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.
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