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Gene Review

HEPH  -  hephaestin

Homo sapiens

Synonyms: CPL, Hephaestin, KIAA0698, UNQ2562/PRO6242
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Disease relevance of HEPH


Psychiatry related information on HEPH

  • In April, testes and CPL develop rapidly reaching a peak in early May when females are laying eggs, and when most copulations occur [6].

High impact information on HEPH


Chemical compound and disease context of HEPH

  • METHODS: Tissues were obtained from 22 pregnant ewes under halothane anesthesia: early controls at 131 days' gestational age (dGA) not in labor (ECNL; n = 6); during cortisol-induced premature labor (CPL at 131 dGA; n = 6); in term spontaneous labor (STL at 140-145 dGA; n = 5); or term control animals not in labor (TCNL at 140-145 dGA; n = 5) [11].

Biological context of HEPH

  • Duodenal Dcytb and hephaestin mRNA expression are not significantly modulated by variations in body iron homeostasis [12].
  • To test this hypothesis, human hephaestin cDNA has been cloned by reverse transcription of human duodenal mRNA [2].
  • Following in vitro mutagenesis to make the encoded polypeptide suitable for expression and purification, the hephaestin cDNA was cloned into the expression vector pNUT and introduced into baby hamster kidney cells [2].
  • Cell surface biotinylation and immunofluorescent studies of polarized, differentiated colon carcinoma cells detected hephaestin on the basolateral surface under steady-state conditions [13].
  • Immunoblot analysis and pulse-chase metabolic labeling revealed that hephaestin is synthesized as a single-chain polypeptide modified by N-linked glycosylation to a mature 161-kDa species [13].

Anatomical context of HEPH

  • SFT (Stimulator of Iron Transport) is postulated to facilitate both ferric and ferrous iron uptake, and Hephaestin is thought to be important in transfer of iron from enterocytes into the plasma [14].
  • The expression and regulation of the iron transport molecules hephaestin and IREG1: implications for the control of iron export from the small intestine [15].
  • Mice deficient in both Cp and Heph, but not each individually, had a striking, age-dependent increase in retinal pigment epithelium and retinal iron [4].
  • RESULTS: We have demonstrated that hephaestin is primarily localised to a supranuclear compartment in both intestinal enterocytes and in cultured cells [16].
  • Taken together, these studies demonstrate the presence of a quality control system for posttranslational protein modification occurring beyond the endoplasmic reticulum that, in the case of hephaestin, directly links the rate of enteric iron uptake to nutritional copper status [13].

Associations of HEPH with chemical compounds


Physical interactions of HEPH

  • On the basis of this similarity to ceruloplasmin, human hephaestin may also bind copper and possess ferroxidase activity [2].
  • The basolateral transfer of iron requires two components: a copper-containing iron oxidase known as hephaestin and a membrane transport protein IREG1 [15].

Other interactions of HEPH

  • Hephaestin and Dcytb levels were not upregulated in haemochromatosis [19].
  • These results suggest that DMT1, Fpn1, and Heph are involved in the iron uptake process modulated by copper status [20].
  • Our data show that expression levels of human DCT1 mRNA, and to a lesser extent IREG1 mRNA, are regulated in an iron-dependent manner, whereas mRNA of hephaestin is not affected [3].
  • Recombinant expression and functional characterization of human hephaestin: a multicopper oxidase with ferroxidase activity [2].
  • HFE expression did not affect the mRNA levels of most of the genes involved in iron absorption that were tested; however, it did correspond to a decrease in hephaestin message levels [21].

Analytical, diagnostic and therapeutic context of HEPH

  • As judged by SDS-PAGE, N-terminal sequence analysis, and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, the purified hephaestin was homogeneous with a mass of 129600 Da, suggesting a carbohydrate content of 7.7% [2].
  • The histologic grade of regression of 50 osteosarcomas after polychemotherapy - according to the protocol study, COSS 80 - was classified on a six-stage regression scale; 56% of all patients responded well to chemotherapy regression grades I, II, and III and no significant difference between BCD- and CPL-treated patients could be found [22].
  • Recognizing that the patients who comprise the conditionally released CPL 330 category are heterogeneous and multiply disabled, techniques for active focused rehabilitation treatment will be explored [23].


