Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice
Abstract
Coding region mutations in the principal basolateral iron transporter of the duodenal enterocyte, ferroportin 1 (FPN1), lead to autosomal dominant reticuloendothelial iron overload in humans. We report the positional cloning of a hypermorphic, regulatory mutation in Fpn1 from radiation-induced polycythaemia (Pcm) mice. A 58 bp microdeletion in the Fpn1promoter region alters transcription start sites and eliminates the iron responsive element (IRE) in the 5′ untranslated region, resulting in increased duodenal and hepatic Fpn1 protein levels during early postnatal development. Pcm mutants, which are iron deficient at birth,exhibited increased Fpn1-mediated iron uptake and reticuloendothelial iron overload as young adult mice. Additionally, Pcm mutants displayed an erythropoietin (Epo)-dependent polycythemia in heterozygotes and a hypochromic, microcytic anemia in homozygotes. Interestingly, both defects in erythropoiesis were transient, correcting by young adulthood. Delayed upregulation of the negative hormonal regulator of iron homeostasis, hepcidin(Hamp), during postnatal development correlates strongly with profound increases in Fpn1 protein levels and polycythemia in Pcmheterozygotes. Thus, our data suggest that a Hamp-mediated regulatory interference alleviates the defects in iron homeostasis and transient alterations in erythropoiesis caused by a regulatory mutation in Fpn1.
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Suppression of hepcidin alone cannot fully explain the polycythemia associated with testosterone administration.
“The suppression of hepcidin alone cannot fully explain the polycythemia associated with testosterone administration because hemochromatosis patients with inactivating mutations in the hepcidin gene (hAMP) and mice with disruption of the hepcidin gene expression do not display a phenotype of polycythemia (27,28).”
From Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point (2014) · cites this paper as [28]
Suppression of hepcidin by itself may play a contributory role in testosterone-induced erythrocytosis.
“Nonetheless, genetic alterations in iron regulatory genes in mice (hamp knockout, ferroportin deletion mutant pcm mice) alone are sufficient to cause transient polycythemia, thus supporting the hypothesis that suppression of hepcidin by itself may play a contributory role in testosterone-induced erythrocytosis (28,29).”
From Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point (2014) · cites this paper as [28]
Genetic alterations in iron regulatory genes in mice (hamp knockout, ferroportin deletion mutant pcm mice) alone are sufficient to cause transient polycythemia.
“Nonetheless, genetic alterations in iron regulatory genes in mice (hamp knockout, ferroportin deletion mutant pcm mice) alone are sufficient to cause transient polycythemia, thus supporting the hypothesis that suppression of hepcidin by itself may play a contributory role in testosterone-induced erythrocytosis (28,29).”
From Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point (2014) · cites this paper as [28]
A mutation that prevents formation of the mouse ferroportin IRE causes an unusual and complex disorder of iron homeostasis.
“Interestingly, a mutation that prevents formation of the mouse ferroportin IRE causes an unusual and complex disorder of iron homeostasis, underscoring the significance of this IRE in vivo.50”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [50]
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References 57 · Cited by 73
- Authors
- Mok, H., Jelinek, J., Pai, S., Cattanach, B. M., Prchal, J. T., Youssoufian, H., & Schumacher, A.
- Affiliations
- Baylor College of Medicine (US)
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030,USA
- Medical Research Council (GB)
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2004-04-15
- Volume
- 131
- Issue
- 8
- Pages
- 1859-1868
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W1967036581
- Cited by
- 73
- References
- 57
- Citations by year
- 2022: 2 · 2021: 1 · 2020: 3 · 2019: 2 · 2017: 2 · 2016: 2 · 2014: 2 · 2013: 2 · 2012: 3
- FWCI
- 7.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
- Keywords
- ferroportin 1, iron homeostasis, erythropoiesis, polycythemia, positional cloning, iron-responsive element, hepcidin, erythropoietin, microcytic anemia, postnatal development, radiation-induced mutations
- MeSH terms
- Ferroportin, Aging, Animals, Erythropoiesis, Hematocrit, Homeostasis, Iron, Liver, Polycythemia, Promoter Regions, Genetic, Sequence Deletion, Cation Transport Proteins, Mice
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