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Gene Review

HFE2  -  hemochromatosis type 2 (juvenile)

Homo sapiens

Synonyms: HFE2A, HJV, Hemochromatosis type 2 protein, Hemojuvelin, JH, ...
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Disease relevance of HFE2

  • Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis [1].
  • Juvenile hemochromatosis (JH) is an autosomal recessive disorder that leads to severe iron loading in the 2d to 3d decade of life [2].
  • Mutations in the recently described hemojuvelin gene were found in patients with juvenile hemochromatosis, who usually manifest clinical signs of iron overload, including cardiomyopathy and hypogonadism, in their teens and early 20s [3].
  • Two cases of immunoblastic lymphoma and one case of high-grade B-NOS were polyclonal regarding JH rearrangement, but EBV tested with 1.9-Kb Xhol fragment was clonal [4].
  • Our observations suggest that osteoporosis might occur in the state of JH even at a young age, mainly due to the deprivation of sex steroids and the direct tissue toxicity of iron [5].

High impact information on HFE2

  • Mutations in hemojuvelin disrupt its ability to stimulate expression of the iron regulatory peptide hepcidin and result in the severe iron loading disorder juvenile hemochromatosis [6].
  • Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2(-/-) hepatocytes [7].
  • Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression [7].
  • HFE2 transcript expression was restricted to liver, heart and skeletal muscle, similar to that of hepcidin, a key protein implicated in iron metabolism [1].
  • The normal splenic DNA component of antibody-secreting hybridomas displays rearrangements between JH and Cmu genes as well as among CH genes other than Cmu, with concomitant deletion of CH genes 5' to those expressed [8].

Chemical compound and disease context of HFE2


Biological context of HFE2

  • The localization of Hjv and TfR2 at the same membrane domain renders a functional interaction of these two proteins in iron homeostasis possible [10].
  • However, the fact that many other haplotypes carrying the JH defect were observed in the two populations indicates that the respective mutations may have occurred in different genetic backgrounds [11].
  • A significant correlation was found between the degree of downregulation of HAMP and HFE2 induced by beta-thalassaemia major sera (r = 0.852, P < 0.0009) [12].
  • We addressed the question of whether hemojuvelin mutations may influence the phenotype of patients with adult-onset haemochromatosis with or without mutations of the HFE gene [13].
  • One patient with severe iron overload was found to be a compound heterozygote for HJV mutations, one of which had previously been identified in patients with juvenile haemochromatosis (G320V) and the other was novel (C321W) [13].

Anatomical context of HFE2

  • Furthermore, BMP upregulates hepatocyte hepcidin expression, a process enhanced by hemojuvelin and blunted in Hfe2-/- hepatocytes [14].
  • RESULTS: One of 240 white control subjects was heterozygous for HJV I222N; she was also heterozygous for HFE C282Y, but had normal serum iron measures and bone marrow iron stores [15].
  • Evidence for selection based on the D segment and the JH gene usage was noted in CD5(+) B cells [16].
  • Nevertheless, we find that G6-reactive lymphocytes constitute a multiclonal population of cells that express homologous heavy chain variable region genes, each rearranged to one of several distinct and apparently nonmutated D and JH gene segments [17].
  • Using Southern blotting the authors studied the rearrangements of the T-cell receptor beta--chain (C beta) and gamma-chain (J gamma) genes and immunoglobulin heavy (JH)- and light (C kappa, C lambda)- chain genes [18].

Associations of HFE2 with chemical compounds

  • Thus, Rgmc regulation by LPS is Hfe-independent [19].
  • Although monoclonal anti-Fl antibodies 18-2-3 and 4-4-20 possessed similar binding affinities and quenched bound fluorescein to the same extent (Qmax greater than 96%), they utilized different VH, D, V kappa, and J kappa genes, but the same JH gene segment (JH4) [20].
  • Asymmetry in spontaneous rate of JH release was abolished by exogenous mevalonolactone [21].
  • These results suggest that the spontaneous asymmetry of JH biosynthesis and the low rate of JH biosynthesis by denervated corpora allata both result from non-stimulation or inhibition acting on the JH pathway before the utilisation of mevalonate [21].

