Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin.
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.
Drakesmith
Hal
H
Weatherall Institute of Molecular Medicine, Oxford. OX3 9DS, United Kingdom. hdrakes@hammer.imm.ox.ac.uk
Schimanski
Lisa M
LM
Ormerod
Emma
E
Merryweather-Clarke
Alison T
AT
Viprakasit
Vip
V
Edwards
Jon P
JP
Sweetland
Emma
E
Bastin
Judy M
JM
Cowley
Diana
D
Chinthammitr
Yingyong
Y
Robson
Kathryn J H
KJ
Townsend
Alain R M
AR
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
D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; D064451:Hepcidins; D007504:Iron Radioisotopes; D014168:Transferrin; D000098742:Ferroportin; D007501:Iron