Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice.
Coding region mutations in the principal basolateral iron transporter of the duodenal enterocyte, ferroportin 1 (FPN1), lead to autosomal dominant reticuloendothelial iron overload in humans. We report the positional cloning of a hypermorphic, regulatory mutation in Fpn1 from radiation-induced polycythaemia (Pcm) mice. A 58 bp microdeletion in the Fpn1 promoter region alters transcription start sites and eliminates the iron responsive element (IRE) in the 5' untranslated region, resulting in increased duodenal and hepatic Fpn1 protein levels during early postnatal development. Pcm mutants, which are iron deficient at birth, exhibited increased Fpn1-mediated iron uptake and reticuloendothelial iron overload as young adult mice. Additionally, Pcm mutants displayed an erythropoietin (Epo)-dependent polycythemia in heterozygotes and a hypochromic, microcytic anemia in homozygotes. Interestingly, both defects in erythropoiesis were transient, correcting by young adulthood. Delayed upregulation of the negative hormonal regulator of iron homeostasis, hepcidin (Hamp), during postnatal development correlates strongly with profound increases in Fpn1 protein levels and polycythemia in Pcm heterozygotes. Thus, our data suggest that a Hamp-mediated regulatory interference alleviates the defects in iron homeostasis and transient alterations in erythropoiesis caused by a regulatory mutation in Fpn1.
Mok
Henry
H
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Jelinek
Jaroslav
J
Pai
Sonia
S
Cattanach
Bruce M
BM
Prchal
Josef T
JT
Youssoufian
Hagop
H
Schumacher
Armin
A
D000375:Aging / Q000378:metabolism; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004920:Erythropoiesis / Q000502:physiology*; D006400:Hematocrit; D006706:Homeostasis / Q000502:physiology; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion; D000098742:Ferroportin
D027682:Cation Transport Proteins; D000098742:Ferroportin; D007501:Iron