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Gene Review

Slc11a2  -  solute carrier family 11 (proton-coupled...

Mus musculus

Synonyms: DCT1, DMT-1, DMT1, Dct1, Divalent cation transporter 1, ...
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Disease relevance of Slc11a2

  • Hepatic and/or duodenal response patterns of iron metabolism genes, such as Trfr, cybrd1, and Slc11a2, explained the transition from early postnatal iron deficiency to iron overload by 12 weeks of age [1].
  • Microcytic anemia (mk) mice and Belgrade (b) rats have severe iron deficiency anemia due to defects in intestinal iron transport and erythroid iron utilization [2].
  • Based on these observations and on reports that show that the closely related Nramp2 gene is a metal ion transporter, we evaluated the effect of iron on the growth of Mycobacterium avium within macrophages as well as on the stability of Nramp1 mRNA [3].

High impact information on Slc11a2

  • Endosomal acidification leads to iron release, and iron is transported out of the endosome through the activity of divalent metal transporter 1 (DMT1, formerly Nramp2), a transmembrane iron transporter that functions only at low pH [4].
  • Homozygous mk/mk mice have microcytic, hypochromic anaemia due to severe defects in intestinal iron absorption and erythroid iron utilization [5].
  • We report the identification of a strong candidate gene for mk, and suggest that the phenotype is a consequence of a missense mutation in Nramp2 (ref. 5), a previously identified gene of unknown function [5].
  • The mk allele carries a missense mutation that causes substitution of valine by alanine at amino acid 173 of the p45 NF-E2 protein [6].
  • These findings suggest that Nramp2 plays a key role in the metabolism of transferrin-bound iron by transporting free Fe2+ across the endosomal membrane and into the cytoplasm [7].

Biological context of Slc11a2


Anatomical context of Slc11a2

  • Coexpression of DMT1 and TfR in reticulocytes was also detected by double immunofluorescence and confocal microscopy [12].
  • Iron transport and expression of the 2 isoforms of DMT1 was studied in erythroid cells that consume large quantities of iron for biosynthesis of hemoglobin [12].
  • Hfe(-/-) mice do not necessarily display features of iron deficiency in the duodenum, indicated by an increase in mRNA and protein levels of DMT1 and Ireg1 [9].
  • These results indicate that Dmt1 can be modulated by the enterocyte iron level, whereas Hephaestin and Ireg1 expression respond to systemic rather than local signals of iron status [13].
  • In this study, RAW264.7 macrophages and 2 independently derived murine Sertoli cells lines, TM4 and 15P-1, were used to further study the subcellular localization of Nramp2/DMT1 in phagocytic cells, including possible recruitment to the phagosomal membrane [14].

Associations of Slc11a2 with chemical compounds


Physical interactions of Slc11a2

  • As Nramp2 can transport Fe from non-Tf-bound Fe, the effect of preincubation with DFO and FAC was also examined on Fe uptake from [59Fe]nitrilotriacetate and [59Fe]citrate [17].

Regulatory relationships of Slc11a2

  • Nramp2 is a widely expressed metal-ion transporter that is involved in dietary iron absorption in the duodenum and iron uptake from transferrin in peripheral tissues [18].
  • Induction of Nramp2 in activated mouse macrophages is dissociated from regulation of the Nramp1, classical inflammatory genes, and genes involved in iron metabolism [18].

Other interactions of Slc11a2

  • Divalent metal transporter 1 (DMT1) is the major transferrin-independent iron uptake system at the apical pole of intestinal cells, but it may also transport iron across the membrane of acidified endosomes in peripheral tissues [12].
  • Slc11a2 is also required for normal hemoglobin production during the development of erythroid precursors [8].
  • In contrast to the previously described macrophage-specific Nramp gene, Nramp2 mRNAs were found to be expressed at low levels in all tissues tested [19].
  • We examined the expression of the ferric reductase Dcytb, DMT1 and some other genes involved in Fe metabolism in tissues of mice dosed with PHZ [20].
  • Nramp2/DMT1 was also found associated with erythrocyte-containing phagosomes in RAW macrophages and with the periphery of sperm-containing phagosomes in Sertoli cells [14].