Other interactions of HFE2


Analytical, diagnostic and therapeutic context of HFE2

  • Their cellular localization was studied by immunofluorescence with antibodies raised against Hjv and TfR2 [10].
  • The expression of Hjv and TfR2 was shown on mRNA and protein level by RT-PCR and immunoblot experiments [10].
  • Hepcidin, a negative regulator of intestinal iron absorption, is found to be inappropriately low in both patients and in animal models, indicating that proper control of basal hepcidin levels requires both hemojuvelin and HFE [19].
  • The clonality was determined by the detection of cytoplasmic immunoglobulin, surface immunoglobulin, and the analysis of joining region (JH) immunoglobulin gene configuration by Southern blot [4].
  • In 17 cases a bcl-2/JH gene fusion sequence was amplified by PCR [26].


  1. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Papanikolaou, G., Samuels, M.E., Ludwig, E.H., MacDonald, M.L., Franchini, P.L., Dubé, M.P., Andres, L., MacFarlane, J., Sakellaropoulos, N., Politou, M., Nemeth, E., Thompson, J., Risler, J.K., Zaborowska, C., Babakaiff, R., Radomski, C.C., Pape, T.D., Davidas, O., Christakis, J., Brissot, P., Lockitch, G., Ganz, T., Hayden, M.R., Goldberg, Y.P. Nat. Genet. (2004) [Pubmed]
  2. Juvenile hemochromatosis locus maps to chromosome 1q. Roetto, A., Totaro, A., Cazzola, M., Cicilano, M., Bosio, S., D'Ascola, G., Carella, M., Zelante, L., Kelly, A.L., Cox, T.M., Gasparini, P., Camaschella, C. Am. J. Hum. Genet. (1999) [Pubmed]
  3. Three patients with middle-age-onset hemochromatosis caused by novel mutations in the hemojuvelin gene. Koyama, C., Hayashi, H., Wakusawa, S., Ueno, T., Yano, M., Katano, Y., Goto, H., Kidokoro, R. J. Hepatol. (2005) [Pubmed]
  4. Immunophenotypic and genotypic analysis of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas. Correlation with histologic features in 36 cases. French Study Group of Pathology for HIV-Associated Tumors. Raphael, M.M., Audouin, J., Lamine, M., Delecluse, H.J., Vuillaume, M., Lenoir, G.M., Gisselbrecht, C., Lennert, K., Diebold, J. Am. J. Clin. Pathol. (1994) [Pubmed]
  5. Osteoporosis in HFE2 juvenile hemochromatosis. A case report and review of the literature. Angelopoulos, N.G., Goula, A.K., Papanikolaou, G., Tolis, G. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. (2006) [Pubmed]
  6. Iron metabolism meets signal transduction. Anderson, G.J., Frazer, D.M. Nat. Genet. (2006) [Pubmed]
  7. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Babitt, J.L., Huang, F.W., Wrighting, D.M., Xia, Y., Sidis, Y., Samad, T.A., Campagna, J.A., Chung, R.T., Schneyer, A.L., Woolf, C.J., Andrews, N.C., Lin, H.Y. Nat. Genet. (2006) [Pubmed]
  8. CH gene rearrangements in IgM-bearing B cells and in the normal splenic DNA component of hybridomas making different isotypes of antibody. Hurwitz, J.L., Coleclough, C., Cebra, J.J. Cell (1980) [Pubmed]
  9. Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Fabio, G., Minonzio, F., Delbini, P., Bianchi, A., Cappellini, M.D. Blood (2007) [Pubmed]
  10. Localization of the iron-regulatory proteins hemojuvelin and transferrin receptor 2 to the basolateral membrane domain of hepatocytes. Merle, U., Theilig, F., Fein, E., Gehrke, S., Kallinowski, B., Riedel, H.D., Bachmann, S., Stremmel, W., Kulaksiz, H. Histochem. Cell Biol. (2007) [Pubmed]
  11. Linkage to chromosome 1q in Greek families with juvenile hemochromatosis. Papanikolaou, G., Politou, M., Roetto, A., Bosio, S., Sakelaropoulos, N., Camaschella, C., Loukopoulos, D. Blood Cells Mol. Dis. (2001) [Pubmed]
