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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3985-3987.
Prepublished online as a Blood First Edition Paper on August 9, 2005; DOI 10.1182/blood-2005-04-1550.
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Submitted April 15, 2005
Accepted July 31, 2005
Functional consequences of the human DMT1 mutation on protein expression and iron uptake
Monika Priwitzerova, Guangjun Nie, Alex D Sheftel, Dagmar Pospisilova, Vladimir Divoky, and Prem Ponka*
Department of Biology, Faculty of Medicine Palacky University, Olomouc, Czech Republic; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada
Department of Pediatrics, Faculty of Medicine Palacky University, Olomouc, Czech Republic
Department of Biology, Faculty of Medicine Palacky University, Olomouc, Czech Republic; Department of Hemato-oncology, Faculty of Medicine Palacky University, Olomouc, Czech Republic
* Corresponding author; email: prem.ponka{at}mcgill.ca.
We have previously described a case of severe hypochromic microcytic anemia caused by a homozygous mutation in the divalent metal transporter 1 (DMT1 1285G>C). This mutation encodes for an amino acid substitution (E399D) and causes preferential skipping of exon 12 during processing of the DMT1 mRNA. To examine the functional consequences of this mutation, full length DMT1 transcript with the patient's point mutation or a DMT1 transcript with exon 12 deleted was expressed in Chinese hamster ovary (CHO) cells. Our results demonstrate that the E399D substitution has no effect on protein expression and function. In contrast, deletion of exon 12 led to a decreased expression of the protein and disruption of its subcellular localization and iron uptake activity. We hypothesize that the residual protein in hematopoietic cells represents the functional E399D DMT1 variant, but because of its quantitative reduction, the iron uptake activity of DMT1 in the patient's erythroid cells is severely suppressed.
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