Alternative titles; symbols
HGNC Approved Gene Symbol: SLC11A2
SNOMEDCT: 711161006;
Cytogenetic location: 12q13.12 Genomic coordinates (GRCh38): 12:50,952,263-51,028,886 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.12 | Anemia, hypochromic microcytic, with iron overload 1 | 206100 | Autosomal recessive | 3 |
The SLC11A2 gene encodes a divalent metal transporter (DMT1), which carries iron, manganese, cobalt, nickel, cadmium, lead, copper, and zinc. DMT1 participates in cellular iron absorption at the luminal surface of the duodenum as well as in other areas of the body (Hubert and Hentze, 2002; Ludwiczek et al., 2007).
Gruenheid et al. (1995) identified the Nramp2 gene in mouse. Vidal et al. (1995) isolated and characterized a cDNA clone corresponding to the second member of the human NRAMP family, NRAMP2. Predicted amino acid sequence analysis of the NRAMP2 polypeptide identified a polytopic membrane protein highly homologous to human NRAMP1 (600266), with 66% identical residues (80% overall homology), resulting in identical predicted secondary structure of the 2 proteins. Sequence conservation is particularly high in the predicted transmembrane domains (90%), suggesting that these regions play a key role in the structural and functional aspects common to both proteins. As opposed to its NRAMP1 counterpart, whose expression is restricted to phagocytic cells, Northern blot analysis indicated that NRAMP2 mRNA transcripts are expressed at low levels in all tissues analyzed.
Metal ions are essential cofactors for a wealth of biologic processes, including oxidative phosphorylation, gene regulation, and free-radical homeostasis. Failure to maintain appropriate levels of metal ions in humans is a feature of hereditary hemochromatosis (235200), Menkes syndrome (309400), Wilson disease (277900), and other disorders. Gunshin et al. (1997) identified a metal-ion transporter in the rat, symbolized DCT1 (divalent cation transporter) by them, which was found to have an unusually broad substrate range that included divalent cations of iron, zinc, manganese, cobalt, cadmium, copper, nickel, and lead. DCT1 mediated active transport that was proton-coupled and depended on the cell membrane potential. DCT1 is upregulated by dietary iron deficiency and may represent a key mediator of intestinal iron absorption.
Hubert and Hentze (2002) found that the DMT1 gene encodes 4 different protein isoforms. They identified a previously unrecognized upstream 5-prime exon, termed exon 1A, which adds an in-frame translation initiation codon and extends the open reading frame of the protein by 29 to 31 amino acids. The expression of exon 1A is tissue-specific and particularly prevalent in the duodenum and the kidney. In addition, DMT1 mRNA levels are regulated by an iron-responsive element (IRE) in the 3-prime untranslated region. Four isoforms are produced by alternative splicing of exon 1A and the IRE, yielding DMT-1A-IRE, DMT-1B-IRE, DMT-1A-nonIRE, and DMT-1B-nonIRE. Ludwiczek et al. (2007) found that iron uptake was most effective in cells transfected with the DMT-1A-IRE isoform at pH 5.5-6.5.
Vidal et al. (1995) used fluorescence in situ hybridization to identify 12q13 as the chromosomal location of the human NRAMP2 gene.
Foot et al. (2011) stated that NDFIP1 (612050) and NDFIP2 (610041) regulate DMT1 by acting as adaptors between DMT1 and the ubiquitin ligases WWP2 (602308) and NEDD4-2 (NEDD4L; 606384), thereby directing DMT1 ubiquitination and subsequent degradation. They found that Dmt1 expression and activity were increased in duodenal enterocytes of Ndfip1 -/- mice, particularly in Ndfip1 -/- mice fed a low-iron diet. Increased duodenal Dmt1 activity led to higher serum iron levels and greater transferrin (TF; 190000) saturation. Ndfip1 -/- mice also developed anemia, which appeared to be due to reduced erythropoiesis in bone marrow and inflammation.
In a female with severe hypochromic microcytic anemia and iron overload (206100), Mims et al. (2005) identified a missense mutation in the DMT1 gene (E399D; 600523.0001).
In a 5-year-old boy with hypochromic, microcytic anemia, and hepatic iron overload, Iolascon et al. (2006) identified compound heterozygosity for mutations in the DMT1 gene (600523.0002, 600523.0003).
In a 6-year-old French girl with hypochromic, microcytic anemia, Beaumont et al. (2006) identified compound heterozygosity for an in-frame deletion and a substitution mutation in the DMTA1 gene (600523.0004 and 600523.0005, respectively).
Fleming et al. (1997) undertook a positional cloning strategy to identify the causative mutation in mice with microcytic anemia (mk). Homozygous mk/mk mice have hypochromic microcytic anemia due to severe defects in intestinal iron absorption and erythroid iron utilization. Fleming et al. (1997) identified a strong candidate gene for mk and suggested that the phenotype is a consequence of a missense mutation in Nramp2, a homolog of Nramp1, a gene active in host defense. The mutation they found was a G-to-A transition at a CpG dinucleotide, resulting in substitution of arginine for glycine at codon 185. They commented that the findings have broad implications for the understanding of iron transport and resistance to intracellular pathogens.
