The Human Nramp2 Gene: Characterization of the Gene Structure, Alternative Splicing, Promoter Region and Polymorphisms

Lee, Pauline L.; Gelbart, Terri; West, Carol; Halloran, Carol; Beutler, Ernest

doi:10.1006/bcmd.1998.0186

Cited by 290 publications

(204 citation statements)

References 0 publications

Supporting

Mentioning

195

Contrasting

Order By: Relevance

“…At the tissue level, DMT1 is ubiquitously expressed, most notably in the proximal duodenum, as compared to areas such as the kidney or the brain (Andrews, 1999;Gunshin et al, 1997;Lee et al, 1998). Immunostaining studies suggest that DMT1 expression is strongest at the brush border of the apical pole of the enterocytes, which is consistent with the role for DMT1 in luminal metal uptake .…”

Section: Dmt1 Localizationsupporting

confidence: 58%

“…The two alternatively spliced mRNA differ by a specific sequence either containing or lacking an iron regulatory element (+IRE and −IRE respectively). They encode two transporters with distinct carboxy-termini Lee et al, 1998). The 3′ untranslated region (UTR) that contains an IRE has a stem-loop structure whose stability is modulated by the intracellular Fe pool (Gunshin et al, 1997).…”

Section: Divalent Metal Transporter-1mentioning

confidence: 99%

“…On the other hand, -IRE isoforms are found predominantly in early and recycling endosomes Kannurpatti et al, 2000;Touret et al, 2003). In addition, DMT1 also has been shown to colocalize with TfR, both at the plasma membrane and in the recycling endosome .At the tissue level, DMT1 is ubiquitously expressed, most notably in the proximal duodenum, as compared to areas such as the kidney or the brain (Andrews, 1999;Gunshin et al, 1997;Lee et al, 1998). Immunostaining studies suggest that DMT1 expression is strongest at the brush border of the apical pole of the enterocytes, which is consistent with the role for DMT1 in luminal metal uptake .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Manganese transport in eukaryotes: The role of DMT1

2008

View full text Add to dashboard Cite

Manganese (Mn) is a transition metal that is essential for normal cell growth and development, but is toxic at high concentrations. While Mn deficiency is uncommon in humans, Mn toxicity is known to be readily prevalent due to occupational overexposure in miners, smelters and possibly welders. Excessive exposure to Mn can cause Parkinson's disease-like syndrome; patients typically exhibit extrapyramidal symptoms that include tremor, rigidity and hypokinesia (Calne et al., 1994;Dobson et al., 2004).Mn-induced motor neuron diseases have been the subjects of numerous studies; however, this review is not intended to discuss its neurotoxic potential or its role in the etiology of motor neuron disorders. Rather, it will focus on Mn uptake and transport via the orthologues of the divalent metal transporter (DMT1) and its possible implications to Mn toxicity in various categories of eukaryotic systems, such as in vitro cell lines, in vivo rodents, the fruitfly, Drosophila melanogaster, the honeybee, Apis mellifera L., the nematode, Caenorhabditis elegans, and the baker's yeast, Saccharomyces cerevisiae. Keywords DMT1; Manganese; NRAMP-2; Transport ManganeseMn is one of the most abundant naturally occurring elements in the earth's crust; it does not occur naturally in a pure state. Oxides, carbonates and silicates are the most important Mncontaining minerals (Post, 1999). Depending on its oxidation state, Mn is utilized in countless industrial processes, such as the production of dry cell batteries, steel (Post, 1999; Saric, 1986), fuel oil additives and antiknock agents (Pfeifer et al., 2004;Ressler et al., 1999;Rollin et al., 2005). *Corresponding Author: Michael Aschner, PhD, 2215-B Garland Avenue, 11425 MRB IV, Vanderbilt University Medical Center, Nashville, michael.aschner@vanderbilt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurotoxicology. Author manuscript; available in PMC 2009 July 1. Published in final edited form as:Neurotoxicology. 2008 July ; 29(4): 569-576. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe major source of Mn in humans is through dietary ingestion. Approximately 3-5% of ingested Mn is absorbed across the intestinal wall, and the remainder is excreted in feces, representing tight homeostatic control over Mn absorption. Mn toxicity from dietary intake is rare; its uptake is tightly regulated, and any excess of ingested Mn is readily excreted via the bile. In contrast, both pulmonary uptake and particulate transport via the olfactory bulb (Saric, 1986;Aschner et al., 1991...

show abstract

Section: Dmt1 Localizationsupporting

confidence: 58%

Section: Divalent Metal Transporter-1mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Manganese transport in eukaryotes: The role of DMT1

2008

View full text Add to dashboard Cite

show abstract

“…DMT1, also known as Nramp2 (nature resistance associated macrophage protein 2) or DCT1 (divalent cation transporter 1), is a major duodenal ferrous iron transporter (Gunshin et al, 1997;Fleming et al, 1997;CanonneHergaux et al, 1999). DMT1 exists in at least four distinct isoforms, which differ in both the C-terminus (with IRE and without IRE) and the N-terminus (two different promoters) (Gunshin et al, 1997;Lee et al, 1998). The function of DMT1 + IRE was investigated in this study, which encodes a protein of 561 amino acids and contains an iron regulatory element (IRE) in the 3 0 -untranslated regions.…”

