…”

Section: Introductionmentioning

confidence: 99%

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

Silvestri

Pagani

Fazi

et al. 2007

Blood

100

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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 ( IntroductionThe study of hereditary hemochromatosis (HH) has contributed major advances to our understanding of the systemic iron regulation. 1 The key regulatory protein is hepcidin, a small antimicrobial liver peptide 2 that has an inhibitory effect on the release of iron from duodenal cells and macrophages to the circulating transferrin. 3 Mutations of hepcidin cause a recessive form of severe, early-onset hemochromatosis, known as juvenile hemochromatosis (JH; type 2B HH). 4 The same severe phenotype is more commonly caused by mutations of HJV, the gene encoding hemojuvelin (type 2A HH). 3 Studies in humans and mice provide evidence that HJV positively modulates hepcidin expression. Urinary hepcidin levels are remarkably low in patients carrying HJV mutations, 5 and Hjv-deficient mice have dramatically decreased liver hepcidin mRNA. 6,7 The mechanism of hepcidin activation by HJV remains to be clarified. Recently, it has been shown that HJV could act as a bone morphogenetic protein (BMP) coreceptor, enhancing BMPmediated signaling 8 and likely up-regulating hepcidin expression through BMP-activated SMA and MAD proteins (SMAD). 9 HJV is highly homologous to proteins belonging to the family of repulsive guidance molecules (RGMs). In the mouse, the expression of Rgma and Rgmb is limited to developing and adult central nervous system, while Rgmc, the ortholog of human HJV, is detected in the same tissues (skeletal muscle, heart, and liver) where hepcidin is expressed. 3 Similar to RGM members, the HJV gene encodes a protein characterized by multiple domains, including a N-terminal signal peptide, a RGD integrin-binding motif, a partial von Willebrand factor (VWF) type D domain, and a C-terminal glycosilphosphatidylinositol (GPI) anchor domain. All RGM proteins possess a Gly-Asp-Pro-His (GDPH) sequence, 10,11 which undergoes a partial autocatalytic cleavage at the Asp-Pro bond at acidic pH, compatible with that of the late secretory pathway. 12 HJV is retained on the outer layer of the plasma membrane (m-HJV) through the GPI anchor motif, but can also be found as a soluble form (s-HJV) both in vitro and in vivo. 13,14 Recent studies in murine muscle cells and fibroblasts have analyzed the complex biosynthesis of Rgmc during myoblast differentiation. Two classes of GPI anchor Rgmc molecules exist that are differently processed and have distinct fat...

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HJV gene mutations in European patients with juvenile hemochromatosis

Cited by 58 publications

References 19 publications

Interaction of Hemojuvelin with Neogenin Results in Iron Accumulation in Human Embryonic Kidney 293 Cells

Interaction of Hemojuvelin with Neogenin Results in Iron Accumulation in Human Embryonic Kidney 293 Cells

Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice

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

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