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Iron is essential for the function of almost all cells due to its role in oxygen transport, energy production, and cell proliferation. Cell membranes are relatively impermeable to iron, so that its transport across these structures must be mediated by iron carriers. In the duodenum where the majority of iron is absorbed, it is proposed that at least one iron carrier exists on the apical membrane of enterocytes, and a second on the basolateral surface to transfer iron to the bloodstream. 1 Once absorbed it is believed that nearly all the iron is bound by the plasma protein transferrin; it is taken up by most types of cells by transferrin receptor mediated endocytosis. This process involves the internalisation of the transferrin-receptor complex into an endosome where the iron is released from transferrin and is then transported across the endosomal membrane to the cell cytosol by an iron carrier. 1 Irrespective of the way the iron is presented to the cell, either as transferrin bound iron or non-transferrin bound iron such as in the absorptive process, the mechanisms of iron transport across cell membranes are poorly understood.
Recently Gunshin et al , 2 using expression cloning of mRNA derived from rat duodenum, identified a gene which encoded a protein capable of transporting metal ions, including iron, which was previously called divalent cation transporter 1 (DCT1) and has been renamed divalent metal transporter 1 (DMT1). The product of this gene is homologous to a natural resistance associated macrophage protein (Nramp1) which is associated with natural resistance to infection with intracellular parasites. 3 Although DMT1 was isolated from duodenal tissue, it is likely to function as a carrier of iron in a variety of tissues. This assumption is based on the findings that high stringency northern analysis of DMT1 mRNA from different tissues showed that the gene is widely expressed and is found in the alimentary canal, bone marrow, and liver, tissues which have very important roles in iron metabolism. The strongest evidence to date for a central role of DMT1 in iron metabolism is derived from two recent studies by Fleming et al , 4 5 who identified by positional cloning and PCR that a missense mutation G185R in the DMT1 gene is responsible for the...