DMT1 is a divalent metal transporter with 12 transmembrane domains. It is expressed at the apical membrane of duodenal enterocytes, where it mediates pH-dependent uptake of Fe2+. In erythroid cells, it is found in the endosomal membrane where it transfers iron internalized through the transferrin-transferrin receptor pathway from the endosome to the cytosol. The same homozygous G>A substitution resulting in the G185A replacement is responsible for a severe hypochromic microcytic anemia in both the mk mouse and in the Belgrade rat. In humans, a homozygous G>C mutation has been described in a Czech patient, affecting the last nucleotide of exon 12. This mutation leads to the G399A replacement, without affecting the transport function of the protein. However, this mutation also induces a preferential in-frame skipping of exon 12, albeit not in all tissues. Accordingly, the patient has impaired iron acquisition in erythrocytes while duodenal iron absorption is increased leading to progressive iron overload.

Here, we report a female patient born in 1996, with low birth weight and hypochromic microcytic anemia (Hb = 7.5 g/dl; MCV = 53 fL). She was transfused at day 0 and put on oral iron treatment. She was then lost to follow-up for five years. At the age of five, more extensive explorations showed a persistent microcytic anemia. The bone marrow displayed normal cellularity, 30% of nucleated cells were erythroid precursors with a moderate maturation defect, acidophilic forms being under-represented as compared to more immature forms. Soluble transferrin receptors were increased (8.3 mg/L; N = 0.83–1.76). Following oral iron therapy, serum ferritin levels remained low (15–25 μg/L; N = 14–197) despite an increase in transferrin saturation from 68 to 95 %. This high transferrin saturation resulted from the combination of reduced transferrin levels (1.64 g/L, N = 2.2–4.0) and increased serum iron levels (35 μmol/L; N = 11–24). On the other hand, hemoglobin raised from 7 to 9 g/dL only through increased number of RBC (5 to 5.7 T/L), since MCV and MCHC remained unchanged.

We sequenced the entire transferrin receptor cDNA in this patient and found no mutation. We then sequenced the exons and the intron-exon boundaries of the DMT1 gene and found two heterozygous mutations. One mutation was a deletion of a GTG codon in exon 5, leading to the V114 in-frame deletion, in transmembrane domain 2. The other mutation is a G>T substitution in exon 8 leading to the G212V replacement in transmembrane domain 5. Both parents were asymptomatic, the father being heterozygous for the delV114 mutation and the mother heterozygous for the G212V mutation.

This is the second patient described with a neonatal hypochromic microcytic anemia due to DMT1 mutations. Our data suggest that the two combined DMT1 mutations are responsible for the defect in iron utilization by erythroid cells, resulting in persistant microcytosis and impaired red cell maturation. The effect of the mutations on intestinal iron absorption is more difficult to evaluate since iron therapy allowed serum iron and transferrin saturation to increase but serum ferritin remained low and hemoglobin did not reach normal values.

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