Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2).
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 and defective intestinal iron use and erythroid iron use. We report the hematologic phenotype of a child, compound heterozygote for 2 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 analysis. The proband required blood transfusions until erythropoietin treatment allowed transfusion independence when hemoglobin levels between 75 and 95 g/L (7.5 and 9.5 g/dL) were achieved. Hematologic 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 the up-regulation of other pathways of iron use.
Iolascon
Achille
A
Genetica Medica, Dipartimento di Biochimica e Biotecnologie Mediche, Università Federico II, Naples, Italy. iolascon@dbbm.unina.it
d'Apolito
Maria
M
Servedio
Veronica
V
Cimmino
Flora
F
Piga
Antonio
A
Camaschella
Clara
C
D000740:Anemia / Q000235:genetics* / Q000628:therapy; D027682:Cation Transport Proteins / Q000097:blood / Q000235:genetics*; D002675:Child, Preschool; D004920:Erythropoiesis; D004921:Erythropoietin / Q000627:therapeutic use; D006579:Heterozygote; D006801:Humans; D019190:Iron Overload / Q000235:genetics* / Q000628:therapy; D033862:Iron-Binding Proteins / Q000097:blood / Q000235:genetics*; D009154:Mutation; D017354:Point Mutation; D017384:Sequence Deletion; D000099236:Solute Carrier Family 11, Member 2
D027682:Cation Transport Proteins; D004921:Erythropoietin; D033862:Iron-Binding Proteins; D000099236:Solute Carrier Family 11, Member 2