Taken together, our studies demonstrate that decreased expression of DMT1 in intestinal mucosa leads to compromised absorption and transportation of iron and that blockade of TNF could rescue anemia and promote DMT1 expression in gut mucosa.
Our data confirm the major role of DMT1 in the maintenance of iron homeostasis in humans and demonstrate that the N491S mutation, through its deleterious effect on protein trafficking, contributes together with the G212V mutation to the development of anemia and hepatic iron overload.
Finally, two DMT1 intronic SNPs showed positive association with RLS in patients with a history of anemia, when compared to RLS patients without anemia.
The importance of DMT1 function at the level of the whole organism and the individual cell and mechanisms of its regulation on a molecular scale are only beginning to be understood; an appreciation of these process will lead to an understanding of the role of iron in various cellular processes and improved treatments for both anemia and iron-overload.
Gene mapping studies in animal mutants with anaemia due to defects in the uptake or tissue transfer of iron have yielded novel proteins involved in iron transport: DMT1 (brush border transporter of ferrous iron) in the mk/mk mouse, hephaestin (basolateral multi-copper ferroxidase) in the sex-linked anaemic mouse (sla) and ferroportin1 (basolateral iron exporter) in zebrafish weh mutants.