The divalent metal transporter 1 (DMT1), also known as natural resistance-associated macrophage protein 2 (NRAMP 2), and divalent cation transporter 1 (DCT1), is a protein that in humans is encoded by the SLC11A2 (solute carrier family 11, member 2) gene. DMT1 represents a large family of orthologous metal ion transporter proteins that are highly conserved from bacteria to humans.
As its name suggests, DMT1 binds a variety of divalent metals including cadmium (Cd2+), copper (Cu2+), and zinc (Zn2+,,) 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+). 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.
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. DMT1 expression in the brain may increase with age, 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 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, and is implicated in Alzheimer's disease onset in males as well. The CC haplotype for SNPs 1254T/C IVS34+44C/A is associated with Parkinson's disease susceptibility. Finally, variant alleles on several SLC11A2 SNPs are associated with iron anemia, a risk factor for manganese intoxication and restless legs syndrome.
^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. PMID7613023. doi:10.1007/BF00352405.
^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. PMID15708449. doi:10.1016/j.neurobiolaging.2004.06.002.
^ abJamieson 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. PMID15644277. doi:10.1016/j.neulet.2004.10.038.
^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. PMID21276595. doi:10.1016/j.jns.2010.12.018.
^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. PMID21777657. doi:10.1016/j.neulet.2011.07.001.
^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. PMID17510944. doi:10.1002/ajmg.b.30528.
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. PMID9642100. doi:10.1006/bcmd.1998.0186.
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. PMID9790986. doi:10.1006/bbrc.1998.9415.
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. PMID10751401. doi:10.1074/jbc.M001478200.
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. PMID10984552. doi:10.1093/qjmed/93.9.575.
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. PMID11095929. doi:10.1053/plac.2000.0566.
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. PMID11755534. doi:10.1016/S0014-5793(01)03225-2.
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. PMID11842004. doi:10.1152/ajpgi.00199.2001.
Simovich MJ, Conrad ME, Umbreit JN (2002). "Cellular location of proteins related to iron absorption and transport". Am. J. Hematol. 69 (3): 164–70. PMID11891802. doi:10.1002/ajh.10052.
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. PMID11897618. doi:10.1152/ajpgi.00371.2001.
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. PMID11943663. doi:10.1152/ajplung.00253.2001.
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. PMID12127992. doi:10.1016/S0006-291X(02)00756-8.
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. PMID12139757. doi:10.1046/j.1365-2141.2002.03626.x.