Nramp
 2
 is mutated in the anemic Belgrade (
 b
 ) rat: Evidence of a role for Nramp2 in endosomal iron transport

Fleming, Mark D.; Romano, Michelle A.; Su, Maureen A.; Garrick, Laura M.; Garrick, Michael D.; Andrews, Nancy C.

doi:10.1073/pnas.95.3.1148

Cited by 872 publications

(605 citation statements)

References 32 publications

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“…The Belgrade rat and mk mouse have a defect in the DMT-1 protein, and have an iron-deficient phenotype [30,31]. The location of the defect, either at the plasma membrane transport system, at the paraferritin stage, or at an even later stage in iron processing has not been determined.…”

Section: Discussionmentioning

confidence: 99%

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

et al. 2003

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There are two pathways for inorganic iron uptake in the intestine, the ferric pathway, mediated by the key protein mobilferrin, and the ferrous pathway, mediated by DMT-1. Previous studies reported that the amount of DMT-1 increased in the intestinal mucosa in iron deficiency and the increase was seen in the apical portion of the villus of the duodenal mucosa. Mobilferrin did not quantitatively increase but became localized at the cell membrane. However, studies on fresh tissue have not previously been performed and the localization to the microvillae has not been demonstrated. In order to more definitively localize these proteins immunofluorescent and electron microscopic studies were undertaken. Samples were also subjected to biochemical analysis and Western analysis. In iron-deficient animals both DMT-1 and Mobilferrin were concentrated in the apical surface of the villae. Electron microscopy revealed that the majority of this increase in the amount of these proteins near the luminal surface was due to increased binding of the proteins to mucin in vesicles near the surface. A significant portion of the iron transport proteins was localized in the goblet cells and outside the cell in the luminal mucin, as demonstrated by immunofluorescence, electron microscopy, and isolation of the mucin by cesium chloride gradient centrifugation and Western analysis. A new model for the transport of metal ions was suggested. The metal transport proteins travel from vesicles inside the cell out to the lumen mucin. This increases the surface area and allows a greater portion of the lumen contents to be exposed to the binding proteins. Once the metal is bound to the externalized protein it is internalized into the cell. This explains many of the unique properties of the iron-binding proteins and suggests that it may be a more general model for the absorption of other nutrients. Am. J. Hematol. 74:32-45, 2003.

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Section: Discussionmentioning

confidence: 99%

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

et al. 2003

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“…DMT1 also colocalizes with transferrin in the recycling endosomes of many cell types, including reticulocytes, where it transports iron from the acidified lumen of the endosomes into the cytoplasm. Two animal models exist, mk (microcytic anemic) mouse and the Belgrade rat (b/b) (Canonne-Hergaux et al, 2001;Fleming et al, 1998). Both animals are anemic from birth and require iron supplementation to survive.…”

Section: Divalent Metal Transporter (Dmt1) In Mn Transportmentioning

confidence: 99%

Manganese neurotoxicity: A focus on the neonate

Erikson

Thompson

Aschner

et al. 2007

Pharmacology & Therapeutics

224

141

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Manganese (Mn) is an essential trace metal found in all tissues, and it is required for normal amino acid, lipid, protein, and carbohydrate metabolism. While Mn deficiency is extremely rare in humans, toxicity due to overexposure of Mn is more prevalent. The brain appears to be especially vulnerable. Mn neurotoxicity is most commonly associated with occupational exposure to aerosols or dusts that contain extremely high levels (> 1-5 mg Mn/m 3 ) of Mn, consumption of contaminated well water, or parenteral nutrition therapy in patients with liver disease or immature hepatic functioning such as the neonate. This review will focus primarily on the neurotoxicity of Mn in the neonate. We will discuss putative transporters of the metal in the neonatal brain and then focus on the implications of high Mn exposure to the neonate focusing on typical exposure modes (e.g., dietary and parenteral). Although Mn exposure via parenteral nutrition is uncommon in adults, in premature infants, it is more prevalent, so this mode of exposure becomes salient in this population. We will briefly review some of the mechanisms of Mn neurotoxicity and conclude with a discussion of ripe areas for research in this underreported area of neurotoxicity.

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“…It was assumed that this mutation was ''leaky'' because the animals were alive, but the nonleaky equivalent mutation in zebrafish is also alive, which implies that the DMT-1 pathway cannot be the sole pathway [32]. There are data to suggest that the Belgrade rat defect is not at the intestinal membrane but further into the iron transport sequence, perhaps at the endosomal stage [33]. The DMT-1 protein transports a number of divalent metals in model systems, including ferrous, but not ferric, iron.…”

Section: Physiology Of Ironmentioning

confidence: 99%

Iron deficiency: A concise review

2005

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Iron deficiency is a major worldwide health problem. There is recent evidence that the anemia is only the last manifestation of the syndrome and that symptoms occur before the anemia is manifest. Advances in outlining the physiology of iron deficiency have been made, gaps remain in the current understanding. While oral iron supplement remains the mainstay, some indications for the intravenous administration have developed. This review will highlight the epidemiology, physiology, clinical presentation, and treatment options. Am.

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Nramp 2 is mutated in the anemic Belgrade ( b ) rat: Evidence of a role for Nramp2 in endosomal iron transport

Cited by 872 publications

References 32 publications

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

Localization of the iron transport proteins mobilferrin and DMT‐1 in the duodenum: The surprising role of mucin

Manganese neurotoxicity: A focus on the neonate

Iron deficiency: A concise review

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