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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1337-1342.
Prepublished online as a Blood First Edition Paper on September 30, 2004; DOI 10.1182/blood-2004-07-2966.
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RED CELLS
Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload
Martha P. Mims,
Yongli Guan,
Dagmar Pospisilova,
Monika Priwitzerova,
Karel Indrak,
Prem Ponka,
Vladimir Divoky, and
Josef T. Prchal
From the Division of Hematology/Oncology, Baylor College of Medicine and Houston VA Medical Center, Houston, TX; the Departments of Pediatrics, Biology, and Hemato-oncology, Faculty of Medicine, Palacky University, Olomouc, Czech Republic; and McGill University, Montreal, ON, Canada.
Divalent metal transporter 1 (DMT1) is a transmembrane protein crucial for duodenal iron absorption and erythroid iron transport. DMT1 function has been elucidated largely in studies of the mk mouse and the Belgrade rat, which have an identical single nucleotide mutation of this gene that affects protein processing, stability, and function. These animals exhibit hypochromic microcytic anemia due to impaired intestinal iron absorption, and defective iron utilization in red cell precursors. We report here the first human mutation of DMT1 identified in a female with severe hypochromic microcytic anemia and iron overload. This homozygous mutation in the ultimate nucleotide of exon 12 codes for a conservative E399D amino acid substitution; however, its pre-dominant effect is preferential skipping of exon 12 during processing of pre–messenger RNA (mRNA). The lack of full-length mRNA would predict deficient iron absorption in the intestine and deficient iron utilization in erythroid precursors; however, unlike the animal models of DMT1 mutation, the patient is iron overloaded. This does not appear to be due to up-regulation of total DMT1 mRNA. DMT1 protein is easily detectable by immunoblotting in the patient's duodenum, but it is unclear whether the protein is properly processed or targeted.
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