DMT1

Solute carrier family 11 (proton-coupled divalent metal ion transporter), member 2
Identifiers
Symbols	SLC11A2 ; DCT1; DMT1; NRAMP2
External IDs	OMIM: 600523 MGI: 1345279 HomoloGene: 55471 GeneCards: SLC11A2 Gene
Gene ontology Molecular function • copper ion transmembrane transporter activity • manganese ion transmembrane transporter activity • zinc ion transmembrane transporter activity • iron ion binding • copper ion binding • protein binding • zinc ion binding • hydrogen ion transmembrane transporter activity • calcium ion transmembrane transporter activity • cadmium ion transmembrane transporter activity • cobalt ion transmembrane transporter activity • ferrous iron transmembrane transporter activity • lead ion transmembrane transporter activity • nickel cation transmembrane transporter activity • vanadium ion transmembrane transporter activity • solute:proton symporter activity • ferrous iron uptake transmembrane transporter activity • nickel cation binding • inorganic cation transmembrane transporter activity • manganese ion binding • transferrin transmembrane transporter activity • cadmium ion binding • transition metal ion transmembrane transporter activity • cobalt ion binding • chromium ion transmembrane transporter activity Cellular component • nucleus • cytoplasm • mitochondrial outer membrane • lysosome • lysosomal membrane • early endosome • late endosome • vacuole • trans-Golgi network • plasma membrane • integral component of plasma membrane • brush border • cell surface • membrane • apical plasma membrane • retromer complex • cytoplasmic vesicle • late endosome membrane • apical part of cell • basal part of cell • perinuclear region of cytoplasm • recycling endosome • paraferritin complex Biological process • response to hypoxia • detection of oxygen • heme biosynthetic process • cobalt ion transport • copper ion transport • manganese ion transport • cellular copper ion homeostasis • cellular iron ion homeostasis • activation of cysteine-type endopeptidase activity involved in apoptotic process • learning or memory • response to iron ion • response to manganese ion • response to lead ion • nickel cation transport • vanadium ion transport • ferrous iron transport • lead ion transport • transferrin transport • cellular response to oxidative stress • copper ion transmembrane transport • nickel cation transmembrane transport • response to cadmium ion • dendrite morphogenesis • erythrocyte development • transmembrane transport • multicellular organismal iron ion homeostasis • cadmium ion transmembrane transport • ferrous iron import • cellular response to iron ion • cellular response to tumor necrosis factor • manganese ion transmembrane transport • cellular response to hypoxia • zinc II ion transmembrane transport • cation transmembrane transport • hydrogen ion transmembrane transport • copper ion import into cell • ferrous iron transmembrane transport Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4891	18174
Ensembl	ENSG00000110911	ENSMUSG00000023030
UniProt	P49281	P49282
RefSeq (mRNA)	NM_000617	NM_001146161
RefSeq (protein)	NP_000608	NP_001139633
Location (UCSC)	Chr 12: 50.98 – 51.03 Mb	Chr 15: 100.39 – 100.43 Mb
PubMed search

The divalent metal transporter 1 (DMT1), also known as natural resistance-associated macrophage protein 2 (NRAMP 2), and divalent cation transporter 1 (DCT1),^[1] is a protein that in humans is encoded by the SLC11A2 (solute carrier family 11, member 2) gene.^[2] DMT1 represents a large family of orthologous metal ion transporter proteins that are highly conserved from bacteria to humans.^[3]

As its name suggests, DMT1 binds a variety of divalent metals including cadmium (Cd²⁺), copper (Cu²⁺), and zinc (Zn^2+,,) however it is best known for its role in transporting ferrous iron (Fe²⁺); DMT1 expression is regulated by body iron stores to maintain iron homeostasis. DMT1 is also important in the absorption and transport of manganese (Mn²⁺).^[4] In the digestive tract, it is located on the apical membrane of enterocytes, where it carries out H⁺ coupled transport of divalent metal cations from the intestinal lumen into the cell.

Role in neurodegenerative diseases

Toxic accumulation of divalent metals, especially iron and/or manganese, are frequently discussed aetiological factors in a variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. DMT1 may be the major transporter of manganese across the blood brain barrier and expression of this protein in the nasal epithelium provides a route for direct absorption of metals into the brain.^[5] DMT1 expression in the brain may increase with age,^[6] increasing susceptibility to metal induced pathologies. DMT1 expression is found to be increased in the substantia nigra of Parkinson's patients and in the ventral mesencephalon of animal models intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) - a neurotoxin widely used experimentally to produce Parkinsonian symptoms.

