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Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features

1
Department of Internal Medicine, Haaglanden MC-Bronovo, 2597AX The Hague, The Netherlands
2
Department of Laboratory Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
3
Liver Diseases Department, French Reference Centre for Rare Iron Overload Diseases of Genetic Origin, University Hospital Pontchaillou, 35033 Rennes, France
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Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud, University Medical Center, P.O. Box 9191, 6500 HB Nijmegen, The Netherlands
5
Molecular Genetics Department, French Reference Centre for Rare Iron Overload Diseases of Genetic Origin, University Hospital Pontchaillou, 35033 Rennes, France
6
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX39DS, UK
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2019, 12(3), 132; https://doi.org/10.3390/ph12030132
Received: 12 July 2019 / Revised: 14 August 2019 / Accepted: 20 August 2019 / Published: 9 September 2019
(This article belongs to the Special Issue Iron as Therapeutic Targets in Human Diseases)
Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin variants. Overall, macrophage iron overload and low/normal transferrin saturation (TSAT) segregated with mutations that caused LOF, while GOF mutations were linked to high TSAT and parenchymal iron accumulation. However, the pathogenicity of individual variants is difficult to establish due to the lack of sufficiently reported data, large inter-assay variability of functional studies, and the uncertainty associated with the performance of available in silico prediction models. Since the phenotypes of hepcidin-resistant GOF variants are indistinguishable from the other types of hereditary hemochromatosis (HH), these variants may be categorized as ferroportin-associated HH, while the entity ferroportin disease may be confined to patients with LOF variants. To further improve the management of ferroportin disease, we advocate for a global registry, with standardized clinical analysis and validation of the functional tests preferably performed in human-derived enterocytic and macrophagic cell lines. Moreover, studies are warranted to unravel the definite structure of ferroportin and the indispensable residues that are essential for functionality. View Full-Text
Keywords: SLC40A1; ferroportin; iron overload; non-HFE; ferritin; hemochromatosis SLC40A1; ferroportin; iron overload; non-HFE; ferritin; hemochromatosis
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Vlasveld, L.T.; Janssen, R.; Bardou-Jacquet, E.; Venselaar, H.; Hamdi-Roze, H.; Drakesmith, H.; Swinkels, D.W. Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features. Pharmaceuticals 2019, 12, 132.

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