Section: Introductionmentioning

confidence: 99%

Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells

Jiang

Wang

et al. 2008

Neurochemistry International

View full text Add to dashboard Cite

Elevated iron accumulation has been reported in brain regions in some neurodegenerative disorders. However, the mechanism for this is largely unknown. Divalent metal transporter 1 (DMT1) is an important divalent cation transporter. The aim of the present study is to construct recombinant adenovirus encoding human DMT1 with iron responsive element (DMT1 + IRE) and infect MES23.5 dopaminergic cells in order to investigate the relationship between increased DMT1 + IRE expression and iron accumulation. The human DMT1 gene was obtained by RT-PCR from tissues of human duodenum. AdDMT1 + IRE was successfully constructed and identified by PCR, restriction endonuclease analyses and DNA sequencing, respectively. It was able to efficiently infect MES23.5 cells, which was confirmed by RT-PCR and Western blots. When incubated with 100 mM ferrous iron for 6 h, the intracellular iron levels dramatically increased in AdDMT1 + IRE infected MES23.5 cells compared to the solely adenovirus infected cells. Meanwhile, the levels of hydroxyl free radicals and malondialdehyde (MDA) in these cells increased. This led to the activation of caspase-3. The apoptosis in AdDMT1 + IRE infected cells was shown with hypercondensed nuclei using Hoechst staining. Analysis of DNA extracted from these cells showed the typical ''ladder pattern'', indicating the formation of mono-and oligonucleosomes. These results suggested that increased DMT1 + IRE expression in MES23.5 cells caused the increased intracellular iron accumulation. This resulted in the increased oxidative stress leading to ultimate cell apoptosis. #

show abstract

“…DMT1 has been shown to transport a variety of divalent metals including Fe 21 Harris et al, 1999;McKie et al, 2001). There are at least two different splice forms of DMT1: DMT1 (1IRE) mRNA containing iron-responsive element (IRE) in the 3 0 -UTR and DMT1 (2IRE) mRNA not containing a classical IRE (Gunshin et al, 1997;Lee et al, 1998).…”

mentioning

confidence: 99%

Effects of Intracerebroventricular Injection of Iron Dextran on the Iron Concentration and Divalent Metal Transporter 1 Expression in the Caudate Putamen and Substantia Nigra of Rats

Chang

Miao

et al. 2008

The Anatomical Record

View full text Add to dashboard Cite

The cellular localization of DMT1 and its functional characterization suggest that DMT1 may play an important role in the physiological brain iron transport. But the regulation of DMT1 expression by iron in the brain is still not clearly understood. In this study, both the contents of ferric and ferrous iron as well as DMT1 expression were evaluated in CPu and SN after ICV of 500 mg iron dextran/rat/day for 3 or 7 days. It was found that the iron levels in CPu and SN were not altered obviously until ICV for 7 days. Immunohistochemistry results indicated that the expression of DMT1 (2IRE) in CPu and SN was not altered significantly after 3 days of ICV. Whereas the expression of DMT1 (2IRE) decreased significantly after 7 days of ICV when ferrous iron was increased significantly. Contrary to that of DMT1 (2IRE) in the same regions, there were no significant alterations in DMT1 (1IRE) expression in CPu and SN in spite of the existence of the altered iron levels, compared with that of control groups. The results demonstrate that DMT1 (2IRE) expression was correlated probably with brain iron levels; especially, its regulation was Abbreviations used: CG 5 saline-injected control groups; CNS 5 central nervous system; CPu 5 caudate putamen; DCT1 5 divalent cation transporter; DMT1 5 divalent metal transporter 1; Ft 5 ferritin; ICV 5 intracerebroventricular injection; IG 5 iron dextran-injected groups; IHC 5 immunohistochemistry; IRE 5 iron-responsive element; Nramp2 5 natural resistance associated macrophage protein 2; PBS 5 phosphate buffered saline; PD 5 Parkinson's disease; Slc11a2 5 solute carrier family 11, member a2; SN 5 substantia nigra; Tf 5 transferrin; TfR 5 transferrin receptor; UTR 5 untranslated regions.

show abstract

The Human Nramp2 Gene: Characterization of the Gene Structure, Alternative Splicing, Promoter Region and Polymorphisms

Cited by 290 publications

References 0 publications

Manganese transport in eukaryotes: The role of DMT1

Manganese transport in eukaryotes: The role of DMT1

Over-expressed human divalent metal transporter 1 is involved in iron accumulation in MES23.5 cells

Effects of Intracerebroventricular Injection of Iron Dextran on the Iron Concentration and Divalent Metal Transporter 1 Expression in the Caudate Putamen and Substantia Nigra of Rats

Contact Info

Product

Resources

About