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Gene Review

Heph  -  hephaestin

Mus musculus

Synonyms: C130006F04Rik, Cpl, Hephaestin, Kiaa0698, mKIAA0698, ...
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Disease relevance of Heph

  • We compared iron levels and expression of genes involved in iron uptake and storage in sla mice and C57BL/6J mice fed iron-deficient, iron-overload, or control diets [1].
  • The anaemia in newborn sla mice is attributable to iron deficiency, since their total body iron is lower than in normal newborn mice, while their birth weights are almost identical [2].
  • Using the Jackson Laboratory BSS panel, we have localized Praja1 on chromosome X at 36 cM, which may be a candidate gene for mouse sla (sex linked sideroblastic anemia), near the X inactivation center gene, Xist [3].
  • The duodenal mucosa of genotypically normal iron replete and iron deficient mice and mice with sex-linked (sla) and microcytic anemias (mk) was examined for the presence of iron-binding proteins [4].
  • We have identified an animal model, the 'sex-linked anemic' (gene symbol, sla) mouse, characterized by iron deficiency anemia, to study the relationship between anemia and cholesterol metabolism [5].

High impact information on Heph

  • We describe here a novel gene, Heph, encoding a transmembrane-bound ceruloplasmin homologue that is mutant in the sla mouse and highly expressed in intestine [6].
  • CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium [7].
  • We suggest that hephaestin, by way of its ferroxidase activity, facilitates iron export from intestinal enterocytes, most likely in cooperation with the basolateral iron transporter, Ireg1 [8].
  • Here, we demonstrate that Hp has both amine oxidase and ferroxidase activity in cultured cells and primary intestinal enterocytes with the use of both gel and solution assays [8].
  • Molecular modeling of the truncated hephaestin suggests retention of a minimum catalytic core required for enzymatic activity [8].

Biological context of Heph


Anatomical context of Heph

  • Unlike iron-deficient mice, sla mouse enterocytes accumulated nonheme iron and ferritin [1].
  • CONCLUSION: We suggest that mislocalisation of hephaestin likely contributes to the functional defect in sla intestinal epithelium [13].
  • We also examined the effect of copper deficiency on hephaestin in vitro in the HT29 cell line and found dramatically decreased hephaestin synthesis and activity [9].
  • The sla gene is already known to have a major effect in reducing iron transport in the small intestine [2].
  • Analysis of the sla mouse has supported our model for the regulation of intestinal iron absorption whereby changes in systemic iron requirements alter the levels of basolateral transport components with subsequent regulation of brush border transport [14].

Associations of Heph with chemical compounds

  • For example, copper-containing proteins like ceruloplasmin and hephaestin oxidize Fe(2+) during cellular export processes for transport in the circulation bound to transferrin [15].
  • Parenteral iron administration produced an increase in the duodenal, liver, and splenic ferritin concentration in both sla/Y and +/Y animals that was most striking in the case of the liver [16].
  • Relationship between anemia and cholesterol metabolism in 'sex-linked anemic' (gene symbol, sla) mouse [5].

Physical interactions of Heph


Regulatory relationships of Heph

  • In contrast, the iron permease Ireg1 localised to the basolateral membrane in both control and sla mice [13].

Other interactions of Heph

  • Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency [1].
  • In the HT versus H comparison, only a few genes were found that had increased expression in the HT line compared with expression in the H line, including GSH-S-transferase alpha 3 and hephaestin [17].

Analytical, diagnostic and therapeutic context of Heph

  • In sla mice, in spite of tissue iron deficiency, the amount of iron deposited was similar to that of normal mice and markedly increased after treatment of the anemia [18].
  • Using electron microscopy radioautography, the deposition of intravenously administered iron in the duodenal epithelium was studied in normal mice, iron-overloaded and iron-deficient mice, and in mice with X-linked anemia (gene symbol sla) 4 and 24 hours after injection of 59Fe [18].