The DMT1 encoding gene SLC11A2 is located on the long arm of chromosome 12 (12q13) close to susceptibility regions for Alzheimer's disease^[7] and restless legs syndrome. The C allele of SNP rs407135 on the DMT1 encoding gene SLC11A2 is associated with shorter disease duration in cases of spinal onset amyotrophic lateral sclerosis,^[8] and is implicated in Alzheimer's disease onset in males as well.^[7] The CC haplotype for SNPs 1254T/C IVS34+44C/A is associated with Parkinson's disease susceptibility.^[9] Finally, variant alleles on several SLC11A2 SNPs are associated with iron anemia, a risk factor for manganese intoxication and restless legs syndrome.^[10]

References

1. "Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2". GeneCards. Retrieved 2011-12-16.
2. Vidal S, Belouchi AM, Cellier M, Beatty B, Gros P (April 1995). "Cloning and characterization of a second human NRAMP gene on chromosome 12q13". Mamm. Genome 6 (4): 224–30. doi:10.1007/BF00352405. PMID 7613023.
3. Au C, Benedetto A, Aschner M (July 2008). "Manganese transport in eukaryotes: the role of DMT1". Neurotoxicology 29 (4): 569–76. doi:10.1016/j.neuro.2008.04.022. PMC 2501114. PMID 18565586.
4. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA (July 1997). "Cloning and characterization of a mammalian proton-coupled metal-ion transporter". Nature 388 (6641): 482–8. doi:10.1038/41343. PMID 9242408.
5. Aschner M (May 2006). "The transport of manganese across the blood–brain barrier". Neurotoxicology 27 (3): 311–4. doi:10.1016/j.neuro.2005.09.002. PMID 16460806.
6. Ke Y, Chang YZ, Duan XL, Du JR, Zhu L, Wang K, Yang XD, Ho KP, Qian ZM (May 2005). "Age-dependent and iron-independent expression of two mRNA isoforms of divalent metal transporter 1 in rat brain". Neurobiol. Aging 26 (5): 739–48. doi:10.1016/j.neurobiolaging.2004.06.002. PMID 15708449.
7. Jamieson SE, White JK, Howson JM, Pask R, Smith AN, Brayne C, Evans JG, Xuereb J, Cairns NJ, Rubinsztein DC, Blackwell JM (February 2005). "Candidate gene association study of solute carrier family 11a members 1 (SLC11A1) and 2 (SLC11A2) genes in Alzheimer's disease". Neurosci. Lett. 374 (2): 124–8. doi:10.1016/j.neulet.2004.10.038. PMID 15644277.
8. Blasco H, Vourc'h P, Nadjar Y, Ribourtout B, Gordon PH, Guettard YO, Camu W, Praline J, Meininger V, Andres CR, Corcia P (April 2011). "Association between divalent metal transport 1 encoding gene (SLC11A2) and disease duration in amyotrophic lateral sclerosis". J. Neurol. Sci. 303 (1-2): 124–7. doi:10.1016/j.jns.2010.12.018. PMID 21276595.
9. He Q, Du T, Yu X, Xie A, Song N, Kang Q, Yu J, Tan L, Xie J, Jiang H (September 2011). "DMT1 polymorphism and risk of Parkinson's disease". Neurosci. Lett. 501 (3): 128–31. doi:10.1016/j.neulet.2011.07.001. PMID 21777657.
10. Xiong L, Dion P, Montplaisir J, Levchenko A, Thibodeau P, Karemera L, Rivière JB, St-Onge J, Gaspar C, Dubé MP, Desautels A, Turecki G, Rouleau GA (October 2007). "Molecular genetic studies of DMT1 on 12q in French-Canadian restless legs syndrome patients and families". Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B (7): 911–7. doi:10.1002/ajmg.b.30528. PMID 17510944.