Analytical, diagnostic and therapeutic context of Slc11a2


  1. The molecular circuitry regulating the switch between iron deficiency and overload in mice. Mok, H., Mlodnicka, A.E., Hentze, M.W., Muckenthaler, M., Schumacher, A. J. Biol. Chem. (2006) [Pubmed]
  2. The G185R mutation disrupts function of the iron transporter Nramp2. Su, M.A., Trenor, C.C., Fleming, J.C., Fleming, M.D., Andrews, N.C. Blood (1998) [Pubmed]
  3. Role of iron in Nramp1-mediated inhibition of mycobacterial growth. Zwilling, B.S., Kuhn, D.E., Wikoff, L., Brown, D., Lafuse, W. Infect. Immun. (1999) [Pubmed]
  4. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Levy, J.E., Jin, O., Fujiwara, Y., Kuo, F., Andrews, N.C. Nat. Genet. (1999) [Pubmed]
  5. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Fleming, M.D., Trenor, C.C., Su, M.A., Foernzler, D., Beier, D.R., Dietrich, W.F., Andrews, N.C. Nat. Genet. (1997) [Pubmed]
  6. Mouse microcytic anaemia caused by a defect in the gene encoding the globin enhancer-binding protein NF-E2. Peters, L.L., Andrews, N.C., Eicher, E.M., Davidson, M.B., Orkin, S.H., Lux, S.E. Nature (1993) [Pubmed]
  7. The iron transport protein NRAMP2 is an integral membrane glycoprotein that colocalizes with transferrin in recycling endosomes. Gruenheid, S., Canonne-Hergaux, F., Gauthier, S., Hackam, D.J., Grinstein, S., Gros, P. J. Exp. Med. (1999) [Pubmed]
  8. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. Gunshin, H., Fujiwara, Y., Custodio, A.O., Direnzo, C., Robine, S., Andrews, N.C. J. Clin. Invest. (2005) [Pubmed]
  9. Iron overload in adult Hfe-deficient mice independent of changes in the steady-state expression of the duodenal iron transporters DMT1 and Ireg1/ferroportin. Herrmann, T., Muckenthaler, M., van der Hoeven, F., Brennan, K., Gehrke, S.G., Hubert, N., Sergi, C., Gröne, H.J., Kaiser, I., Gosch, I., Volkmann, M., Riedel, H.D., Hentze, M.W., Stewart, A.F., Stremmel, W. J. Mol. Med. (2004) [Pubmed]
  10. Comparative analysis of two slc11 (Nramp) loci in Takifugu rubripes. Sibthorpe, D., Baker, A.M., Gilmartin, B.J., Blackwell, J.M., White, J.K. DNA Cell Biol. (2004) [Pubmed]
  11. 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]
  12. Characterization of the iron transporter DMT1 (NRAMP2/DCT1) in red blood cells of normal and anemic mk/mk mice. Canonne-Hergaux, F., Zhang, A.S., Ponka, P., Gros, P. Blood (2001) [Pubmed]
  13. 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]
  14. Iron transporter Nramp2/DMT-1 is associated with the membrane of phagosomes in macrophages and Sertoli cells. Jabado, N., Canonne-Hergaux, F., Gruenheid, S., Picard, V., Gros, P. Blood (2002) [Pubmed]
  15. Nramp 2 (DCT1/DMT1) expressed at the plasma membrane transports iron and other divalent cations into a calcein-accessible cytoplasmic pool. Picard, V., Govoni, G., Jabado, N., Gros, P. J. Biol. Chem. (2000) [Pubmed]
  16. Interferon-gamma and lipopolysaccharide regulate the expression of Nramp2 and increase the uptake of iron from low relative molecular mass complexes by macrophages. Wardrop, S.L., Richardson, D.R. Eur. J. Biochem. (2000) [Pubmed]
  17. The effect of intracellular iron concentration and nitrogen monoxide on Nramp2 expression and non-transferrin-bound iron uptake. Wardrop, S.L., Richardson, D.R. Eur. J. Biochem. (1999) [Pubmed]
  18. Induction of Nramp2 in activated mouse macrophages is dissociated from regulation of the Nramp1, classical inflammatory genes, and genes involved in iron metabolism. Wardrop, S.L., Wells, C., Ravasi, T., Hume, D.A., Richardson, D.R. J. Leukoc. Biol. (2002) [Pubmed]
  19. Identification and characterization of a second mouse Nramp gene. Gruenheid, S., Cellier, M., Vidal, S., Gros, P. Genomics (1995) [Pubmed]
  20. Tissue-specific changes in iron metabolism genes in mice following phenylhydrazine-induced haemolysis. Latunde-Dada, G.O., Vulpe, C.D., Anderson, G.J., Simpson, R.J., McKie, A.T. Biochim. Biophys. Acta (2004) [Pubmed]
  21. Expression of the iron transporter DMT1 in kidney from normal and anemic mk mice. Canonne-Hergaux, F., Gros, P. Kidney Int. (2002) [Pubmed]
  22. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Iolascon, A., d'Apolito, M., Servedio, V., Cimmino, F., Piga, A., Camaschella, C. Blood (2006) [Pubmed]
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