Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin

Author:

Drakesmith Hal1,Schimanski Lisa M.1,Ormerod Emma1,Merryweather-Clarke Alison T.1,Viprakasit Vip1,Edwards Jon P.1,Sweetland Emma1,Bastin Judy M.1,Cowley Diana1,Chinthammitr Yingyong1,Robson Kathryn J. H.1,Townsend Alain R. M.1

Affiliation:

1. From the Weatherall Institute of Molecular Medicine, Oxford, United Kingdom; Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom; Department of Paediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; and Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.

Abstract

AbstractFerroportin (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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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