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Hereditary hemochromatosis (HH) is a common autosomal recessive disorder causing inappropriate dietary iron absorption that affects North Europeans. HH is associated with the C282Y mutation of the HFE gene, and the H63D mutation to a lesser degree. Both mutations are abundant in Europe, with H63D also appearing in North Africa, the Middle East, and Asia. Emigration from Europe over the past 500 years has introduced C282Y and H63D to America, Australia, New Zealand, and South Africa in an essentially predictable fashion. The distinctive characteristics of the population genetics of HH are the confined racial distribution and high frequency in North European peoples. C282Y frequencies in North Europeans are typically between 5% and 10%, with homozygotes accounting for between 1/100 and 1/400 of these populations. The scarcity of the C282Y mutation in other populations accounts for the lack of HH in non-Europeans.

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Type IV hemochromatosis is associated with dominant mutations in the SLC40A1 gene encoding ferroportin (FPN). Known as the "ferroportin disease," this condition is typically characterized by high serum ferritin, reduced transferrin saturation, and macrophage iron loading. Previously FPN expression in vitro has been shown to cause iron deficiency in human cell lines and mediate iron export from Xenopus oocytes. We confirm these findings by showing that expression of human FPN in a human cell line results in an iron deficiency because of a 3-fold increased export of iron. We show that FPN mutations A77D, V162⌬, and G490D that are associated with a typical pattern of disease in vivo cause a loss of iron export function in vitro but do not physically or functionally impede wild-type FPN. These mutants may, therefore, lead to disease by haploinsufficiency. By contrast the variants Y64N, N144D, N144H, Q248H, and C326Y, which can be associated with greater transferrin saturation and more prominent iron deposition in liver parenchyma in vivo, retained iron export function in vitro. Because FPN is a target for negative feedback in iron homeostasis, we postulate that the latter group of mutants may resist inhibition, resulting in a permanently "turned on" iron exporter. IntroductionHemochromatosis is an iron overload disease characterized by excessive iron uptake through the enterocytes of the gut and subsequent deposition in the liver, spleen, and heart, leading to tissue damage. Currently 4 subtypes of hemochromatosis are recognized. In Caucasian populations disease is predominantly associated with mutations in the HFE gene, discovered in 1996 1 ; HFE-linked hemochromatosis is designated type I. A more severe form of the disease, juvenile hemochromatosis (type II hemochromatosis), is linked to mutations in either the recently identified hemojuvelin 2 or the antimicrobial peptide hepcidin. 3,4 Hepcidin is normally up-regulated in response to high serum iron, but it is unexpectedly low in patients with hemochromatosis because of mutations in HFE, 5 hemojuvelin, 2 and transferrin receptor 2 (TfR2). 6,7 TfR2, which is expressed by hepatocytes, 8,9 is mutated in hemochromatosis type III. The iron exporter ferroportin/iron-regulated transporter 1/metal transporter protein 1 (FPN/IREG-1/MTP-1; gene symbol SLC40A1) was discovered simultaneously by 3 groups. [10][11][12] Since that time, numerous mutations in the gene have been implicated in patients from diverse ethnic origins with previously unexplained hemochromatosis. Iron overload disease because of a mutation in FPN is referred to as type IV hemochromatosis or ferroportin disease. 13 FPN is expressed on basolateral membranes of mature intestinal enterocytes and the basal membrane of the placental syncytiotrophoblast. [10][11][12] Another site of high expression of FPN is in macrophages, including Kupffer cells in the liver and in the red pulp of the spleen. 12,14 These sites of expression are consistent with a role for FPN in transport of iron from the gut to the serum, f...