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.
Zohn
Irene E
IE
Howard Hughes Medical Institute, Department of Pediatrics, Section of Developmental Biology, University of Colorado at Denver and Health Sciences Center, Aurora.
De Domenico
Ivana
I
Pollock
Andrew
A
Ward
Diane McVey
DM
Goodman
Jessica F
JF
Liang
Xiayun
X
Sanchez
Amaru J
AJ
Niswander
Lee
L
Kaplan
Jerry
J
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
D027682:Cation Transport Proteins; D000098742:Ferroportin; D007501:Iron