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Gene Review

HFE  -  hemochromatosis

Homo sapiens

Synonyms: HFE1, HH, HLA-H, HLAH, Hereditary hemochromatosis protein, ...
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Disease relevance of HFE

  • CONCLUSIONS: Our data show that duodenal-cytochrome b activity in iron deficiency is stimulated via enhanced protein expression, whereas in HFE hemochromatosis it is up-regulated post-translationally [1].
  • These findings also raise the question of whether mutations in the HFE gene can disrupt this association and thereby contribute to some forms of neonatal iron overload [2].
  • A mutation that interferes with proper folding and assembly of HFE complexes results in a severe iron-overload disease hereditary hemochromatosis [3].
  • In particular, we demonstrated in a transient expression system that human cytomegalovirus (HCMV) US2 targeted HFE for proteasomal degradation [3].
  • Although limited by low numbers, an increased prevalence of the HFE Tyr282 minor allele was observed in breast cancer cases with a high number of affected lymph nodes (P = 0.032) [4].
  • The HFE C282Y heterozygous mutation is associated with advanced fibrosis among Caucasians with NASH [5].

Psychiatry related information on HFE


High impact information on HFE

  • 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 [11].
  • Juvenile hemochromatosis has previously been linked to the centromeric region of chromosome 1q (refs. 3-6), a region that is incomplete in the human genome assembly [12].
  • Juvenile hemochromatosis is an early-onset autosomal recessive disorder of iron overload resulting in cardiomyopathy, diabetes and hypogonadism that presents in the teens and early 20s (refs. 1,2) [12].
  • Hepcidin, a peptide hormone (HAMP; OMIM 606464), seems to act in the same regulatory pathway as HFE [13].
  • Most individuals affected with hereditary hemochromatosis are homozygous with respect to a missense mutation that disrupts the conformation of HFE, an atypical HLA class I molecule (ref. 1; OMIM 235200) [13].

Chemical compound and disease context of HFE


Biological context of HFE


Anatomical context of HFE

  • We propose that hepcidin acts as a signaling molecule that is required in conjunction with HFE to regulate both intestinal iron absorption and iron storage in macrophages [23].
  • In agreement with prior studies on other cell lines, we found that overexpression of HFE, without overexpressing beta2M, resulted in a decrease in TfR1dependent iron uptake and in lower iron levels in the cells, as evidenced by ferritin and TfR1 levels measured at steady state [24].
  • Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum [25].
  • HeLa cells expressing fW81AHFE behaved in a similar manner to cells expressing wild-type HFE with respect to decreased intracellular iron levels measured by iron regulatory protein gel-shift assays and ferritin levels [20].
  • The HFE protein was shown by immunohistochemistry to be expressed in certain epithelial cells throughout the human alimentary tract and to have a unique localization in the cryptal cells of small intestine, where signals to regulate iron absorption are received from the body [2].

Associations of HFE with chemical compounds

  • Using an HeLa cell line stably transfected with HFE under the control of a tetracycline-sensitive promoter, we investigated the effect of HFE expression on cellular iron uptake [26].
  • Because of similarities in the transport of gallium and iron and the use of (67)Ga scanning in lymphoid malignancies, we examined the effect of HFE expression on (67)Ga uptake [27].
  • Transferrin saturation, serum ferritin, uric acid, lipids, glucose tolerance, insulin resistance, HFE gene mutations, liver histology, and hepatic iron concentration were analyzed [7].
  • Expression and Polarized Localization of the Hemochromatosis Gene Product HFE in Retinal Pigment Epithelium [28].
  • Our findings indicate that the treatment rather than the disease increased the cadmium uptake in homozygous HH [29].

