The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease.
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Ferroportin disease is caused by mutation of one allele of the iron exporter ferroportin (Fpn/IREG1/Slc40a1/MTP1). All reported human mutations are missense mutations and heterozygous null mutations in mouse Fpn do not recapitulate the human disease. Here we describe the flatiron (ffe) mouse with a missense mutation (H32R) in Fpn that affects its localization and iron export activity. Similar to human patients with classic ferroportin disease, heterozygous ffe/+ mice present with iron loading of Kupffer cells, high serum ferritin, and low transferrin saturation. In macrophages isolated from ffe/+ heterozygous mice and through the use of Fpn plasmids with the ffe mutation, we show that Fpn(ffe) acts as a dominant negative, preventing wild-type Fpn from localizing on the cell surface and transporting iron. These results demonstrate that mutations in Fpn resulting in protein mislocalization act in a dominant-negative fashion to cause disease, and the Fpn(ffe) mouse represents the first mouse model of ferroportin disease.
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The flatiron (ffe) mouse model of human Ferroportin Disease harbors the FPNH32R mutation.
“the flatiron (ffe) mouse model of human Ferroportin Disease, which harbors the FPNH32R mutation [36].”
From Host Iron Withholding Demands Siderophore Utilization for Candida glabrata to Survive Macrophage Killing (2011) · cites this paper as [36]
A mouse model of the disease associated with loss-of-function ferroportin mutations, flatiron, was identified through a positional cloning effort.
“Recently, a mouse model of the disease associated with loss-of-function ferroportin mutations, flatiron, was identified through a positional cloning effort.160”
From Forging a field: the golden age of iron biology. (2008) · cites this paper as [160]
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References 25 · Cited by 104
Research works printed but not linked: 1
- Montosi G, Donovan A, Totaro A, et al. Autoso- mal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001;108:619-623.
- Authors
- Zohn, I. E., De Domenico, I., Pollock, A., Ward, D. M., Goodman, J. F., Liang, X., Sanchez, A. J., Niswander, L., & Kaplan, J.
- Affiliations
- Howard Hughes Medical Institute (US)
- Department of Pathology, School of Medicine, University of Utah, Salt Lake City;
- University of Utah (US)
- Department of Pathology, University of Colorado Health Sciences Center, Denver
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2007-02-08
- Volume
- 109
- Issue
- 10
- Pages
- 4174-4180
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1885502
- OpenAlex
- W2058180300
- Cited by
- 104
- References
- 25
- Citations by year
- 2025: 3 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 7 · 2015: 8 · 2014: 3 · 2013: 6 · 2012: 4
- FWCI
- 6.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Flatiron Health
- National Institutes of Health
- National Cancer Institute (T32CA8608604)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK070947)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32-HD08605)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Trace Elements in Health
- Keywords
- ferroportin, ferroportin disease, dominant negative effect, missense mutations, iron export, protein mislocalization, Kupffer cells, serum ferritin, transferrin saturation, macrophages, mouse model, SLC40A1
- MeSH terms
- Ferroportin, Animals, Base Sequence, Cells, Cultured, DNA Mutational Analysis, Genes, Dominant, Humans, Iron, Macrophages, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation, Iron Metabolism Disorders, Protein Transport, Cation Transport Proteins, Mice
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