title: Human mutation D157G in ferroportin leads to hepcidin-independent binding of Jak2 and ferroportin down-regulation.
abstract: Mutations in the iron exporter ferroportin (Fpn) result in iron overload in macrophages or hepatocytes depending upon the mutation. Patients with Fpn mutation D157G show high serum ferritin and normal to slightly elevated transferrin saturation. Here, we show that Fpn(D157G)-green fluorescent protein (GFP) is down-regulated independent of hepcidin, and that this down-regulation is due to the constitutive binding of Jak2 and Fpn phosphorylation. Expression of Fpn(D157G)-GFP in Danio rerio results in a severe growth defect, which can be rescued by iron supplementation. These results identify a hepcidin-independent regulation of Fpn that can result in alterations in iron homeostasis.
authors.affiliation: Division of Hematology, Department of Medicine, School of Medicine, University of Utah, Salt Lake City, USA.
authors.forename: Ivana
authors.initials: I
authors.lastname: De Domenico
authors.forename: Eric
authors.initials: E
authors.lastname: Lo
authors.forename: Diane M
authors.initials: DM
authors.lastname: Ward
authors.forename: Jerry
authors.initials: J
authors.lastname: Kaplan
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D023181:Antimicrobial Cationic Peptides / Q000235:genetics; D027682:Cation Transport Proteins / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D015536:Down-Regulation; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D015027:Zebrafish; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; D064451:Hepcidins; D000098742:Ferroportin; D007501:Iron; C507924:JAK2 protein, human; D053614:Janus Kinase 2