DOI: 10.1073/pnas.0503804102. The molecular basis of ferroportin-linked hemochromatosis

The molecular basis of ferroportin-linked hemochromatosis

10.1073/pnas.0503804102

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Mutations in the iron exporter ferroportin (Fpn) (IREG1, SLC40A1 , and MTP1) result in hemochromatosis type IV, a disorder with a dominant genetic pattern of inheritance and heterogeneous clinical presentation. Most patients develop iron loading of Kupffer cells with relatively low saturation of plasma transferrin, but others present with high transferrin saturation and iron-loaded hepatocytes. We show that known human mutations introduced into mouse Fpn-GFP generate proteins that either are defective in cell surface localization or have a decreased ability to be internalized and degraded in response to hepcidin. Studies using coimmunoprecipitation of epitope-tagged Fpn and size-exclusion chromatography demonstrated that Fpn is multimeric. Both WT and mutant Fpn participate in the multimer, and mutant Fpn can affect the localization of WT Fpn, its stability, and its response to hepcidin. The behavior of mutant Fpn in cell culture and the ability of mutant Fpn to act as a dominant negative explain the dominant inheritance of the disease as well as the different patient phenotypes.

Bibliography

De Domenico, I., Ward, D. M., Nemeth, E., Vaughn, M. B., Musci, G., Ganz, T., & Kaplan, J. (2005). The molecular basis of ferroportin-linked hemochromatosis. Proceedings of the National Academy of Sciences, 102(25), 8955â8960.

Authors 7

Ivana De Domenico (first)
Diane McVey Ward (additional)
Elizabeta Nemeth (additional)
Michael B. Vaughn (additional)
Giovanni Musci (additional)
Tomas Ganz (additional)
Jerry Kaplan (additional)

References 26 Referenced 181

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Dates

Type	When
Created	20 years, 2 months ago (June 15, 2005, 6:18 a.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 10:04 a.m.)
Indexed	3 weeks, 4 days ago (Aug. 5, 2025, 9:02 a.m.)
Issued	20 years, 2 months ago (June 13, 2005)
Published	20 years, 2 months ago (June 13, 2005)
Published Online	20 years, 2 months ago (June 13, 2005)
Published Print	20 years, 2 months ago (June 21, 2005)

Funders 0

None

BibTeX

@article{De_Domenico_2005, title={The molecular basis of ferroportin-linked hemochromatosis}, volume={102}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.0503804102}, DOI={10.1073/pnas.0503804102}, number={25}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={De Domenico, Ivana and Ward, Diane McVey and Nemeth, Elizabeta and Vaughn, Michael B. and Musci, Giovanni and Ganz, Tomas and Kaplan, Jerry}, year={2005}, month=jun, pages={8955–8960} }

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