Haemochromatosis is a common recessive disorder characterized by progressive iron overload, which may lead to severe clinical complications. Most patients are homozygous for the C282Y mutation in HFE on 6p (refs 1-5). A locus for juvenile haemochromatosis (HFE2) maps to 1q (ref. 7). Here we report a new locus (HFE3) on 7q22 and show that a homozygous nonsense mutation in the gene encoding transferrin receptor-2 (TFR2) is found in people with haemochromatosis that maps to HFE3.

The hepatic peptide hepcidin is the key regulator of iron metabolism in mammals. Recent evidence indicates that certain forms of hereditary hemochromatosis are caused by hepcidin deficiency. Juvenile hemochromatosis is associated with hepcidin or hemojuvelin mutations, and these patients have low or absent urinary hepcidin. Patients with C282Y HFE hemochromatosis also have inappropriately low hepcidin levels for the degree of iron loading. The relationship between the hemochromatosis due to transferrin receptor 2 (TFR2) mutations and hepcidin was unknown. We measured urinary hepcidin levels in 10 patients homozygous for TFR2 mutations, all with increased transferrin saturation. IntroductionThe hepatic peptide hepcidin is the central regulator of iron absorption in mammals. Evidence is accumulating that the pathophysiology of hemochromatosis, a genetic disorder characterized by deregulation of iron absorption, converges on hepcidin. Total hepcidin deficiency characterizes the severe iron overload of juvenile hemochromatosis, which rarely results from hepcidin-inactivating mutations 1 and more frequently from mutations of the HJV gene encoding hemojuvelin. [2][3] Patients with hemojuvelin-related hemochromatosis have low/undetectable urinary hepcidin levels, 2 suggesting that hemojuvelin protein is an important regulator of hepcidin expression. Hepcidin mRNA is also decreased or inappropriately low for the degree of iron overload both in Hfe-deficient or Hfe (845A/ 845A) (C282Y) mice 4 and in patients with HFE hemochromatosis, 5 implying that HFE is another modulator of hepcidin production in response to iron loading.A rare form of hemochromatosis is due to mutations of transferrin receptor 2 (TFR2), 6 a member of the transferrin receptor family with an unclear function in iron metabolism. TFR2 has a capability of binding and internalizing diferric transferrin. 7 However, cellular iron uptake might not be the function of TFR2 in vivo, because mutational disruption of TFR2, both in humans 7 and in animal models, 8 leads to liver iron accumulation and not to iron restriction. In addition, iron overload that follows TFR2 inactivation occurs early in life, 9 as in juvenile hemochromatosis, although TFR2-related disease runs a milder clinical course. Based on these observations, TFR2 could be another regulator of hepcidin, but its relationship with hepcidin in humans has so far remained speculative.To ascertain the involvement of TFR2 in the hepcidin pathway, we measured urinary hepcidin levels in 10 hemochromatosis patients carrying different TFR2 mutations. Our results show low/absent hepcidin in most patients, except for 2 who had concomitant inflammatory conditions. These results confirm the proposed role of TFR2 as a regulator of hepcidin production. Patients, materials, and methodsClinical data and molecular defects of the patients studied have been previously reported. 9-11 Controls were healthy adult subjects from the laboratory staff and their children. Informed consent was obtained from all subjects involved...

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