Expression of the DMT1 (NRAMP2/DCT1) iron transporter in mice with genetic iron overload disorders.

Iron overload is highly prevalent, but its molecular pathogenesis is poorly understood. Recently, DMT1 was shown to be a major apical iron transporter in absorptive cells of the duodenum. In vivo, it is the only transporter known to be important for the uptake of dietary non-heme iron from the gut lumen. The expression and subcellular localization of DMT1 protein in 3 mouse models of iron overload were examined: hypotransferrinemic (Trf(hpx)) mice, Hfe knockout mice, and B2m knockout mice. Interestingly, in Trf(hpx) homozygotes, DMT1 expression was strongly induced in the villus brush border when compared to control animals. This suggests that DMT1 expression is increased in response to iron deficiency in the erythron, even in the setting of systemic iron overload. In contrast, no increase was seen in DMT1 expression in animals with iron overload resembling human hemochromatosis. Therefore, it does not appear that changes in DMT1 levels are primarily responsible for iron loading in hemochromatosis.

[1]  N. Andrews,et al.  Iron transport across biologic membranes. , 2009, Nutrition reviews.

[2]  N. Andrews,et al.  The molecular defect in hypotransferrinemic mice. , 2000, Blood.

[3]  S. Abboud,et al.  A Novel Mammalian Iron-regulated Protein Involved in Intracellular Iron Metabolism* , 2000, The Journal of Biological Chemistry.

[4]  N. Andrews,et al.  Genes that modify the hemochromatosis phenotype in mice. , 2000, The Journal of clinical investigation.

[5]  A. Brownlie,et al.  Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter , 2000, Nature.

[6]  R J Simpson,et al.  A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. , 2000, Molecular cell.

[7]  Dena E. Cohen,et al.  The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. , 1999, Blood.

[8]  W. Vogel,et al.  Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis , 1999, The Lancet.

[9]  P. Gros,et al.  Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. , 1999, Blood.

[10]  W. Sly,et al.  Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  S. Grinstein,et al.  The Iron Transport Protein NRAMP2 Is an Integral Membrane Glycoprotein That Colocalizes with Transferrin in Recycling Endosomes , 1999, The Journal of experimental medicine.

[12]  Gregory J. Anderson,et al.  Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse , 1999, Nature Genetics.

[13]  H Clevers,et al.  Adaptive response of iron absorption to anemia, increased erythropoiesis, iron deficiency, and iron loading in beta2-microglobulin knockout mice. , 1998, Blood.

[14]  Jianming Yu,et al.  Functional Expression Cloning and Characterization of SFT, a Stimulator of Fe Transport , 1997, The Journal of cell biology.

[15]  N. Andrews,et al.  Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene , 1997, Nature genetics.

[16]  Stephan Nussberger,et al.  Cloning and characterization of a mammalian proton-coupled metal-ion transporter , 1997, Nature.

[17]  R. Crystal.  Managed care for viruses , 1997, Nature Medicine.

[18]  M. C. Ellis,et al.  A novel MHC class I–like gene is mutated in patients with hereditary haemochromatosis , 1996, Nature Genetics.

[19]  R. Simpson,et al.  A duodenal mucosal abnormality in the reduction of Fe(III) in patients with genetic haemochromatosis. , 1996, Gut.

[20]  R. Leboeuf,et al.  Dissociation between tissue iron concentrations and transferrin saturation among inbred mouse strains. , 1995, The Journal of laboratory and clinical medicine.

[21]  J. Woods,et al.  Congenital atransferrinemia. A case report and review of the literature. , 1991, American journal of clinical pathology.

[22]  M. Nathanson,et al.  Regulation of intestinal iron absorption and mucosal iron kinetics in hereditary hemochromatosis. , 1991, The Journal of laboratory and clinical medicine.

[23]  P. Marrack,et al.  Normal development of mice deficient in beta 2M, MHC class I proteins, and CD8+ T cells. , 1990, Science.

[24]  N. Goya,et al.  A family of congenital atransferrinemia. , 1972, Blood.

[25]  N. Andrews,et al.  The Nramp2/DMT1 iron transporter is induced in the duodenum of microcytic anemiamkmice but is not properly targeted to the intestinal brush border , 2000 .

[26]  M. Conrad,et al.  Iron absorption and cellular transport: the mobilferrin/paraferritin paradigm. , 1998, Seminars in hematology.