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Gene Review

SLC39A4  -  solute carrier family 39 (zinc...

Homo sapiens

Synonyms: AEZ, AWMS2, Solute carrier family 39 member 4, ZIP-4, ZIP4, ...
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Disease relevance of SLC39A4


High impact information on SLC39A4

  • The chromosomal location and expression of SLC39A4, together with mutational analysis of eight families affected with acrodermatitis enteropathica, suggest that SLC39A4 is centrally involved in the pathogenesis of this condition [1].
  • These findings suggest that the hZIP4 transporter is responsible for intestinal absorption of zinc [5].
  • The gene encodes a histidine-rich protein, which we refer to as "hZIP4," which is a member of a large family of transmembrane proteins, some of which are known to serve as zinc-uptake proteins [5].
  • Expression of SLC30A1, SLC30A5, and SLC39A4 was also examined by immunoblotting [6].
  • This gene encodes one member of a human zinc/iron-regulated transporter-like protein, also known as ZIP4, and consists of 12 exons and spans about 4.7 kb [7].

Associations of SLC39A4 with chemical compounds

  • Mutational analysis identified a cytoplasmic histidine-rich domain that was essential for ubiquitin-dependent degradation of ZIP4 and protection against zinc toxicity [8].

Anatomical context of SLC39A4

  • Commensurate with these observations in zinc supplemented human subjects, SLC30A1, SLC30A5, and SLC39A4 mRNA and protein were reduced in Caco-2 cells cultured at 200 muM compared with 100 muM zinc [6].
  • Genetic studies have specifically implicated SLC39A4 in the uptake of dietary zinc into intestinal enterocytes [9].
  • Studies of SLC39A1, SLC39A2, and SLC39A4, encoding the proteins hZip1, hZip2, and hZip4, have indicated roles in zinc uptake across the plasma membrane of various cell types [9].

Other interactions of SLC39A4

  • The cloning of human Zn transporters ZnT-like transporter 1 (hZTL1)/ZnT5 (SLC30A5) and hZIP4 (SLC39A4) were major advances in the understanding of the molecular mechanisms of dietary Zn absorption [2].
  • Two zinc-related diseases, acrodermatitis enteropathica and the lethal milk syndrome, have been recently related to mutations in zinc transporters, SLC39A4 and ZnT-4, respectively [10].


  1. Identification of SLC39A4, a gene involved in acrodermatitis enteropathica. Küry, S., Dréno, B., Bézieau, S., Giraudet, S., Kharfi, M., Kamoun, R., Moisan, J.P. Nat. Genet. (2002) [Pubmed]
  2. Intestinal and placental zinc transport pathways. Ford, D. The Proceedings of the Nutrition Society. (2004) [Pubmed]
  3. Down-regulation of ZIP4 by RNA interference inhibits pancreatic cancer growth and increases the survival of nude mice with pancreatic cancer xenografts. Li, M., Zhang, Y., Bharadwaj, U., Zhai, Q.J., Ahern, C.H., Fisher, W.E., Brunicardi, F.C., Logsdon, C.D., Chen, C., Yao, Q. Clin. Cancer Res. (2009) [Pubmed]
  4. ZIP4 regulates pancreatic cancer cell growth by activating IL-6/STAT3 pathway through zinc finger transcription factor CREB. Zhang, Y., Bharadwaj, U., Logsdon, C.D., Chen, C., Yao, Q., Li, M. Clin. Cancer Res. (2010) [Pubmed]
  5. A novel member of a zinc transporter family is defective in acrodermatitis enteropathica. Wang, K., Zhou, B., Kuo, Y.M., Zemansky, J., Gitschier, J. Am. J. Hum. Genet. (2002) [Pubmed]
  6. Homeostatic regulation of zinc transporters in the human small intestine by dietary zinc supplementation. Cragg, R.A., Phillips, S.R., Piper, J.M., Varma, J.S., Campbell, F.C., Mathers, J.C., Ford, D. Gut (2005) [Pubmed]
  7. A new mutation in exon 3 of the SCL39A4 gene in a Tunisian family with severe acrodermatitis enteropathica. Meftah, S.P., Kuivaniemi, H., Tromp, G., Kerkeni, A., Sfar, M.T., Ayadi, A., Prasad, A.S. Nutrition (Burbank, Los Angeles County, Calif.) (2006) [Pubmed]
  8. A histidine-rich cluster mediates the ubiquitination and degradation of the human zinc transporter, hZIP4, and protects against zinc cytotoxicity. Mao, X., Kim, B.E., Wang, F., Eide, D.J., Petris, M.J. J. Biol. Chem. (2007) [Pubmed]
  9. The SLC39 family of metal ion transporters. Eide, D.J. Pflugers Arch. (2004) [Pubmed]
  10. Zinc homeostasis-regulating proteins: new drug targets for triggering cell fate. Chimienti, F., Aouffen, M., Favier, A., Seve, M. Current drug targets. (2003) [Pubmed]
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