Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding.

521 Normal iron homeostasis requires close matching of dietary iron absorption with body iron needs (1). Hereditary hemochromatosis (HH), a common abnormality of iron metabolism, is characterized by excess absorption of dietary iron despite elevated stores, and secondary damage to the liver, pancreas, and other organs (2). Classic HH is caused by mutation of the HFE gene and is inherited as an autosomal recessive trait. However, a substantial percentage of individuals with hemochromatosis, especially in non–Northern European populations, have no mutations in HFE (3). Many such cases differ from classic HH in the relative distribution of iron between the plasma, hepatocytes, and reticuloendothelial (RE) cells (4). Pietrangelo et al. recently reported a pedigree with atypical hemochromatosis inherited as an autosomal dominant trait (5). In this issue of the JCI, Montosi et al. report the surprising finding that the gene mutated in these patients (SLC11A3) encodes the iron export protein ferroportin1 (also known as IREG1, or MTP1) (6). They conclude that the identified mutation (A77D) probably results in loss of ferroportin1 function, suggesting that the affected individuals are haploinsufficient for this gene product. In a nearly simultaneous report, Njajou et al. (7) describe a similar pedigree with autosomal dominant hemochromatosis and a different missense mutation (N144H) in the same gene. Njajou et al., however, conclude that the iron overload phenotype was likely due to gain rather than loss of ferroportin function (i.e., an activating mutation). Why the opposite conclusions? As shown in Figure 1, ferroportin1 plays key roles in two different aspects of iron homeostasis, absorption of dietary iron by duodenal enterocytes and release of iron from body stores by RE cells (8–10). One might expect a gain-of-function mutation in ferroportin1 to lead to iron loading by increasing iron absorption. Increased ferroportin1 expression in duodenal enterocytes of patients with classic HH may contribute to their iron loading (11). However, we suggest that the primary cause of iron overload in patients with both described ferroportin1 mutations is decreased ferroportin1 function in RE cells, rather than increased function in enterocytes. While excess dietary iron absorption in classic HH leads to hepatocellular loading prior to RE cell loading (2), patients with the A77D ferroportin1 mutation demonstrate early and predominant loading of iron in RE cells. This situation is analogous to that seen with defects in the gene encoding ceruloplasmin (Cp). The ferroxidase activity of ceruloplasmin converts ferrous iron Ferroportin mutation in autosomal dominant hemochromatosis: loss of function, gain in understanding