The Belgrade (b) rat has an autosomal recessively inherited, microcytic, hypochromic anemia associated with abnormal reticulocyte iron uptake and gastrointestinal iron absorption. The b reticulocyte defect appeared to be failure of iron transport out of endosomes within the transferrin cycle. Aspects of this phenotype were similar to those reported for the mk mutation in the mouse. Fleming et al. (1998) established linkage of the Belgrade phenotype to the centromeric region of rat chromosome 7. This region exhibits synteny with the telomeric portion of mouse chromosome 15, where mouse Nramp2 and the mk phenotype had previously been mapped. Surprisingly, Fleming et al. (1998) found that the Belgrade rat had the same mutation, G185R, as the mk mouse. They showed that the b allele encodes a protein with little or no activity in iron uptake assays.
Waheed et al. (1999) reported that HFE (613609), the protein defective in one form of hemochromatosis (235200), is physically associated with the transferrin receptor (TFRC; 190010) in duodenal crypt cells and proposed that mutations in HFE attenuate the uptake of transferrin (190000)-bound iron from plasma by duodenal crypt cells, leading to upregulation of transporters for dietary iron. Fleming et al. (1999) tested the hypothesis that Hfe -/- mice have increased duodenal expression of the divalent metal transporter (DMT1). By 4 weeks of age, the homozygous deficient mice demonstrated iron loading when compared with homozygous normal littermates, with elevated transferrin saturations (68.4% vs 49.8%) and elevated liver iron concentrations. Using Northern blot analyses, they quantitated duodenal expression of both classes of DMT1 transcripts: 1 containing an iron-responsive element (IRE), called DMT1(IRE), and 1 containing no IRE, called DMT1(non-IRE). The positive control for DMT1 upregulation was a murine model of dietary iron deficiency that demonstrated greatly increased levels of duodenal DMT1(IRE) mRNA. Homozygous Hfe-deficient mice also demonstrated an increase in duodenal DMT1(IRE) mRNA (average, 7.7-fold), despite their elevated transferrin saturation and hepatic iron content. Duodenal expression of DMT1(non-IRE) was not increased, nor was hepatic expression of DMT1 increased. These data support the model for hereditary hemochromatosis in which HFE mutations lead to inappropriately low crypt cell iron, with resultant stabilization of DMT1(IRE) mRNA, upregulation of DMT1, and increased absorption of dietary iron.
Gunshin et al. (2005) inactivated the mouse Slc11a2 gene globally and in selected tissues through gene targeting and homologous recombination in pluripotent embryonic stem cells. They found that fetal Slc11a2 was not needed for maternofetal iron transfer but that Slc11a2 activity was essential for intestinal nonheme iron absorption after birth. Slc11a2 was also required for normal hemoglobin production during the development of erythroid precursors. Iron dextran administered to Slc11a2-null mice markedly increased liver iron stores in both hepatocytes and macrophages, indicating that hepatocytes and other cells must have an alternative iron uptake mechanism. Gunshin et al. (2005) also noted that inactivation of mouse Hfe ameliorated the Slc11a2-null phenotype.
Ludwiczek et al. (2007) found that the L-type calcium channel blocker nifedipine increased Dmt1-mediated cellular iron transport in vitro. In mice with primary (Hfe-null mice; see 235200) and secondary iron overload, nifedipine mobilized iron from the liver and enhanced urinary iron excretion. Mechanistically, the effect resulted from prolonging the iron-transporting activity of Dmt1 and delaying current inactivation.
In a patient with hypochromic microcytic anemia and iron overload (206100), Mims et al. (2005) found homozygosity for a 1285G-C transversion in exon 12 of the DMT1 gene, resulting in a glu399-to-asp substitution (E399D). The predominant effect of the substitution was preferential skipping of exon 12 during processing of pre-mRNA. The lack of full-length mRNA would predict deficient iron absorption in the intestine and deficient iron utilization in erythroid precursors; however, unlike the animal models of DMT1 mutations, the mk mouse and the Belgrade rat, the patient was iron overloaded.
In a 5-year-old boy with hypochromic microcytic anemia and iron overload (206100), born of nonconsanguineous parents from southern Italy, Iolascon et al. (2006) identified compound heterozygosity for a 3-bp deletion (310delCTT) in intron 4 of the SLC11A2 gene, resulting in a splicing abnormality, and a 1246C-T transition in exon 13, resulting in an arg416-to-cys (R416C) substitution (600523.0003). His father and mother were heterozygous for the deletion and missense mutation, respectively. A striking reduction of DMT1 protein in peripheral blood mononuclear cells was demonstrated by Western blot analysis.
For discussion of the arg416-to-cys (R416C) mutation in the SLC11A2 gene that was found in compound heterozygous state in a patient with hypochromic microcytic anemia and iron overload (206100) by Iolascon et al. (2006), see 600523.0002.
