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Review
. 2006 Jan;91(1):92-5.

Iron overload due to mutations in ferroportin

Ivana De Domenico  1 , Diane McVey Ward, Giovanni Musci, Jerry Kaplan
Affiliations
Review

Iron overload due to mutations in ferroportin

Ivana De Domenico et al. Haematologica. 2006 Jan.

Abstract

Iron overload disease due to mutations in ferroportin has a dominant inheritance and a variable clinical phenotype, such that some patients show early Küpffer cell iron loading and low transferrin saturation, while others show hepatocyte iron loading and high transferrin saturation. Studies expressing ferroportin mutant proteins in cultured cells have shown that mutant proteins fall into two main classes; proteins that do not localize to the cell surface and are unable to export iron, and those that localize to the cell surface but are unable to respond to the antimicrobial peptide hepcidin. Patients with mutant ferroportin proteins that do not localize to the cell surface show typical ferroportin disease with low transferrin saturation and early Küpffer cell iron loading, while patients with mutant proteins unable to respond to hepcidin show high transferrin saturation and early hepatocyte iron loading similar to classic hereditary hemochromatosis. The dominant genetic transmission of ferroportin-linked disorders is explained by the in vitro data, which suggest that ferroportin is a multimer and that the behavior of the mutant protein can affect the behavior of the wild type protein.

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Figures

Figure 1
Figure 1
Predicted structure of ferroportin. Fpn is a membrane protein with twelve predicted transmembrane domains. Several mutations in the Fpn gene have been reported. Mutations that lead to Kupffer cell iron loading are shown in green and those that lead to hepatocyte iron loading are shown in red.
Figure 2
Figure 2
Schematic diagram of the location of ferroportin iron export in the enterocyte and the macrophage. Iron is transported into the enterocyte by DMT1 localized on the apical membrane. Within enterocytes, iron can be stored in ferritin or it can be transported out of the enterocyte by Fpn at the basolateral surface. Macrophages phagocytose damaged or senescent red blood cells. The hemoglobin is degraded within lysosomes and iron is released. The released iron can be stored in ferritin or it can be exported out of the macrophage by Fpn.
Figure 3
Figure 3
Effects of ferroportin mutations on iron metabolism.
See this image and copyright information in PMC

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