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: 10.43). 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.

  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "In macrophages, it has been shown that increases in ferroportin result in lowered levels of ferritin (Zohn et al., 2007). Experiments have also shown that this mechanism is preserved in breast cancer cells (Pinnix et al., 2010), suggesting that it is a conserved feature of iron regulation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Iron is a metal essential for cellular metabolism. However, excess iron available for reactions contributes to the formation of dangerous reactive oxygen species, such as the hydroxyl radical, via the Fenton reaction. Therefore, intracellular iron levels are tightly constrained by a control system of proteins. This paper contains a mathematical model, in the form of a system of five ordinary differential equations, of the core of this control system, including the labile iron pool as well as proteins that regulate uptake, storage, and export and are connected through negative feedback loops. The model is validated using data from an overexpression experiment with cultured human breast epithelial cells. The parameters in the mathematical model are not known for this particular cell culture system, so the analysis of the model was done for a generic choice of parameters. Through a mixture of analytical arguments and extensive simulations it is shown that for any choice of parameters the model reaches a unique stable steady state, thereby ruling out oscillatory behavior. It is shown furthermore that the model parameters are identifiable through suitable experiments.
    Journal of Theoretical Biology 01/2012; 300:91-9. DOI:10.1016/j.jtbi.2012.01.024 · 2.30 Impact Factor
Show more