Microcytic Anemia and Hepatic Iron Overload in a Child with Compound Heterozygous Mutations in Dmt1

Divalent metal transporter 1 (DMT1) mediates apical iron uptake in duodenal enterocytes and iron transfer from the transferrin receptor endosomal cycle into the cytosol in erythroid cells. Both mk mice and Belgrade rats, which carry an identical DMT1 mutation, exhibit severe microcytic anemia at birth, defective intestinal iron absorption and erythroid iron utilization. We report the hematological phenotype of a child, compound heterozygote for two DMT1 mutations, who was affected by severe anemia since birth and showed hepatic iron overload. The novel mutations were a 3 bp deletion in intron 4 (c.310 3_5del CTT) resulting in a splicing abnormality and a C>T transition at nucleotide 1246(p. R416C). A striking reduction of DMT1 protein in peripheral blood mononuclear cells was demonstrated by western blot. The proband required blood transfusions until erythropoietin treatment allowed transfusionindependence with haemoglobin levels between 7.5-9.5 g/dL. Hematological data of this patient at birth and in the first years of life strengthen the essential role of DMT1 in erythropoiesis. The early onset of iron overload indicates that, as in animal models, DMT1 is dispensable for liver iron uptake, whereas its deficiency in the gut is likely bypassed by upregulation of other pathways of iron absorption. For personal use only. on August 31, 2017. by guest www.bloodjournal.org From