Further reading

• Fleming MD, Trenor CC, Su MA (1997). "Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene.". Nat. Genet. 16 (4): 383–6. doi:10.1038/ng0897-383. PMID 9241278.
• Kishi F, Tabuchi M (1998). "Complete nucleotide sequence of human NRAMP2 cDNA.". Mol. Immunol. 34 (12–13): 839–42. doi:10.1016/S0161-5890(97)00110-7. PMID 9464519.
• Lee PL, Gelbart T, West C (1998). "The human Nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms". Blood Cells Mol. Dis. 24 (2): 199–215. doi:10.1006/bcmd.1998.0186. PMID 9642100.
• Kishi F, Tabuchi M (1998). "Human natural resistance-associated macrophage protein 2: gene cloning and protein identification". Biochem. Biophys. Res. Commun. 251 (3): 775–83. doi:10.1006/bbrc.1998.9415. PMID 9790986.
• Tabuchi M, Yoshimori T, Yamaguchi K (2000). "Human NRAMP2/DMT1, which mediates iron transport across endosomal membranes, is localized to late endosomes and lysosomes in HEp-2 cells". J. Biol. Chem. 275 (29): 22220–8. doi:10.1074/jbc.M001478200. PMID 10751401.
• Griffiths WJ, Kelly AL, Smith SJ, Cox TM (2000). "Localization of iron transport and regulatory proteins in human cells". QJM : monthly journal of the Association of Physicians 93 (9): 575–87. doi:10.1093/qjmed/93.9.575. PMID 10984552.
• Georgieff MK, Wobken JK, Welle J (2001). "Identification and localization of divalent metal transporter-1 (DMT-1) in term human placenta". Placenta 21 (8): 799–804. doi:10.1053/plac.2000.0566. PMID 11095929.
• Tallkvist J, Bowlus CL, Lönnerdal B (2001). "DMT1 gene expression and cadmium absorption in human absorptive enterocytes". Toxicol. Lett. 122 (2): 171–7. doi:10.1016/S0378-4274(01)00363-0. PMID 11439223.
• Sharp P, Tandy S, Yamaji S (2002). "Rapid regulation of divalent metal transporter (DMT1) protein but not mRNA expression by non-haem iron in human intestinal Caco-2 cells". FEBS Lett. 510 (1–2): 71–6. doi:10.1016/S0014-5793(01)03225-2. PMID 11755534.
• Umbreit JN, Conrad ME, Hainsworth LN, Simovich M (2002). "The ferrireductase paraferritin contains divalent metal transporter as well as mobilferrin". Am. J. Physiol. Gastrointest. Liver Physiol. 282 (3): G534–9. doi:10.1152/ajpgi.00199.2001. PMID 11842004.
• Simovich MJ, Conrad ME, Umbreit JN (2002). "Cellular location of proteins related to iron absorption and transport". Am. J. Hematol. 69 (3): 164–70. doi:10.1002/ajh.10052. PMID 11891802.
• Rolfs A, Bonkovsky HL, Kohlroser JG (2002). "Intestinal expression of genes involved in iron absorption in humans". Am. J. Physiol. Gastrointest. Liver Physiol. 282 (4): G598–607. doi:10.1152/ajpgi.00371.2001. PMID 11897618.
• Wang X, Ghio AJ, Yang F (2002). "Iron uptake and Nramp2/DMT1/DCT1 in human bronchial epithelial cells". Am. J. Physiol. Lung Cell Mol. Physiol. 282 (5): L987–95. doi:10.1152/ajplung.00253.2001. PMID 11943663.
• I Bannon D, Portnoy ME, Olivi L (2002). "Uptake of lead and iron by divalent metal transporter 1 in yeast and mammalian cells". Biochem. Biophys. Res. Commun. 295 (4): 978–84. doi:10.1016/S0006-291X(02)00756-8. PMID 12127992.
• Zoller H, Decristoforo C, Weiss G (2002). "Erythroid 5-aminolevulinate synthase, ferrochelatase and DMT1 expression in erythroid progenitors: differential pathways for erythropoietin and iron-dependent regulation". Br. J. Haematol. 118 (2): 619–26. doi:10.1046/j.1365-2141.2002.03626.x. PMID 12139757.
• Hubert N, Hentze MW (2002). "Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function". Proc. Natl. Acad. Sci. U.S.A. 99 (19): 12345–50. doi:10.1073/pnas.192423399. PMC 129447. PMID 12209011.
• Tabuchi M, Tanaka N, Nishida-Kitayama J (2003). "Alternative Splicing Regulates the Subcellular Localization of Divalent Metal Transporter 1 Isoforms". Mol. Biol. Cell 13 (12): 4371–87. doi:10.1091/mbc.E02-03-0165. PMC 138640. PMID 12475959.
• Okubo M, Yamada K, Hosoyamada M (2003). "Cadmium transport by human Nramp 2 expressed in Xenopus laevis oocytes". Toxicol. Appl. Pharmacol. 187 (3): 162–7. doi:10.1016/S0041-008X(02)00078-9. PMID 12662899.

External links

• DMT1 protein (iron transporter) at the US National Library of Medicine Medical Subject Headings (MeSH)