Physical interactions of HFE

  • The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding [30].
  • Furthermore, at 4 degrees C, the added soluble complex of HFE/beta2m inhibited binding of transferrin to HeLa cell TfR in a concentration-dependent manner [30].
  • Co-immunoprecipitation studies of cell lysates from human embryonic kidney cells transfected with wild-type or mutant HLA-H cDNA demonstrate that wild-type HLA-H binds beta2-microglobulin and that the C282Y mutation, but not the H63D mutation, completely abrogates this interaction [31].
  • Increased IRP1 and IRP2 RNA binding activity accompanies a reduction of the labile iron pool in HFE-expressing cells [32].
  • We further observed that, unlike TfR1/HFE, Tf does not compete with HFE for binding to TfR2 and that binding is independent of pH (pH 6-7.5) [33].

Enzymatic interactions of HFE

  • A single cut-off point of 55% for transferrin saturation and a cut-off point at the 90th percentile for the serum ferritin level were adequate for the detection of hemochromatosis if homozygosity was considered to be present when the results of one or both tests were positive [34].

Regulatory relationships of HFE

  • Herein we show that TfR is required for and controls the assembly and the intracellular transport and surface expression of HFE [35].
  • HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells [26].
  • The haemochromatosis protein HFE induces an apparent iron-deficient phenotype in H1299 cells that is not corrected by co-expression of beta 2-microglobulin [36].
  • 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 [37].
  • Haptoglobin type neither influences iron accumulation in normal subjects nor predicts clinical presentation in HFE C282Y haemochromatosis: phenotype and genotype analysis [38].

