Introduction: hereditary disorders of iron metabolism.

IRON IS REQUIRED bymost organisms and is used for the synthesis of hemoproteins and proteins containing iron-sulfur clusters or di-iron groups. The ability of iron to readily alter its oxidation state is responsible for the biological activity of these proteins. Unicellular and multicellular organisms have evolved various methods for iron acquisition but the proteins mediating transmembrane iron transport have been remarkably conserved. Themovement and compartmentalization of intracellular iron must be tightly controlled, as the oxidation of ferrous iron has the potential to generate highly toxic oxygen radicals. Iron excess, either in the cytosol or in mitochondria, can lead to cell damage unless adequate measures are taken to sequester iron. This issue of Seminars in Hematology is focused on the genes that regulate iron metabolism and to inherited diseases caused by mutations in these genes. The introduction of microbial genetics led to the characterization of ferroreductases, ferroxidases, iron transporters, and iron regulatory proteins, which proved to have homologs and orthologs in mammals. Evolutionary aspects of regulated iron metabolism are reviewed by Kaplan. Characterization of both naturally occurring and induced mutations in multicellular organisms such as zebrafish and rodents led to an understanding of the function and interactions of genes controlling cellular iron uptake, transport and utilization. The use of animal models of genetically altered iron metabolism has been extremely productive and has led to new hypotheses about the regulation of iron metabolism, as reviewed by Andrews. Mutations in at least 15 human genes involved in iron metabolism have now been recognized as causative for hereditary diseases characterized by iron overload. The most common inherited iron overload disorder, hereditary hemochromatosis, is due to a mutation of the HFE gene. Homozygosity for the cysteine to tyrosine (C282Y) mutation of HFE leads to an increase in dietary iron absorption by the enterocyte and iron recycling by the macrophage but the molecular mechanism by which HFE regulates these processes has not yet been defined. One of the key clinical questions related to hereditary hemochromatosis concerns the proportion of homozygotes for the C282Y mutation that develop organ damage from iron overload. Estimates of the frequency of iron-induced organ damage vary greatly and the controversies that have been generated are reviewed by Ajioka and Kushner. The HFE gene imparts a minor downregulatory effect on intestinal iron absorption but the gene responsible for juvenile hemochromatosis exerts a much greater effect. Juvenile hemochromatosis represents a phenocopy of HLA-related hemochromatosis but the iron burden is far greater and the onset of organ damage occurs decades earlier. The gene responsible for juvenile hemochromatosis has been mapped to a region on chromosome 1 but the gene has not yet been isolated. Camaschella and colleagues review the clinical features of juvenile hemochromatosis and summarize the progress made towards isolation of the gene. A number of rare disorders due to mutations of