In a 6-year-old French girl with hypochromic microcytic anemia and iron overload (206100), Beaumont et al. (2006) identified compound heterozygosity for a 3-bp deletion (428delGTG) in exon 5 and a 723G-T transversion (600523.0005) in exon 8 of the SLC11A2 gene, resulting in the in-frame deletion of val114 and a gly212-to-val (G212V) substitution. The unaffected father was heterozygous for the val114 deletion, and the unaffected mother and sister were heterozygous for the G212V mutation. Neither mutation was found in 55 healthy controls.
For discussion of the gly212-to-val (G212V) mutation in the SLC11A2 gene that was found in compound heterozygous state in a patient with hypochromic microcytic anemia and iron overload (206100) by Beaumont et al. (2006), see 600523.0004.
Beaumont, C., Delaunay, J., Hetet, G., Grandchamp, B., de Montalembert, M., Tchernia, G. Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood 107: 4168-4170, 2006. [PubMed: 16439678] [Full Text: https://doi.org/10.1182/blood-2005-10-4269]
Fleming, M. D., Romano, M. A., Su, M. A., Garrick, L. M., Garrick, M. D., Andrews, N. C. Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc. Nat. Acad. Sci. 95: 1148-1153, 1998. [PubMed: 9448300] [Full Text: https://doi.org/10.1073/pnas.95.3.1148]
Fleming, M. D., Trenor, C. C., III, Su, M. A., Foernzler, D., Beier, D. R., Dietrich, W. F., Andrews, N. C. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nature Genet. 16: 383-386, 1997. [PubMed: 9241278] [Full Text: https://doi.org/10.1038/ng0897-383]
Fleming, R. E., Migas, M. C., Zhou, X. Y., Jiang, J., Britton, R. S., Brunt, E. M., Tomatsu, S., Waheed, A., Bacon, B. R., Sly, W. S. Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. Proc. Nat. Acad. Sci. 96: 3143-3148, 1999. [PubMed: 10077651] [Full Text: https://doi.org/10.1073/pnas.96.6.3143]
Foot, N. J., Leong, Y. A., Dorstyn, L. E., Dalton, H. E., Ho, K., Zhao, L., Garrick, M. D., Yang, B., Hiwase, D., Kumar, S. Ndfip1-deficient mice have impaired DMT1 regulation and iron homeostasis. Blood 117: 638-646, 2011. [PubMed: 20959604] [Full Text: https://doi.org/10.1182/blood-2010-07-295287]
Gruenheid, S., Cellier, M., Vidal, S., Gros, P. Identification and characterization of a second mouse Nramp gene. Genomics 25: 514-525, 1995. [PubMed: 7789986] [Full Text: https://doi.org/10.1016/0888-7543(95)80053-o]
Gunshin, H., Fujiwara, Y., Custodio, A. O., DiRenzo, C., Robine, S., Andrews, N. C. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Invest. 115: 1258-1266, 2005. [PubMed: 15849611] [Full Text: https://doi.org/10.1172/JCI24356]
Gunshin, H., Mackenzie, B., Berger, U. V., Gunshin, Y., Romero, M. F., Boron, W. F., Nussberger, S., Gollan, J. L., Hediger, M. A. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388: 482-488, 1997. [PubMed: 9242408] [Full Text: https://doi.org/10.1038/41343]
Hubert, N., Hentze, M. W. Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc. Nat. Acad. Sci. 99: 12345-12350, 2002. [PubMed: 12209011] [Full Text: https://doi.org/10.1073/pnas.192423399]
Iolascon, A., d'Apolito, M., Servedio, V., Cimmino, F., Piga, A., Camaschella, C. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2) (sic). Blood 107: 349-354, 2006. [PubMed: 16160008] [Full Text: https://doi.org/10.1182/blood-2005-06-2477]
Ludwiczek, S., Theurl, I., Muckenthaler, M. U., Jakab, M., Mair, S. M., Theurl, M., Kiss, J., Paulmichl, M., Hentze, M. W., Ritter, M., Weiss, G. Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Nature Med. 13: 448-454, 2007. [PubMed: 17293870] [Full Text: https://doi.org/10.1038/nm1542]
Mims, M. P., Guan, Y., Pospisilova, D., Priwitzerova, M., Indrak, K., Ponka, P., Divoky, V., Prchal, J. T. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood 105: 1337-1342, 2005. [PubMed: 15459009] [Full Text: https://doi.org/10.1182/blood-2004-07-2966]
Vidal, S., Belouchi, A.-M., Cellier, M., Beatty, B., Gros, P. Cloning and characterization of a second human NRAMP gene on chromosome 12q13. Mammalian Genome 6: 224-230, 1995. [PubMed: 7613023] [Full Text: https://doi.org/10.1007/BF00352405]
Waheed, A., Parkkila, S., Saarnio, J., Fleming, R. E., Zhou, X. Y., Tomatsu, S., Britton, R. S., Bacon, B. R., Sly, W. S. Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum. Proc. Nat. Acad. Sci. 96: 1579-1584, 1999. [PubMed: 9990067] [Full Text: https://doi.org/10.1073/pnas.96.4.1579]