  12. Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell-line HepG2 induced by thalassaemic sera. Weizer-Stern, O., Adamsky, K., Amariglio, N., Levin, C., Koren, A., Breuer, W., Rachmilewitz, E., Breda, L., Rivella, S., Ioav Cabantchik, Z., Rechavi, G. Br. J. Haematol. (2006) [Pubmed]
  13. Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis. Lee, P.L., Barton, J.C., Brandhagen, D., Beutler, E. Br. J. Haematol. (2004) [Pubmed]
  14. Juvenile hemochromatosis. Pietrangelo, A. J. Hepatol. (2006) [Pubmed]
  15. Allele frequencies of hemojuvelin gene (HJV) I222N and G320V missense mutations in white and African American subjects from the general Alabama population. Barton, J.C., Rivers, C.A., Niyongere, S., Bohannon, S.B., Acton, R.T. BMC Med. Genet. (2004) [Pubmed]
  16. Analysis of the human VH gene repertoire. Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM+ and CD5(-)/IgM+ B cells. Brezinschek, H.P., Foster, S.J., Brezinschek, R.I., Dörner, T., Domiati-Saad, R., Lipsky, P.E. J. Clin. Invest. (1997) [Pubmed]
  17. Relationship of the CD5 B cell to human tonsillar lymphocytes that express autoantibody-associated cross-reactive idiotypes. Kipps, T.J., Duffy, S.F. J. Clin. Invest. (1991) [Pubmed]
  18. Hairy cell leukemia associated with large granular lymphocyte leukemia: immunologic and genomic study, effect of interferon treatment. Marolleau, J.P., Henni, T., Gaulard, P., Le Couedic, J.P., Gourdin, M.F., Divine, M., Katz, A., Tulliez, M., Goossens, M., Reyes, F. Blood (1988) [Pubmed]
  19. Repression of Repulsive Guidance Molecule C during Inflammation Is Independent of Hfe and Involves Tumor Necrosis Factor-{alpha}. Constante, M., Wang, D., Raymond, V.A., Bilodeau, M., Santos, M.M. Am. J. Pathol. (2007) [Pubmed]
  20. Variable region primary structures of a high affinity anti-fluorescein immunoglobulin M cryoglobulin exhibiting oxazolone cross-reactivity. Dombrink-Kurtzman, M.A., Johnson, L.S., Riordan, G.S., Bedzyk, W.D., Voss, E.W. J. Biol. Chem. (1989) [Pubmed]
  21. Evidence for regulation of juvenile hormone biosynthesis operating before mevalonate in locust corpora allata. Couillaud, F. Mol. Cell. Endocrinol. (1991) [Pubmed]
  22. Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes. Pietrangelo, A., Caleffi, A., Henrion, J., Ferrara, F., Corradini, E., Kulaksiz, H., Stremmel, W., Andreone, P., Garuti, C. Gastroenterology (2005) [Pubmed]
  23. The evaluation of hyperferritinemia: an updated strategy based on advances in detecting genetic abnormalities. Aguilar-Martinez, P., Schved, J.F., Brissot, P. Am. J. Gastroenterol. (2005) [Pubmed]
  24. Hepatic iron metabolism gene expression profiles in HFE associated Hereditary Hemochromatosis. Gleeson, F., Ryan, E., Barrett, S., Russell, J., Crowe, J. Blood Cells Mol. Dis. (2007) [Pubmed]
  25. Neogenin-mediated hemojuvelin shedding occurs after hemojuvelin traffics to the plasma membrane. Zhang, A.S., Yang, F., Meyer, K., Hernandez, C., Chapman-Arvedson, T., Bjorkman, P.J., Enns, C.A. J. Biol. Chem. (2008) [Pubmed]
  26. Frequency and structure of t(14;18) major breakpoint regions in non-Hodgkin's lymphomas typed according to the Kiel classification: analysis by direct DNA sequencing. Kneba, M., Eick, S., Herbst, H., Willigeroth, S., Pott, C., Bolz, I., Bergholz, M., Neumann, C., Stein, H., Krieger, G. Cancer Res. (1991) [Pubmed]
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