Other interactions of HFE


Analytical, diagnostic and therapeutic context of HFE


  1. Duodenal cytochrome b and hephaestin expression in patients with iron deficiency and hemochromatosis. Zoller, H., Theurl, I., Koch, R.O., McKie, A.T., Vogel, W., Weiss, G. Gastroenterology (2003) [Pubmed]
  2. Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Parkkila, S., Waheed, A., Britton, R.S., Bacon, B.R., Zhou, X.Y., Tomatsu, S., Fleming, R.E., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  3. A single viral protein HCMV US2 affects antigen presentation and intracellular iron homeostasis by degradation of classical HLA class I and HFE molecules. Vahdati-Ben Arieh, S., Laham, N., Schechter, C., Yewdell, J.W., Coligan, J.E., Ehrlich, R. Blood (2003) [Pubmed]
  4. Investigation of genetic variants of genes of the hemochromatosis pathway and their role in breast cancer. Abraham, B.K., Justenhoven, C., Pesch, B., Harth, V., Weirich, G., Baisch, C., Rabstein, S., Ko, Y.D., Brüning, T., Fischer, H.P., Haas, S., Brod, S., Oberkanins, C., Hamann, U., Brauch, H. Cancer Epidemiol. Biomarkers Prev. (2005) [Pubmed]
  5. HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis. Nelson, J.E., Bhattacharya, R., Lindor, K.D., Chalasani, N., Raaka, S., Heathcote, E.J., Miskovsky, E., Shaffer, E., Rulyak, S.J., Kowdley, K.V. Hepatology (2007) [Pubmed]
  6. Association between the HFE mutations and unsuccessful ageing: a study in Alzheimer's disease patients from Northern Italy. Candore, G., Licastro, F., Chiappelli, M., Franceschi, C., Lio, D., Rita Balistreri, C., Piazza, G., Colonna-Romano, G., Grimaldi, L.M., Caruso, C. Mech. Ageing Dev. (2003) [Pubmed]
  7. Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis. Fargion, S., Mattioli, M., Fracanzani, A.L., Sampietro, M., Tavazzi, D., Fociani, P., Taioli, E., Valenti, L., Fiorelli, G. Am. J. Gastroenterol. (2001) [Pubmed]
  8. Hemochromatosis mutations in the general population: iron overload progression rate. Andersen, R.V., Tybjaerg-Hansen, A., Appleyard, M., Birgens, H., Nordestgaard, B.G. Blood (2004) [Pubmed]
  9. Clinical expression of C282Y homozygous HFE haemochromatosis at 14 years of age. Rossi, E., Wallace, D.F., Subramaniam, V.N., St Pierre, T.G., Mews, C., Jeffrey, G.P. Ann. Clin. Biochem. (2006) [Pubmed]
  10. 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]
  11. Iron metabolism meets signal transduction. Anderson, G.J., Frazer, D.M. Nat. Genet. (2006) [Pubmed]
  12. 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]
  13. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nicolas, G., Viatte, L., Lou, D.Q., Bennoun, M., Beaumont, C., Kahn, A., Andrews, N.C., Vaulont, S. Nat. Genet. (2003) [Pubmed]
  14. Dominant hemochromatosis due to N144H mutation of SLC11A3: clinical and biological characteristics. Njajou, O.T., de Jong, G., Berghuis, B., Vaessen, N., Snijders, P.J., Goossens, J.P., Wilson, J.H., Breuning, M.H., Oostra, B.A., Heutink, P., Sandkuijl, L.A., van Duijn, C.M. Blood Cells Mol. Dis. (2002) [Pubmed]
  15. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Bulaj, Z.J., Phillips, J.D., Ajioka, R.S., Franklin, M.R., Griffen, L.M., Guinee, D.J., Edwards, C.Q., Kushner, J.P. Blood (2000) [Pubmed]
  16. Hemochromatosis (HFE) gene mutations and response to chloroquine in porphyria cutanea tarda. Stölzel, U., Köstler, E., Schuppan, D., Richter, M., Wollina, U., Doss, M.O., Wittekind, C., Tannapfel, A. Archives of dermatology. (2003) [Pubmed]
  17. Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer's disease. Robson, K.J., Lehmann, D.J., Wimhurst, V.L., Livesey, K.J., Combrinck, M., Merryweather-Clarke, A.T., Warden, D.R., Smith, A.D. J. Med. Genet. (2004) [Pubmed]
  18. Expression of the hemochromatosis gene modulates the cytotoxicity of doxorubicin in breast cancer cells. Chitambar, C.R., Kotamraju, S., Wereley, J.P. Int. J. Cancer (2006) [Pubmed]
  19. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Muckenthaler, M., Roy, C.N., Custodio, A.O., Miñana, B., deGraaf, J., Montross, L.K., Andrews, N.C., Hentze, M.W. Nat. Genet. (2003) [Pubmed]
  20. Mechanisms of HFE-induced regulation of iron homeostasis: Insights from the W81A HFE mutation. Zhang, A.S., Davies, P.S., Carlson, H.L., Enns, C.A. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  21. Iron transport in a lymphoid cell line with the hemochromatosis C282Y mutation. Chitambar, C.R., Wereley, J.P. Blood (2001) [Pubmed]
  22. The hereditary hemochromatosis protein, HFE, lowers intracellular iron levels independently of transferrin receptor 1 in TRVb cells. Carlson, H., Zhang, A.S., Fleming, W.H., Enns, C.A. Blood (2005) [Pubmed]
