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Query: UMLS:C0240066 (iron deficiency)
 7,156 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Metal ions are essential cofactors for a wealth of biological processes, including oxidative phosphorylation, gene regulation and free-radical homeostasis. Failure to maintain appropriate levels of metal ions in humans is a feature of hereditary haemochromatosis, disorders of metal-ion deficiency, and certain neurodegenerative diseases. Despite their pivotal physiological roles, however, there is no molecular information on how metal ions are actively absorbed by mammalian cells. We have now identified a new metal-ion transporter in the rat, DCT1, which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+. DCT1 mediates active transport that is proton-coupled and depends on the cell membrane potential. It is a 561-amino-acid protein with 12 putative membrane-spanning domains and is ubiquitously expressed, most notably in the proximal duodenum. DCT1 is upregulated by dietary iron deficiency, and may represent a key mediator of intestinal iron absorption. DCT1 is a member of the 'natural-resistance-associated macrophage protein' (Nramp) family and thus its properties provide insight into how these proteins confer resistance to pathogens.
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PMID:Cloning and characterization of a mammalian proton-coupled metal-ion transporter. 924 8

Iron deficiency and iron overload disorders are common in clinical practice. Both can result from perturbations in the flux of iron across the absorptive intestinal enterocyte. Until recently iron transport has been poorly understood. In 1997 two independent cloning strategies identified Nramp2 (DCT1) as the first mammalian transmembrane iron transporter. In this review we discuss evidence that Nramp-related proteins play essential roles in metal homeostasis and host defense.
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PMID:Mammalian iron transport: an unexpected link between metal homeostasis and host defense. 985 35

Iron deficiency is the most common nutritional disorder worldwide, whereas pathologic elevations of body iron stores can occur under certain circumstances due to genetic abnormalities or in association with other diseases. The intestine is the exclusive locus of homeostatic regulation of body iron stores, which is accomplished by changes in iron absorption efficiency by largely unknown molecular mechanisms in response to alterations in body iron stores. Recently, a number of novel genes involved in iron metabolism, such as the iron uptake transporter DMT1/DCT1/Nramp2 and the iron export transporter IREG1/ferroportin1/MTP1, have been identified, providing important insights about molecular aspects of intestinal iron absorption and its regulation. The aim of this study was to investigate the effects of iron treatment on DMT1 and IREG1 mRNA expression in Caco-2 cells, a human intestinal cell line. Exposure of the cells to iron (200 micromol/L ferric nitrilotriacetic acid for 72 h) significantly decreased transferrin receptor mRNA (80%), DMT1 mRNA (57%) and IREG1 mRNA (52%). These observations are consistent with the notion of parallel regulation of these iron-responsive genes in vivo to protect the enterocyte from iron toxicity and mediate a decreased efficiency of intestinal iron absorption to prevent iron overload.
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PMID:Iron treatment downregulates DMT1 and IREG1 mRNA expression in Caco-2 cells. 1192 62

Individuals with hereditary hemochromatosis suffer from systemic iron overload due to duodenal hyperabsorption. Most cases arise from a founder mutation in HFE (845G-->A; ref. 2) that results in the amino-acid substitution C282Y and prevents the association of HFE with beta2-microglobulin. Mice homozygous with respect to a null allele of Hfe (Hfe-/-) or homozygous with respect to the orthologous 882G-->A mutation (Hfe(845A/845A)) develop iron overload that recapitulates hereditary hemochromatosis in humans, confirming that hereditary hemochromatosis arises from loss of HFE function. Much work has focused on an exclusive role for the intestine in hereditary hemochromatosis. HFE deficiency in intestinal crypt cells is thought to cause intestinal iron deficiency and greater expression of iron transporters such as SLC11A2 (also called DMT1, DCT1 and NRAMP2) and SLC11A3 (also called IREG1, ferroportin and MTP1; ref. 3). Published data on the expression of these transporters in the duodenum of HFE-deficient mice and humans are contradictory. In this report, we used a custom microarray to assay changes in duodenal and hepatic gene expression in Hfe-deficient mice. We found unexpected alterations in the expression of Slc39a1 (mouse ortholog of SLC11A3) and Cybrd1, which encode key iron transport proteins, and Hamp (hepcidin antimicrobial peptide), a hepatic regulator of iron transport. We propose that inappropriate regulatory cues from the liver underlie greater duodenal iron absorption, possibly involving the ferric reductase Cybrd1.
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PMID:Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. 1270 90

