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Ferroportin mutations: a tale of two phenotypes

Elizabeta Nemeth

Comment on Schimanski et al, page 4096

Ferroportin disease is becoming recognized as the most common form of hereditary iron overload after HFE hemochromatosis, but explanations for its autosomal dominant inheritance and heterogeneous clinical presentation have been elusive. Schimanski and colleagues provide the first glimpses of mechanistic understanding of this important clinical entity.

Ferroportin disease1 is an autosomal-dominant form of iron overload caused by mutations in SLC40A1 gene encoding ferroportin. This multimembrane-spanning protein is the sole cellular iron exporter and is found in all cells and tissues where major iron flows are regulated2: duodenal enterocytes, placenta, macrophages, and hepatocytes. The rate of iron export from these cells determines plasma iron concentrations, and since both iron deficiency and iron excess are harmful to the organism, the export is tightly regulated. The mechanism is quite simple: a peptide hormone hepcidin binds to ferroportin and induces its internalization and degradation, blocking cellular iron efflux.3 Plasma iron levels, in turn, regulate hepcidin production, thus completing the homeostatic loop.

Either hepcidin deficiency or its ineffective interaction with ferroportin would lead to excessive iron absorption and iron overload. Indeed, hepcidin deficiency appears to be the common characteristic of most hereditary hemochromatoses (those due to mutations in HFE, transferrin receptor 2, hemojuvelin, or hepcidin gene itself).

The remaining type of hereditary iron overload is caused by heterozygous mutations in the hepcidin target, ferroportin. The initially described clinical features, however, were unlike those of classical hemochromatosis.1 Patients had an early rise in ferritin levels despite the low-normal transferrin saturation, iron accumulation predominantly in macrophages, and borderline anemia with low tolerance to phlebotomy. This phenotype was consistent with a loss-of-function hypothesis and haploinsufficiency.4 One normal ferroportin gene would give rise to about one half of the normal amount of protein, insufficient to export the large amount of iron processed by macrophages, resulting in macrophage iron accumulation and decreased circulating iron transferrin. Any anemia could eventually lead to a compensatory increase of duodenal iron absorption. In the alternative scenario, a dominant-negative effect, the mutant protein would interfere with the function of the wild-type ferroportin, resulting in a similar phenotype. However, as more ferroportin mutations were identified, the phenotype turned out to be more heterogeneous—some clinical presentations were similar to classical hemochromatosis,with high transferrin saturation and prominent parenchymal iron loading.5

Schimanski and colleagues showed the in vitro relationship between distinct mutations and functional consequences leading to the particular phenotype. The mutations associated with the macrophage loading pattern cause a trafficking problem: the mutant protein does not localize to the cell surface, resulting in a loss of iron export function (see figure panel A). The authors found no evidence that mutants physically or functionally interfered with wild-type ferroportin, and they concluded that these mutations behaved according to the haploinsufficiency model. However, this model does not explain why among the many patients analyzed to date, no nonsense mutations have been found.

Proposed mechanism of the ferroportin disease pathogenesis. Top panel: a defect in trafficking (“loss-of-function”). Mutant protein is retained inside the cell resulting in a loss of iron export function. The efflux through the wild-type ferroportin represents only half of the normal amount and is inadequate for the macrophages processing large amounts of recycled iron. Iron accumulates in macrophages, leading to high ferritin levels, low transferrin saturation, and possibly borderline anemia. Anemia, in turn, might activate duodenal absorption, which would progressively increase transferrin saturation. Bottom panel: hepcidin resistance (“gain-of-function”). Mutations prevent hepcidin-mediated internalization and degradation of ferroportin either by interfering with hepcidin binding or by altering motifs required for internalization and degradation. As a result, an inappropriately high number of mutant ferroportin molecules is displayed on the cell surface, resulting in increased iron efflux from enterocytes and macrophages. Duodenal iron absorption increases, transferrin saturation rises, and excess iron is deposited in hepatic parenchyma and other tissues.

Mutations associated with the classical hemochromatosis phenotype, on the other hand, retained full iron exporting function in vitro. The authors speculate that these mutations confer resistance to negative regulation, presumably by hepcidin, so that the protein is permanently turned on (see figure panel B), resulting in excessive iron absorption and development of hemochromatosis, similar to hepcidin deficiency. However, the crucial evidence is still lacking that these mutations perturb hepcidin-ferroportin interaction or disrupt ferroportin motifs required for internalization and degradation.

Schimanski et al's findings lend further support to the central role of the hepcidin-ferroportin interaction in regulating the extracellular iron concentrations and to the emerging unifying concept that most iron overload diseases are caused by mutations affecting the production or function of either the ligand hepcidin or its receptor ferroportin. ▪

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