title: The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease.
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.
authors.affiliation: Howard Hughes Medical Institute, Department of Pediatrics, Section of Developmental Biology, University of Colorado at Denver and Health Sciences Center, Aurora.
authors.forename: Irene E
authors.initials: IE
authors.lastname: Zohn
authors.forename: Ivana
authors.initials: I
authors.lastname: De Domenico
authors.forename: Andrew
authors.initials: A
authors.lastname: Pollock
authors.forename: Diane McVey
authors.initials: DM
authors.lastname: Ward
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Goodman
authors.forename: Xiayun
authors.initials: X
authors.lastname: Liang
authors.forename: Amaru J
authors.initials: AJ
authors.lastname: Sanchez
authors.forename: Lee
authors.initials: L
authors.lastname: Niswander
authors.forename: Jerry
authors.initials: J
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D005799:Genes, Dominant; D006801:Humans; D007501:Iron / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000196:embryology / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D021381:Protein Transport; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D000098742:Ferroportin; D007501:Iron