Divalent metal transporter-1 (DMT1/DCT1/Nramp2) is the major Fe(2+) transporter mediating cellular iron uptake in mammals. Phenotypic analyses of animals with spontaneous mutations in DMT1 indicate that it functions at two distinct sites, transporting dietary iron across the apical membrane of intestinal absorptive cells, and transporting endosomal iron released from transferrin into the cytoplasm of erythroid precursors. DMT1 also acts as a proton-dependent transporter for other heavy metal ions including Mn(2+), Co(2+), and Cu(2), but not for Mg(2+) or Ca(2+). A unique mutation in DMT1, G185R, has occurred spontaneously on two occasions in microcytic (mk) mice and once in Belgrade (b) rats. This mutation severely impairs the iron transport capability of DMT1, leading to systemic iron deficiency and anemia. The repeated occurrence of the G185R mutation cannot readily be explained by hypermutability of the gene. Here we show that G185R mutant DMT1 exhibits a new, constitutive Ca(2+) permeability, suggesting a gain of function that contributes to remutation and the mk and b phenotypes.
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PMID:A spontaneous, recurrent mutation in divalent metal transporter-1 exposes a calcium entry pathway. 1502 13

Belgrade rats exhibit microcytic, hypochromic anemia and systemic iron deficiency due to a glycine-to-arginine mutation at residue 185 in a metal ion transporter of a divalent metal transporter/divalent cation transporter/solute carrier 11 group A member 2 or 3 (DMT1/DCT1/SLC11A2), a member of the natural-resistance-associated macrophage protein (Nramp) family. By use of rabbit duodenal tissue, a calcein fluorescence assay has previously been developed to assess transport of divalent metal ions across the small-intestinal brush border membrane (BBM). The assay was readily applied here to rat BBM to learn if it detects DMT1 activity. The results demonstrate protein-mediated transport across the BBM of all tested ions: Mn(2+), Fe(2+), and Ni(2+). Transport into BBM vesicles (BBMV) from (b/b) Belgrade rats was below the detection limit. BBMV of +/b origin had substantial activity. The kinetic rate constant for Ni(2+) membrane transport for +/b BBMV was within the range for normal rabbit tissue. Vesicles from +/b basolateral membranes (BLM) showed similar activity to BBMV while b/b BLM vesicles (BLMV) lacked transport activity. Immunoblots using isoform-specific antibodies demonstrated that intestinal levels of b/b DMT1 were increased compared to +/b DMT1, reflecting iron deficiency. Immunoblots on BBMV indicated that lack of activity in b/b vesicles was not due to a failure of DMT1 to localize to the BBMV; an excess of specific isoforms was present compared to +/b BBMV or duodenal extracts. Immunoblots from BLMV also exhibited enrichment in DMT1 isoforms, despite their distinct origin. Immunofluorescent staining of thin sections of b/b and +/b proximal intestines confirmed that DMT1 localized similarly in mutant and control enterocytes and showed that DMT1 isoforms have distinct distributions within intestinal tissue.
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PMID:Transport of divalent transition-metal ions is lost in small-intestinal tissue of b/b Belgrade rats. 1573 55

Iron is essential to the unicellular green alga Chlamydomonas, but the molecular mechanism for response to iron deficiency remains largely unknown. In previous studies, we have identified FOX1 and ATX1 FEREs (Fe deficiency-responsive elements) as important regulation components of iron response in this organism. Here we present another iron regulated gene FEA1, which promoter was analysed by using a 5'-and 3'-end deletion and a scanning mutagenesis assay. The results reveal that the co-existence of -273/-188 and -118/-49 regions from transcriptional start site of FEA1 were sufficient and necessary for Fe deficiency-induced expression. Further deletion analysis indicates both -273/-253 and -103/-85 regions are essential for inducible expression. The scanning mutagenesis analysis of these regions identifies two cis-acting elements: the FeaFeRE1 at -273/-259 (CTGCGGTGGCAAAGT) and FeaFeRE2 at -106/-85 (CCGCCGCNNNTGGCACCAGCCT). Sequence comparison of FeaFeRE1 and FeaFeRE2 reveals a core sequence of TGGCA, which had been found in our previously reported Fe-deficiency-inducible gene ATX1. Moreover, we show that the promoter region of several genes, including FRE1, IRT1, ISCA, ZRT1, ZRT5, NRAMP2 and COPT1, also contains this core sequence, suggesting that at least two classes FeRE elements exist in Clamydomonas, one in FEA1 and ATX1 and others the second in FOX1, FEA2, MTP4, NRAMP3 and RBOL1.
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PMID:An Fe deficiency responsive element with a core sequence of TGGCA regulates the expression of FEA1 in Chlamydomonas reinharditii. 1935 5