  23. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Nicolas, G., Bennoun, M., Devaux, I., Beaumont, C., Grandchamp, B., Kahn, A., Vaulont, S. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  24. Regulation of transferrin-mediated iron uptake by HFE, the protein defective in hereditary hemochromatosis. Waheed, A., Grubb, J.H., Zhou, X.Y., Tomatsu, S., Fleming, R.E., Costaldi, M.E., Britton, R.S., Bacon, B.R., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  25. Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Waheed, A., Parkkila, S., Saarnio, J., Fleming, R.E., Zhou, X.Y., Tomatsu, S., Britton, R.S., Bacon, B.R., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  26. HFE downregulates iron uptake from transferrin and induces iron-regulatory protein activity in stably transfected cells. Riedel, H.D., Muckenthaler, M.U., Gehrke, S.G., Mohr, I., Brennan, K., Herrmann, T., Fitscher, B.A., Hentze, M.W., Stremmel, W. Blood (1999) [Pubmed]
  27. Expression of the hemochromatosis (HFE) gene modulates the cellular uptake of 67Ga. Chitambar, C.R., Wereley, J.P. J. Nucl. Med. (2003) [Pubmed]
  28. Expression and Polarized Localization of the Hemochromatosis Gene Product HFE in Retinal Pigment Epithelium. Martin, P.M., Gnana-Prakasam, J.P., Roon, P., Smith, R.G., Smith, S.B., Ganapathy, V. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  29. Phlebotomy increases cadmium uptake in hemochromatosis. Akesson, A., Stål, P., Vahter, M. Environ. Health Perspect. (2000) [Pubmed]
  30. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Feder, J.N., Penny, D.M., Irrinki, A., Lee, V.K., Lebrón, J.A., Watson, N., Tsuchihashi, Z., Sigal, E., Bjorkman, P.J., Schatzman, R.C. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  31. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. Feder, J.N., Tsuchihashi, Z., Irrinki, A., Lee, V.K., Mapa, F.A., Morikang, E., Prass, C.E., Starnes, S.M., Wolff, R.K., Parkkila, S., Sly, W.S., Schatzman, R.C. J. Biol. Chem. (1997) [Pubmed]
  32. Increased IRP1 and IRP2 RNA binding activity accompanies a reduction of the labile iron pool in HFE-expressing cells. Roy, C.N., Blemings, K.P., Deck, K.M., Davies, P.S., Anderson, E.L., Eisenstein, R.S., Enns, C.A. J. Cell. Physiol. (2002) [Pubmed]
  33. HFE modulates transferrin receptor 2 levels in hepatoma cells via interactions that differ from transferrin receptor 1-HFE interactions. Chen, J., Chloupková, M., Gao, J., Chapman-Arvedson, T.L., Enns, C.A. J. Biol. Chem. (2007) [Pubmed]
  34. Diagnostic efficacy of screening tests for hereditary hemochromatosis. Borwein, S., Ghent, C.N., Valberg, L.S. Canadian Medical Association journal. (1984) [Pubmed]
  35. Transferrin receptor is negatively modulated by the hemochromatosis protein HFE: implications for cellular iron homeostasis. Salter-Cid, L., Brunmark, A., Li, Y., Leturcq, D., Peterson, P.A., Jackson, M.R., Yang, Y. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  36. The haemochromatosis protein HFE induces an apparent iron-deficient phenotype in H1299 cells that is not corrected by co-expression of beta 2-microglobulin. Wang, J., Chen, G., Pantopoulos, K. Biochem. J. (2003) [Pubmed]
  37. 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]
  38. Haptoglobin type neither influences iron accumulation in normal subjects nor predicts clinical presentation in HFE C282Y haemochromatosis: phenotype and genotype analysis. Carter, K., Bowen, D.J., McCune, C.A., Worwood, M. Br. J. Haematol. (2003) [Pubmed]
  39. 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]
  40. Prevalence of genetic hemochromatosis in a cohort of Italian patients with diabetes mellitus. Conte, D., Manachino, D., Colli, A., Guala, A., Aimo, G., Andreoletti, M., Corsetti, M., Fraquelli, M. Ann. Intern. Med. (1998) [Pubmed]
  41. The hereditary hemochromatosis protein, HFE, inhibits iron uptake via down-regulation of Zip14 in HepG2 cells. Gao, J., Zhao, N., Knutson, M.D., Enns, C.A. J. Biol. Chem. (2008) [Pubmed]
  42. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE. West, A.P., Bennett, M.J., Sellers, V.M., Andrews, N.C., Enns, C.A., Bjorkman, P.J. J. Biol. Chem. (2000) [Pubmed]
  43. Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites. West, A.P., Giannetti, A.M., Herr, A.B., Bennett, M.J., Nangiana, J.S., Pierce, J.R., Weiner, L.P., Snow, P.M., Bjorkman, P.J. J. Mol. Biol. (2001) [Pubmed]
  44. The transferrin receptor binding site on HFE, the class I MHC-related protein mutated in hereditary hemochromatosis. Lebrón, J.A., Bjorkman, P.J. J. Mol. Biol. (1999) [Pubmed]
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