  1. Systemic regulation of Hephaestin and Ireg1 revealed in studies of genetic and nutritional iron deficiency. Chen, H., Su, T., Attieh, Z.K., Fox, T.C., McKie, A.T., Anderson, G.J., Vulpe, C.D. Blood (2003) [Pubmed]
  2. Iron deficiency anaemia in newborn sla mice: a genetic defect of placental iron transport. Kingston, P.J., Bannerman, C.E., Bannerman, R.M. Br. J. Haematol. (1978) [Pubmed]
  3. Praja1, a novel gene encoding a RING-H2 motif in mouse development. Mishra, L., Tully, R.E., Monga, S.P., Yu, P., Cai, T., Makalowski, W., Mezey, E., Pavan, W.J., Mishra, B. Oncogene (1997) [Pubmed]
  4. Mucosal iron binding proteins in sex-linked anemia and microcytic anemia of the mouse. Edwards, J.A., Hoke, J.E. Journal of medicine. (1978) [Pubmed]
  5. Relationship between anemia and cholesterol metabolism in 'sex-linked anemic' (gene symbol, sla) mouse. Au, Y.P., Schilling, R.F. Biochim. Biophys. Acta (1986) [Pubmed]
  6. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Vulpe, C.D., Kuo, Y.M., Murphy, T.L., Cowley, L., Askwith, C., Libina, N., Gitschier, J., Anderson, G.J. Nat. Genet. (1999) [Pubmed]
  7. CDX2-regulated expression of iron transport protein hephaestin in intestinal and colonic epithelium. Hinoi, T., Gesina, G., Akyol, A., Kuick, R., Hanash, S., Giordano, T.J., Gruber, S.B., Fearon, E.R. Gastroenterology (2005) [Pubmed]
  8. Hephaestin is a ferroxidase that maintains partial activity in sex-linked anemia mice. Chen, H., Attieh, Z.K., Su, T., Syed, B.A., Gao, H., Alaeddine, R.M., Fox, T.C., Usta, J., Naylor, C.E., Evans, R.W., McKie, A.T., Anderson, G.J., Vulpe, C.D. Blood (2004) [Pubmed]
  9. Decreased hephaestin activity in the intestine of copper-deficient mice causes systemic iron deficiency. Chen, H., Huang, G., Su, T., Gao, H., Attieh, Z.K., McKie, A.T., Anderson, G.J., Vulpe, C.D. J. Nutr. (2006) [Pubmed]
  10. Mapping the gene for sex-linked anemia: an inherited defect of intestinal iron absorption in the mouse. Anderson, G.J., Murphy, T.L., Cowley, L., Evans, B.A., Halliday, J.W., McLaren, G.D. Genomics (1998) [Pubmed]
  11. Immunolocalization and regulation of iron handling proteins ferritin and ferroportin in the retina. Hahn, P., Dentchev, T., Qian, Y., Rouault, T., Harris, Z.L., Dunaief, J.L. Mol. Vis. (2004) [Pubmed]
  12. Functional studies of hephaestin in yeast: evidence for multicopper oxidase activity in the endocytic pathway. Li, L., Vulpe, C.D., Kaplan, J. Biochem. J. (2003) [Pubmed]
  13. Mislocalisation of hephaestin, a multicopper ferroxidase involved in basolateral intestinal iron transport, in the sex linked anaemia mouse. Kuo, Y.M., Su, T., Chen, H., Attieh, Z., Syed, B.A., McKie, A.T., Anderson, G.J., Gitschier, J., Vulpe, C.D. Gut (2004) [Pubmed]
  14. The ceruloplasmin homolog hephaestin and the control of intestinal iron absorption. Anderson, G.J., Frazer, D.M., McKie, A.T., Vulpe, C.D. Blood Cells Mol. Dis. (2002) [Pubmed]
  15. Mild copper deficiency alters gene expression of proteins involved in iron metabolism. Auclair, S., Feillet-Coudray, C., Coudray, C., Schneider, S., Muckenthaler, M.U., Mazur, A. Blood Cells Mol. Dis. (2006) [Pubmed]
  16. Ferritin distribution and synthesis in sex-linked anemia. Edwards, J.A., Hoke, J.E., Mattioli, M., Reichlin, M. J. Lab. Clin. Med. (1977) [Pubmed]
  17. Differential amplification of gene expression in lens cell lines conditioned to survive peroxide stress. Spector, A., Li, D., Ma, W., Sun, F., Pavlidis, P. Invest. Ophthalmol. Vis. Sci. (2002) [Pubmed]
  18. Uptake of circulating iron by the duodenum of normal mice and mice with altered iron stores, including sex-linked anemia: high resolution radioautographic study. Bédard, Y.C., Pinkerton, P.H., Simon, G.T. Lab. Invest. (1976) [Pubmed]
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