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Gene Review

Hfe  -  hemochromatosis

Mus musculus

Synonyms: Hereditary hemochromatosis protein homolog, MR2, Mr2
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Disease relevance of Hfe

  • These results suggest that other beta2m-interacting protein(s) may be involved in iron regulation and that in the absence of functional Hfe molecules lymphocyte numbers may influence iron overload severity [1].
  • Uroporphyria caused by ethanol in Hfe(-/-) mice as a model for porphyria cutanea tarda [2].
  • Variation in obesity phenotypes explained 49%, 40%, and 37%, respectively, of the variance in Hfe, Lep, and Trfr mRNA levels [3].
  • Acute iron administration or mutations of the hemochromatosis gene (Hfe) have been used to generate hepatic siderosis, a nearly uniform finding in PCT [4].
  • Important distinctions between Hfe(-/-) mice and HH patients include not only differences in the relative rate and magnitude of iron loading but also the lack of fibrosis and phlebotomy treatment in the knockout animals [5].

Psychiatry related information on Hfe


High impact information on Hfe


Chemical compound and disease context of Hfe


Biological context of Hfe

  • To evaluate whether the observed phenotype in beta2mRag1(-/-) mice was due solely to the absence of Hfe or to other beta2m-dependent molecules, we generated HfeRag1(-/-) double-deficient mice [1].
  • We found that whereas basal hepcidin levels were manifestly dependent on the presence of Hfe and on the mouse background, all Hfe-deficient mice were still able to regulate hepcidin in situations of altered iron homeostasis [12].
  • Whereas the prevalence of the mutation is very high, the clinical penetrance of the disease is low, suggesting that the HFE mutation is a necessary but not sufficient cause of clinical HH [13].
  • To determine whether genetic factors other than Hfe genotype influence the severity of iron loading in the murine model of HH, we bred the disrupted murine Hfe allele onto three different genetically defined mouse strains (AKR, C57BL/6, and C3H), which differ in basal iron status and sensitivity to dietary iron loading [14].
  • HFE, a major histocompatibility complex class I-related protein, is implicated in the iron overload disease, hereditary hemochromatosis [15].

Anatomical context of Hfe

  • We conclude that NTBI uptake by hepatocytes from Hfe knockout mice contributed to hepatic iron loading [16].
  • It is shown that the characteristics of HFE hemochromatosis can be reproduced by increasing the setpoint of iron absorption in the duodenum to a level where the system cannot downregulate iron absorption to meet the iron excretion rate [17].
  • Interestingly, in wild-type mice we identified a subset of CD8+ T cells positively selected by Hfe that expresses the AV6.1/AV6.6 gene segments [18].
  • Furthermore, direct recognition of mouse Hfe molecules by cytotoxic T lymphocytes (CTLs) was demonstrated in DBA/2 Hfe knockout mice [18].
  • T cell antigen receptor recognition of MHC molecules independently of bound ligand has potential general implications in alloreactivity and identifies in the Hfe case a cognitive link supporting the concept that the immune system could be involved in the control of iron metabolism [18].

Associations of Hfe with chemical compounds

  • Total ferric citrate uptake by hepatocytes isolated from Hfe knockout mice (34.1 +/- 2.8 pmol Fe/mg protein/min) increased by 2-fold compared with control mice (17.8 +/- 2.7 pmol Fe/mg protein/min; P <.001; mean +/- SEM; n = 7) [16].
  • In HH, plasma nontransferrin-bound iron (NTBI) levels are increased and NTBI is bound mainly by citrate [16].
  • Ethanol-treated Hfe(-/-) mice seem to be an excellent model for studies of alcohol-mediated PCT [2].
  • Homozygosity for an Hfe-null mutation significantly elevated hepatic iron but not to the extent seen with parenteral iron-dextran administration [4].
  • Mice homozygous for the Hfe-null mutation accumulated high levels of hepatic URO when fed 5-aminolevulinate (ALA) [10].
  • Basal but not insulin-stimulated glucose uptake is elevated in isolated soleus muscle from Hfe(-/-) mice (p < 0.03) [19].

Physical interactions of Hfe

  • The aim of this study was to test this hypothesis by comparing clearance of transferrin-bound iron in Hfe knockout (KO) mice with that observed in C57BL/6 control mice [20].

