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

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.

Pubmed ID: 17289807

Authors

  • Zohn IE
  • De Domenico I
  • Pollock A
  • Ward DM
  • Goodman JF
  • Liang X
  • Sanchez AJ
  • Niswander L
  • Kaplan J

Journal

Blood

Publication Data

May 15, 2007

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK070 947
  • Agency: NICHD NIH HHS, Id: F32-HD08 605
  • Agency: NCI NIH HHS, Id: T32CA8608604

Mesh Terms

  • Animals
  • Base Sequence
  • Cation Transport Proteins
  • Cells, Cultured
  • DNA Mutational Analysis
  • Genes, Dominant
  • Humans
  • Iron
  • Iron Metabolism Disorders
  • Macrophages
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mutation
  • Protein Transport