Not all DMT1 mutations lead to iron overload.

DMT1 is a membrane-bound divalent metal transporter, which co-transports protons and (Fe(2+)) from an acidic microenvironment (endosome, duodenal lumen) to the cell cytosol. Results from animal models and from patients have shown that DMT1 is required for intestinal iron absorption and iron acquisition by erythrocytes. Only three human patients with DMT1 mutations have been described so far. They presented with hypochromic microcytic anemia and heavy liver iron overload, even at a very young age. Here, we report the fourth human case, a 7-year old boy with a new homozygous DMT1 mutation, microcytic anemia but no liver iron overload. The mutation introduces a Glycine to Arginine (p.G75R) amino acid substitution. Glycine75 is a highly conserved amino acid present in the first transmembrane domain of the protein and we hypothesize that this mutation fully impairs ferrous iron uptake from the diet and prevents the onset of liver iron overload.