Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload

Beaumont, Carole; Delaunay, Jean; Hetet, Gilles; Grandchamp, Bernard; Montalembert, Mariane de; Tchernia, Gil

doi:10.1182/blood-2005-10-4269

Cited by 107 publications

(70 citation statements)

References 20 publications

(19 reference statements)

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“…The child in this study had microcytic anaemia since birth with a mild liver iron concentration at 9 years of age; although serum ferritin was not significantly increased. This would be supported by the hypothesis that the defective function of the endosomal SLC11A2 in hepatocytes impairs the iron efflux to the cytosol, leading to iron accumulation in a compartment that does not trigger ferritin synthesis (Priwitzerova et al, Beaumont et al, 2006). Moreover, the intestinal absorption of haem iron compensates for deficient ferrous iron uptake (Priwitzerova et al, 2004;Beaumont et al, 2006;Iolascon et al, 2006).…”

supporting

confidence: 52%

“…This would be supported by the hypothesis that the defective function of the endosomal SLC11A2 in hepatocytes impairs the iron efflux to the cytosol, leading to iron accumulation in a compartment that does not trigger ferritin synthesis (Priwitzerova et al, Beaumont et al, 2006). Moreover, the intestinal absorption of haem iron compensates for deficient ferrous iron uptake (Priwitzerova et al, 2004;Beaumont et al, 2006;Iolascon et al, 2006). The volume of transfusions in this patient (approximately 1 g of iron) should not justify the moderate iron deposit in the liver.…”

mentioning

confidence: 49%

“…Solute carrier family 11 (proton-coupled divalent metal ion transporters), member 2 [SLC11A2; also known as (DMT1)] is essential for iron utilization by most types of cells. Mutations in the SLC11A2 gene cause microcytic hypochromic anaemia due to decreased erythroid iron utilization (Mims et al, 2005;Beaumont et al, 2006;Iolascon et al, 2006;Blanco et al, 2009;Bardou-Jacquet et al, 2011). We report a 10-year-old boy with non-consanguineous Ecuadorian parents.…”

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confidence: 99%

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The homozygous mutation G75R in the human SLC11A2 gene leads to microcytic anaemia and iron overload

et al. 2012

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The homozygous mutation G75R in the human SLC11A2 gene leads to microcytic anaemia and iron overload

et al. 2012

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“…Both animal species exhibit severe microcytic anemia that is associated with an impairment of Fe transport as well as an alteration in Mn homeostasis. Similarly, humans with DMT1 mutations at different intron or exon sites, such as an E399D substitution (Mims et al, 2005;Lam-Yuk-Tseung et al, 2005a;Priwitzerova et al, 2005), a R416C substitution Lam-YukTseung et al, 2006) or a G212V substitution (Beaumont et al, 2006) exhibited hypochromic microcytic anemia, proposing a possible commonality in DMT1 function amongst various mammalian species.…”

Section: Function Of Dmt1mentioning

confidence: 99%

Manganese transport in eukaryotes: The role of DMT1

2008

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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...

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“…4,5 Recessive mutations in DMT1 are associated with hypochromic microcytic anemia with ineffective erythropoiesis and with iron overload in the liver in the majority of patients. [6][7][8][9][10] Functional studies have shown that a reduction in the amount of DMT1 protein due to a partial loss-of-function mutation in mk/mk mice and human patients leads to iron-restricted erythropoiesis. 2,11,12 A comprehensive in vitro analysis using erythroid progenitors from the first DMT1-mutant (1285G>C SCL11A2) patient with severe anemia (hemoglobin of 7.4 g/dL) 6,13 revealed defective growth (i.e., decreased number, cellularity, and hemoglobinization) of the patient's erythroid colonies (burst-forming units-erythroid, BFU-E).…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

et al. 2012

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BackgroundHypochromic microcytic anemia associated with ineffective erythropoiesis caused by recessive mutations in divalent metal transporter 1 (DMT1) can be improved with high-dose erythropoietin supplementation. The aim of this study was to characterize and compare erythropoiesis in samples from a DMT1-mutant patient before and after treatment with erythropoietin, as well as in a mouse model with a DMT1 mutation, the mk/mk mice. Design and MethodsColony assays were used to compare the in vitro growth of pre-treatment and post-treatment erythroid progenitors in a DMT1-mutant patient. To enable a comparison with human data, high doses of erythropoietin were administered to mk/mk mice. The apoptotic status of erythroblasts, the expression of anti-apoptotic proteins, and the key components of the bone marrow-hepcidin axis were evaluated. ResultsErythropoietin therapy in vivo or the addition of a broad-spectrum caspase inhibitor in vitro significantly improved the growth of human DMT1-mutant erythroid progenitors. A decreased number of apoptotic erythroblasts was detected in the patient's bone marrow after erythropoietin treatment. In mk/mk mice, erythropoietin administration increased activation of signal transducer and activator of transcription 5 (STAT5) and reduced apoptosis in bone marrow and spleen erythroblasts. mk/mk mice propagated on the 129S6/SvEvTac background resembled DMT1-mutant patients in having increased plasma iron but differed by having functional iron deficiency after erythropoietin administration. Co-regulation of hepcidin and growth differentiation factor 15 (GDF15) levels was observed in mk/mk mice but not in the patient. ConclusionsErythropoietin inhibits apoptosis of DMT1-mutant erythroid progenitors and differentiating erythroblasts. Ineffective erythropoiesis associated with defective erythroid iron utilization due to DMT1 mutations has specific biological and clinical features.Key words: DMT1, apoptosis, ineffective erythropoiesis, erythropoietin.Citation: Horvathova M, Kapralova K, Zidova Z, Dolezal D, Pospisilova D, and Divoky V. Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts. Haematologica 2012;97(10):1480-1488. doi:10.3324/haematol.2011 This is an open-access paper.Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

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Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload

Cited by 107 publications

References 20 publications

The homozygous mutation G75R in the human SLC11A2 gene leads to microcytic anaemia and iron overload

The homozygous mutation G75R in the human SLC11A2 gene leads to microcytic anaemia and iron overload

Manganese transport in eukaryotes: The role of DMT1

Erythropoietin-driven signaling ameliorates the survival defect of DMT1-mutant erythroid progenitors and erythroblasts

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