The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease

University of Utah, Salt Lake City, Utah, United States
Blood (Impact Factor: 10.45). 06/2007; 109(10):4174-80. DOI: 10.1182/blood-2007-01-066068
Source: PubMed

ABSTRACT 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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    • "A complementary approach to test the effect of iron-loaded macrophages on atherosclerosis was recently pursued (Kautz et al., 2013). Atherosclerosis was studied in the flatiron (ffe) mouse (Zohn et al., 2007), a model that specifically accumulates iron in macrophages. Contrary to the refined iron hypothesis , atherosclerosis was not increased in mice with elevated macrophage iron. "
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    ABSTRACT: Iron accumulates in human atherosclerotic lesions but whether it is a cause or simply a downstream consequence of the atheroma formation has been an open question for decades. According to the so called "iron hypothesis," iron is believed to be detrimental for the cardiovascular system, thus promoting atherosclerosis development and progression. Iron, in its catalytically active form, can participate in the generation of reactive oxygen species and induce lipid-peroxidation, triggering endothelial activation, smooth muscle cell proliferation and macrophage activation; all of these processes are considered to be proatherogenic. On the other hand, the observation that hemochromatotic patients, affected by life-long iron overload, do not show any increased incidence of atherosclerosis is perceived as the most convincing evidence against the "iron hypothesis." Epidemiological studies and data from animal models provided conflicting evidences about the role of iron in atherogenesis. Therefore, more careful studies are needed in which issues like the source and the compartmentalization of iron will be addressed. This review article summarizes what we have learnt about iron and atherosclerosis from epidemiological studies, animal models and cellular systems and highlights the rather contributory than innocent role of iron in atherogenesis.
    Frontiers in Pharmacology 05/2014; 5:94. DOI:10.3389/fphar.2014.00094 · 3.80 Impact Factor
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    • "Several mouse models of iron overload (i.e., hereditary hemochromatosis ) are available, but, like their human counterparts, they accumulate iron in hepatocytes rather than macrophages and thus are inappropriate for studies on the role of excess macrophage iron in atherosclerotic plaques. The flatiron (ffe) mouse is the first mouse model that accumulates iron in macrophages without other confounding abnormalities (Zohn et al., 2007). The flatiron mouse has a heterozygous H32R mutation in ferroportin that causes a dominant negative mistrafficking of the iron exporter. "
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    ABSTRACT: Hepcidin, the iron-regulatory hormone and acute phase reactant, is proposed to contribute to the pathogenesis of atherosclerosis by promoting iron accumulation in plaque macrophages, leading to increased oxidative stress and inflammation in the plaque (the "iron hypothesis"). Hepcidin and iron may thus represent modifiable risk factors in atherosclerosis. We measured hepcidin expression in Apoe(-/-) mice with varying diets and ages. To assess the role of macrophage iron in atherosclerosis, we generated Apoe(-/-) mice with macrophage-specific iron accumulation by introducing the ferroportin ffe mutation. Macrophage iron loading was also enhanced by intravenous iron injection. Contrary to the iron hypothesis, we found that hepatic hepcidin expression was not increased at any stage of the atherosclerosis progression in Apoe(-/-) or Apoe/ffe mice and that the atherosclerotic plaque size was not increased in mice with elevated macrophage iron. Our results strongly argue against any significant role of macrophage iron in atherosclerosis progression in mice.
    Cell Reports 12/2013; 5(5). DOI:10.1016/j.celrep.2013.11.009 · 8.36 Impact Factor
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    • "The lack of an obvious phenotype for Fpn null/+ mice could be discounted as mice being different from humans, however, a missense mutation in mice flatiron (Fpn H32R) showed the phenotype of " classic " ferroportin disease and the expected dominant genetic transmission [12]. The mutant protein, when expressed in mammalian cells or when analyzed in cultured flatiron mouse macrophages, showed impaired iron transport activity. "
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    ABSTRACT: The distinguishing feature between iron homeostasis in single versus multicellular organisms is the need for multicellular organisms to transfer iron from sites of absorption to sites of utilization and storage. Ferroportin is the only known iron exporter and ferroportin plays an essential role in the export of iron from cells to blood. Ferroportin can be regulated at many different levels including transcriptionally, post-transcriptionally, through mRNA stability and post-translationally, through protein turnover. Additionally, ferroportin may be regulated in both cell-dependent and cell-autonomous fashions. Regulation of ferroportin is critical for iron homeostasis as alterations in ferroportin may result in either iron deficiency or iron overload. This article is part of a Special Issue entitled: Cell Biology of Metals.
    Biochimica et Biophysica Acta 03/2012; 1823(9):1426-33. DOI:10.1016/j.bbamcr.2012.03.004 · 4.66 Impact Factor
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