Other interactions of Hfe


Analytical, diagnostic and therapeutic context of Hfe


  1. Contributions of beta2-microglobulin-dependent molecules and lymphocytes to iron regulation: insights from HfeRag1(-/-) and beta2mRag1(-/-) double knock-out mice. Miranda, C.J., Makui, H., Andrews, N.C., Santos, M.M. Blood (2004) [Pubmed]
  2. Uroporphyria caused by ethanol in Hfe(-/-) mice as a model for porphyria cutanea tarda. Sinclair, P.R., Gorman, N., Trask, H.W., Bement, W.J., Szakacs, J.G., Elder, G.H., Balestra, D., Sinclair, J.F., Gerhard, G.S. Hepatology (2003) [Pubmed]
  3. Obesity in BSB mice is correlated with expression of genes for iron homeostasis and leptin. Farahani, P., Chiu, S., Bowlus, C.L., Boffelli, D., Lee, E., Fisler, J.S., Krauss, R.M., Warden, C.H. Obes. Res. (2004) [Pubmed]
  4. Uroporphyria in the uroporphyrinogen decarboxylase-deficient mouse: Interplay with siderosis and polychlorinated biphenyl exposure. Franklin, M.R., Phillips, J.D., Kushner, J.P. Hepatology (2002) [Pubmed]
  5. Expression of stimulator of Fe transport is not enhanced in Hfe knockout mice. Knutson, M.D., Levy, J.E., Andrews, N.C., Wessling-Resnick, M. J. Nutr. (2001) [Pubmed]
  6. Genetic factors influence ethanol-induced uroporphyria in Hfe(-/-) mice. Gorman, N., Trask, H.W., Bement, W.J., Szakacs, J.G., Elder, G.H., Balestra, D., Jacobs, N.J., Jacobs, J.M., Sinclair, J.F., Gerhard, G.S., Sinclair, P.R. Hepatology (2004) [Pubmed]
  7. Regulation of Hfe by stress factors in BV-2 cells. Lee, S.Y., Connor, J.R. Neurobiol. Aging (2005) [Pubmed]
  8. An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice. Roy, C.N., Custodio, A.O., de Graaf, J., Schneider, S., Akpan, I., Montross, L.K., Sanchez, M., Gaudino, A., Hentze, M.W., Andrews, N.C., Muckenthaler, M.U. Nat. Genet. (2004) [Pubmed]
  9. 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]
  10. Uroporphyria in Hfe mutant mice given 5-aminolevulinate: a new model of Fe-mediated porphyria cutanea tarda. Sinclair, P.R., Gorman, N., Walton, H.S., Bement, W.J., Sinclair, J.F., Gerhard, G.S., Szakacs, J.G., Andrews, N.C., Levy, J.E. Hepatology (2001) [Pubmed]
  11. Iron in skin of mice with three etiologies of systemic iron overload. Adams, B.D., Lazova, R., Andrews, N.C., Milstone, L.M. J. Invest. Dermatol. (2005) [Pubmed]
  12. Distinct requirements for Hfe in basal and induced hepcidin levels in iron overload and inflammation. Constante, M., Jiang, W., Wang, D., Raymond, V.A., Bilodeau, M., Santos, M.M. Am. J. Physiol. Gastrointest. Liver Physiol. (2006) [Pubmed]
  13. Haptoglobin modifies the hemochromatosis phenotype in mice. Tolosano, E., Fagoonee, S., Garuti, C., Valli, L., Andrews, N.C., Altruda, F., Pietrangelo, A. Blood (2005) [Pubmed]
  14. Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis. Fleming, R.E., Holden, C.C., Tomatsu, S., Waheed, A., Brunt, E.M., Britton, R.S., Bacon, B.R., Roopenian, D.C., Sly, W.S. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  15. Accelerated Transferrin Degradation in HFE-Deficient Mice Is Associated with Increased Transferrin Saturation. Chaudhury, C., Kim, J., Mehnaz, S., Wani, M.A., Oberyszyn, T.M., Bronson, C.L., Mohanty, S., Hayton, W.L., Robinson, J.M., Anderson, C.L. J. Nutr. (2006) [Pubmed]
  16. Nontransferrin-bound iron uptake by hepatocytes is increased in the Hfe knockout mouse model of hereditary hemochromatosis. Chua, A.C., Olynyk, J.K., Leedman, P.J., Trinder, D. Blood (2004) [Pubmed]
  17. A compartmental model of iron regulation in the mouse. Lao, B.J., Kamei, D.T. J. Theor. Biol. (2006) [Pubmed]
  18. Direct recognition by alphabeta cytolytic T cells of Hfe, a MHC class Ib molecule without antigen-presenting function. Rohrlich, P.S., Fazilleau, N., Ginhoux, F., Firat, H., Michel, F., Cochet, M., Laham, N., Roth, M.P., Pascolo, S., Nato, F., Coppin, H., Charneau, P., Danos, O., Acuto, O., Ehrlich, R., Kanellopoulos, J., Lemonnier, F.A. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  19. Increased glucose disposal and AMP-dependent kinase signaling in a mouse model of hemochromatosis. Huang, J., Gabrielsen, J.S., Cooksey, R.C., Luo, B., Boros, L.G., Jones, D.L., Jouihan, H.A., Soesanto, Y., Knecht, L., Hazel, M.W., Kushner, J.P., McClain, D.A. J. Biol. Chem. (2007) [Pubmed]
  20. Iron uptake from plasma transferrin by the duodenum is impaired in the Hfe knockout mouse. Trinder, D., Olynyk, J.K., Sly, W.S., Morgan, E.H. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  21. Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders. Canonne-Hergaux, F., Levy, J.E., Fleming, M.D., Montross, L.K., Andrews, N.C., Gros, P. Blood (2001) [Pubmed]
  22. Iron absorption and hepatic iron uptake are increased in a transferrin receptor 2 (Y245X) mutant mouse model of hemochromatosis type 3. Drake, S.F., Morgan, E.H., Herbison, C.E., Delima, R., Graham, R.M., Chua, A.C., Leedman, P.J., Fleming, R.E., Bacon, B.R., Olynyk, J.K., Trinder, D. Am. J. Physiol. Gastrointest. Liver Physiol. (2007) [Pubmed]
  23. Regulation of transferrin receptor 2 protein levels by transferrin. Robb, A., Wessling-Resnick, M. Blood (2004) [Pubmed]
  24. Hepatic expression of hemochromatosis genes in two mouse strains after phlebotomy and iron overload. Bondi, A., Valentino, P., Daraio, F., Porporato, P., Gramaglia, E., Carturan, S., Gottardi, E., Camaschella, C., Roetto, A. Haematologica (2005) [Pubmed]
  25. Contribution of Hfe expression in macrophages to the regulation of hepatic hepcidin levels and iron loading. Makui, H., Soares, R.J., Jiang, W., Constante, M., Santos, M.M. Blood (2005) [Pubmed]
  26. Iron dysregulation combined with aging prevents sepsis-induced apoptosis. Javadi, P., Buchman, T.G., Stromberg, P.E., Turnbull, I.R., Vyas, D., Hotchkiss, R.S., Karl, I.E., Coopersmith, C.M. J. Surg. Res. (2005) [Pubmed]
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