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 Fpnffe 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 Fpnffe mouse represents the first mouse model of ferroportin disease. © 2007 by The American Society of Hematology.
CITATION STYLE
Zohn, I. E., De Domenico, I., Pollock, A., Ward, D. M. V., Goodman, J. F., Liang, X., … Kaplan, J. (2007). The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood, 109(10), 4174–4180. https://doi.org/10.1182/blood-2007-01-066068
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