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Editorials
acid interaction network in various ferroportin conforma- tion states may reveal additional sites essential for stabiliza- tion and provide molecular explanation for defective iron egress in variants without defective membrane expression, such as Arg88Gly, Leu129Pro, Ile152Phe and Asn174Ile.9-11
Notwithstanding the importance of this finding, it does not clarify the iron overload observed in these patients. Moreover, as reported by Ka and colleagues, it is notable that the patients with a loss-of-function variant ferroportin, that completely disappears from the cellular membrane after exposure to hepcidin, have no anemia and intensive phlebotomy regimens were reported to be well tolerated. In patients with defective iron export transport due to a loss- of-function variant, either due to mislocalization or improp- er folding, one might expect diminished enterocyte iron absorption leading to a phenotype similar to that described for iron-refractory iron deficiency (IRIDA). In IRIDA, muta- tions in the TMPRSS6 gene result in inappropriately elevat- ed serum hepcidin levels with diminished ferroportin activ- ity and a variable degree of iron deficiency anemia, unre- sponsive to oral iron treatment, and intra-enterocyte iron retention in experimental animals (Figure 1C).12,13 Experimental animals with diminished ferroportin activity due to monoallelic wild-type ferroportin expression also display iron deficiency anemia.2 This is in contrast to the situation in patients with diminished ferroportin activity due to loss-of-function ferroportin variants which is char- acterized by iron overload, normal circulating hemoglobin concentrations and absence of intra-enterocyte iron (evalu- ated in a limited number of patients) (Figure 1D,E).14 It appears that in the enterocyte diminished ferroportin activ- ity due to decreased activity of wild-type ferroportin has a different effect on iron export capacity than decreased fer- roportin activity caused by a loss-of-function variant. In addition, the impact of loss-of-function variants on iron export capacity may be different between macrophages and enterocytes, and the results of the functional studies in HEK293T cells are more predictive for macrophage iron handling. It has been suggested that in patients with loss- of-function variants the remaining monoallelic expressed wild-type ferroportin protein would be sufficient to pre- serve iron export in cells with low iron turnover, such as enterocytes, but insufficient to maintain iron export capac- ity in cells with high iron turnover, such as macrophages, with subsequent intracellular iron retention in these cells.5 However, this theory may not provide a full explanation for the state of iron overload in these patients. While the activity of ferroportin in both enterocytes and macrophages in the systemic regulation of iron homeosta- sis is mediated by hepcidin, there is a considerable amount of experimental data indicating that the regulation of ferro- portin expression and activity differ between enterocytes and macrophages. These data include differences in intra- cellular regulatory mechanisms that fine-tune ferroportin membrane expression as well as differences in ferroportin
activity upon various systemic stimuli.15-20 The study by Ka et al. contributes to our understanding of the pathogenic mechanisms involved in decreased ferroportin activity by loss-of-function variants. Studies focused on the conse- quences of these variants on enterocyte iron handling are warranted to further comprehend the pathophysiology of this intriguing iron overload disorder.
References
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14. Corradini E, Montosi G, Ferrara F, et al. Lack of enterocyte iron accu- mulation in the ferroportin disease. Blood Cells Mol Dis. 2005;35(3):315-318.
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