Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene
Abstract
Although disorders of iron metabolism are prevalent, iron transport remains poorly understood. To address this problem, we undertook a positional cloning strategy to identify the causative mutation in mice with microcytic anaemia (mk). Homozygous mk/mk mice have microcytic, hypochromic anaemia due to severe defects in intestinal iron absorption and erythroid iron utilization. We report the identification of a strong candidate gene for mk, and suggest that the phenotype is a consequence of a missense mutation in Nramp2 (ref. 5), a previously identified gene of unknown function. Nramp2 is homologous to Nramp1, a gene activa in host defense. If Nramp2 is mk, as the cumulative evidence suggests, our findings have broad implications for the understanding of iron transport and resistance to intracellular pathogens.
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The freed ferric iron is reduced to Fe2+ by STEAP3 and shuttled into the cytosol from the endosome by DMT1.
“The freed ferric iron is then reduced to its bio-active ferrous form, Fe2+ by the ferrireductase STEAP3 (six-transmembrane epithelial antigen of prostate 3) and shuttled into the cytosol from the endosome by DMT1 (Fleming et al., 1997; Gunshin et al., 1997; Ohgami et al., 2005; Figure 1).”
From The Role of Iron Regulation in Immunometabolism and Immune-Related Disease (2019) · cites this paper as Fleming et al., 1997
Inorganic iron uptake from the gastrointestinal lumen by enterocytes depends upon DMT1, which is not able to import Fe3+.
“However, inorganic iron uptake from the gastrointestinal lumen by enterocytes depends upon the divalent metal transporter protein 1 (DMT1 or NRAMP2), which is not able to import Fe3+. 12 , 13 , 14”
From The battle for iron in enteric infections (2020) · cites this paper as [12]
Liberated inorganic iron is reduced by the ferrireductase STEAP3 to Fe2+, which is the substrate for transmembrane transport by DMT1.
“Liberated inorganic iron is then reduced by the ferrireductase STEAP3 to Fe 2ϩ , 10 which is the substrate for transmembrane transport by divalent metal transporter 1 (DMT1 or SLC11A2, formerly called NRAMP2, DCT1).”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [12]
The first mammalian transmembrane iron transporter was discovered simultaneously in 2 laboratories in Boston using modern techniques.
“In spite of these obstacles and entirely by chance, the first mammalian transmembrane iron transporter was discovered simultaneously in 2 laboratories, located within a city block of each other in Boston, using singularly modern techniques.12,13”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [12]
The clinical phenotype of patients with DMT1 mutations differs slightly from the corresponding mouse model, mk.
“Interestingly, the clinical phenotype of patients with DMT1 mutations differs slightly from the corresponding mouse model, mk. 12”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [12]
Unlike TfR1, TfR2 does not contain an IRE in its mRNA and does not appear to be regulated in an iron-dependent manner.
“Unlike TfR1, TfR2 does not contain an IRE in its mRNA and does not appear to be regulated in an iron-dependent manner (90, 315).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [90]
Studies of TfR2 expression in a mouse model for hemochromatosis revealed that TfR2 was not downregulated in conditions of iron overload.
“Studies of TfR2 expression in a mouse model for hemochromatosis revealed that TfR2 was not downregulated in conditions of iron overload (90), supporting the absence of an iron-mediated posttranscriptional regulatory mechanism.”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [90]
Iron accumulation in the liver in type 1 HH results in the downregulation of TfR1, but TfR2 is continually expressed even during HH-mediated iron loading.
“Interestingly, iron accumulation in the liver in type 1 HH results in the downregulation of TfR1, but in the case of TfR2, it is continually expressed even during HH-mediated iron loading (90).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [90]
TfR2 does not appear to be regulated by iron concentrations, for it lacks IRE in its mRNA and is not inducible by iron deficiency.
“In addition, TfR2 does not appear to be regulated by iron concentrations, for it lacks IRE in its mRNA and is not inducible by iron deficiency (90).”
From Intracellular iron transport and storage: from molecular mechanisms to health implications (2008) · cites this paper as [90]
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- Authors
- Fleming, M. D., Trenor, C. C., Su, M. A., Foernzler, D., Beier, D. R., Dietrich, W. F., & Andrews, N. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Andrews, Nancy C.
- Venue
- Nature Genetics
- Published
- 1997-08
- Volume
- 16
- Issue
- 4
- Pages
- 383-386
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2082806735
- Cited by
- 1,159
- References
- 35
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 11 · 2023: 16 · 2022: 12 · 2021: 14 · 2020: 13 · 2019: 23 · 2018: 20 · 2017: 23 · 2016: 21 · 2015: 24 · 2014: 28 · 2013: 33 · 2012: 35
- FWCI
- 42.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion)
- Funders
- National Institutes of Health (1k08hl003600-01)
- National Heart, Lung, and Blood Institute (K08 HL03600)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- microcytic anemia, DMT1, iron transport, iron metabolism, intestinal iron absorption, missense mutations, positional cloning, NRAMP1, mice
- MeSH terms
- Frataxin, Animals, Friedreich Ataxia, Humans, Mitochondria, Phosphotransferases (Alcohol Group Acceptor), Iron-Binding Proteins
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