title: Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin.
abstract: Ferroportin (FPN) mediates iron export from cells; FPN mutations are associated with the iron overloading disorder hemochromatosis. Previously, we found that the A77D, V162del, and G490D mutations inhibited FPN activity, but that other disease-associated FPN variants retained full iron export capability. The peptide hormone hepcidin inhibits FPN as part of a homeostatic negative feedback loop. We measured surface expression and function of wild-type FPN and fully active FPN mutants in the presence of hepcidin. We found that the Y64N and C326Y mutants of FPN are completely resistant to hepcidin inhibition and that N144D and N144H are partially resistant. Hemochromatosis-associated FPN mutations, therefore, either reduce iron export ability or produce an FPN variant that is insensitive to hepcidin. The former mutation type is associated with Kupffer-cell iron deposition and normal transferrin saturation in vivo, whereas patients with the latter category of FPN mutation have high transferrin saturation and tend to deposit iron throughout the liver parenchyma. FPN-linked hemochromatosis may have a variable pathogenesis depending on the causative FPN mutant.
authors.affiliation: Weatherall Institute of Molecular Medicine, Oxford. OX3 9DS, United Kingdom. hdrakes@hammer.imm.ox.ac.uk
authors.forename: Hal
authors.initials: H
authors.lastname: Drakesmith
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Schimanski
authors.forename: Emma
authors.initials: E
authors.lastname: Ormerod
authors.forename: Alison T
authors.initials: AT
authors.lastname: Merryweather-Clarke
authors.forename: Vip
authors.initials: V
authors.lastname: Viprakasit
authors.forename: Jon P
authors.initials: JP
authors.lastname: Edwards
authors.forename: Emma
authors.initials: E
authors.lastname: Sweetland
authors.forename: Judy M
authors.initials: JM
authors.lastname: Bastin
authors.forename: Diana
authors.initials: D
authors.lastname: Cowley
authors.forename: Yingyong
authors.initials: Y
authors.lastname: Chinthammitr
authors.forename: Kathryn J H
authors.initials: KJ
authors.lastname: Robson
authors.forename: Alain R M
authors.initials: AR
authors.lastname: Townsend
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D002460:Cell Line; D004351:Drug Resistance / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006432:Hemochromatosis / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000378:metabolism; D007504:Iron Radioisotopes / Q000378:metabolism; D020125:Mutation, Missense; D014168:Transferrin / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; D064451:Hepcidins; D007504:Iron Radioisotopes; D014168:Transferrin; D000098742:Ferroportin; D007501:Iron