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Blood. 2007 May 15;109(10):4174-80. Epub 2007 Feb 8.

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

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  • 1Howard Hughes Medical Institute, Department of Pediatrics, Section of Developmental Biology, University of Colorado at Denver and Health Sciences Center, Aurora.

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.

PMID:
17289807
PMCID:
PMC1885502
DOI:
10.1182/blood-2007-01-066068
[PubMed - indexed for MEDLINE]
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