  1. Modulation of iron transport proteins in human colorectal carcinogenesis. Brookes, M.J., Hughes, S., Turner, F.E., Reynolds, G., Sharma, N., Ismail, T., Berx, G., McKie, A.T., Hotchin, N., Anderson, G.J., Iqbal, T., Tselepis, C. Gut (2006) [Pubmed]
  2. Recombinant expression and functional characterization of human hephaestin: a multicopper oxidase with ferroxidase activity. Griffiths, T.A., Mauk, A.G., MacGillivray, R.T. Biochemistry (2005) [Pubmed]
  3. Intestinal expression of genes involved in iron absorption in humans. Rolfs, A., Bonkovsky, H.L., Kohlroser, J.G., McNeal, K., Sharma, A., Berger, U.V., Hediger, M.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  4. Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Hahn, P., Qian, Y., Dentchev, T., Chen, L., Beard, J., Harris, Z.L., Dunaief, J.L. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  5. Pelvic lymph node metastasis of uterine cervical cancer. Noguchi, H., Shiozawa, I., Sakai, Y., Yamazaki, T., Fukuta, T. Gynecol. Oncol. (1987) [Pubmed]
  6. Environmental and endocrine control of reproduction in the song sparrow, Melospiza melodia. I. Temporal organization of the breeding cycle. Wingfield, J.C. Gen. Comp. Endocrinol. (1984) [Pubmed]
  7. 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]
  8. 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]
  9. 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]
  10. Iron homeostasis: new tales from the crypt. Roy, C.N., Enns, C.A. Blood (2000) [Pubmed]
  11. Parathyroid hormone-related protein mRNA in sheep endometrium and myometrium during late gestation and labor. Wu, W.X., Bruns, M.E., Bruns, D., Seaner, R., Nathanielsz, P.W., Ferguson, J.E. J. Soc. Gynecol. Investig. (1998) [Pubmed]
  12. Duodenal Dcytb and hephaestin mRNA expression are not significantly modulated by variations in body iron homeostasis. Gleeson, F., Ryan, E., Barrett, S., Russell, J., Kelleher, B., Crowe, J. Blood Cells Mol. Dis. (2005) [Pubmed]
  13. Role of copper in the proteosome-mediated degradation of the multicopper oxidase hephaestin. Nittis, T., Gitlin, J.D. J. Biol. Chem. (2004) [Pubmed]
  14. Iron absorption and transport-an update. Conrad, M.E., Umbreit, J.N. Am. J. Hematol. (2000) [Pubmed]
  15. The expression and regulation of the iron transport molecules hephaestin and IREG1: implications for the control of iron export from the small intestine. Anderson, G.J., Frazer, D.M., McKie, A.T., Wilkins, S.J., Vulpe, C.D. Cell Biochem. Biophys. (2002) [Pubmed]
  16. 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]
  17. Diastereoselective formation of chiral tris-cyclometalated iridium (III) complexes: characterization and photophysical properties. Schaffner-Hamann, C., von Zelewsky, A., Barbieri, A., Barigelletti, F., Muller, G., Riehl, J.P., Neels, A. J. Am. Chem. Soc. (2004) [Pubmed]
  18. Absolute asymmetric photoreactions of aliphatic amino acids by circularly polarized synchrotron radiation: critically pH-dependent photobehavior. Nishino, H., Kosaka, A., Hembury, G.A., Aoki, F., Miyauchi, K., Shitomi, H., Onuki, H., Inoue, Y. J. Am. Chem. Soc. (2002) [Pubmed]
  19. Duodenal expression of iron transport molecules in untreated haemochromatosis subjects. Stuart, K.A., Anderson, G.J., Frazer, D.M., Powell, L.W., McCullen, M., Fletcher, L.M., Crawford, D.H. Gut (2003) [Pubmed]
  20. Copper repletion enhances apical iron uptake and transepithelial iron transport by Caco-2 cells. Han, O., Wessling-Resnick, M. Am. J. Physiol. Gastrointest. Liver Physiol. (2002) [Pubmed]
  21. Expression of the hereditary hemochromatosis protein HFE increases ferritin levels by inhibiting iron export in HT29 cells. Davies, P.S., Enns, C.A. J. Biol. Chem. (2004) [Pubmed]
  22. Morphological grades of regression in osteosarcoma after polychemotherapy - study COSS 80. Salzer-Kuntschik, M., Delling, G., Beron, G., Sigmund, R. J. Cancer Res. Clin. Oncol. (1983) [Pubmed]
  23. Providing outpatient services to criminal procedure law patients: the clinician's perspective. Epstein, H.J. The Psychiatric quarterly. (1993) [Pubmed]
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