• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of bloodOriginal ArticleBlood JournalCurrent IssueAbout BloodSubmissionsSubscriptionsContact UsASH Homepage
Blood. Jul 15, 2008; 112(2): 219–230.
PMCID: PMC2442739
ASH 50th Anniversary Review

Forging a field: the golden age of iron biology


Oh what a difference a decade makes! In a landmark paper published in 1996, Feder and colleagues identified the long-sought gene mutated in patients with classical hereditary hemochromatosis. In many ways, this seemed to ignite an explosion in iron biology which, over the next 10 years, led to a remarkably detailed (though still incomplete) understanding of the pathophysiology of hemochromatosis. Many discoveries critical for understanding iron homeostasis, however, were kindled by earlier work dating back half a century and more. This review will emphasize advances made between the birth of the American Society of Hematology (ASH) in 1958 and the present. In the early part of that period, ferrokinetic studies provided important insights into human iron homeostasis in vivo (reviewed in Finch et al1). More recently, modern molecular biology and genetic studies of model organisms have extended our knowledge of normal iron biology and led to detailed understanding of human iron disorders. Ironically, a comprehensive review on iron metabolism appeared in Blood exactly 50 years ago, describing a current state of knowledge that was viewed as quite complete at the time.2 Adding to the irony, that author, Hugh Josephs (another pediatric hematologist), had 54 journal pages and I only have 12!

Cellular regulation of iron homeostasis

The earliest molecular studies of iron metabolism focused on 2 molecules that are both abundant and easy to isolate. In 1937, horse spleen ferritin was the second of all proteins to be crystallized.3 Transferrin was identified as an abundant plasma iron transport protein a decade later.4 Both of these molecules are now used clinically in assays of iron status. Both ferritin and transferrin sequester iron to keep it nonreactive, thus precluding the Fenton chemistry that promotes formation of oxygen radicals. But they do so in very different ways. Ferritin, which has homologs in all organisms except yeast, is a cagelike heteropolymer of 24 subunits of H- (heavy or heart) and L- (light or liver) types, which can hold up to 4500 iron atoms.5 As pointed out by Munro, it is unique among enzymes in that it stores its substrate after acting upon it.6 H-ferritin is slightly larger than L-ferritin, and has ferroxidase activity important for movement of iron into the solid-state core of the protein. Most ferritin is used to store within cells, but a very small amount enters a distinct secretory pathway, destined for glycosylation and release into the serum. Aside from its useful role as a semiquantitative indicator of iron stores, the biologic purpose of serum ferritin remains unknown. Ferritin receptors are present on lymphocytes and some other cell types, but their physiologic function has not been fully defined.7 Ferritin is also the precursor to hemosiderin, a heterogeneous aggregate of iron, lysosomal components, and other products of intracellular digestion.8

In contrast, transferrin is actively secreted by hepatocytes, the cells that express it most vigorously. Transferrin is also produced on the sanctuary sides of the blood/testes barrier, by Sertoli cells, and the blood/brain barrier, by several distinct cell types. It serves the general purpose of binding iron, keeping it soluble in an aqueous environment and delivering it to tissues. The mammalian transferrin molecule has 2 similar iron-binding lobes, each capable of holding one atom. Lower eukaryotes have transferrins analogous to 1 of the 2 mammalian lobes. It has been proposed that the double site transferrin molecule evolved at the same time that functional kidneys appeared, increasing the size of the protein to prevent loss by filtration.9

Transferrin keeps iron nonreactive in the circulation and in extravascular fluid, delivering it to cells bearing specific transferrin receptors. The classical transferrin receptor, TFR1, is found in largest amounts on rapidly dividing cells, on activated lymphocytes, and on erythroid precursors. It selectively binds diferric transferrin to internalize it through a constitutive pathway of receptor-mediated endocytosis (the transferrin cycle), which has become a paradigm in cell biology (Figure 1).

Figure 1
Overview of iron homeostasis. The central portion of the figure depicts the flow of iron into the body (through the small intestine), to transferrin (Tf), to the major site of utilization (the erythroid bone marrow), to circulating erythrocytes, to tissue ...

To initiate the transferrin cycle, patches of cell-surface membrane carrying receptor-ligand complexes invaginate to form clathrin-coated endosomes. After clathrin is removed the endosomes become acidified through proton influx, leading to conformational changes in both transferrin and TFR1, and promoting iron release. Liberated inorganic iron is then reduced by the ferrireductase STEAP3 to Fe2+,10 which is the substrate for transmembrane transport by divalent metal transporter 1 (DMT1 or SLC11A2, formerly called NRAMP2, DCT1).1113 Both STEAP3 and DMT1 were discovered through positional cloning of genes altered in rodents carrying spontaneous mutations impairing iron transport.10,11 The use of mutant animal models to identify key iron transport molecules has been remarkably productive, and a hallmark of work of the past decade (reviewed in Andrews14). This powerful strategy takes advantage of mutants discovered and maintained over the last century, analyzed using modern genetic techniques.

Gunshin13 and Hediger15 showed that DMT1 is electrogenic, requiring proton cotransport to move Fe2+ across the membrane. This need is met by the low pH milieu of the transferrin cycle endosome (internal pH approximately 5.5). The subsequent fate of iron that exits the transferrin cycle endosome is not well understood, but in erythroid cells most is needed for heme biosynthesis. To make heme, iron must again cross an ion-impermeable membrane to enter the mitochondrion. The mitochondrial iron importer was recently identified as mitoferrin (also known as SLC25A37), a transmembrane protein that plays a critical role in supplying iron to ferrochelatase for insertion into protoporphyrin IX. Mitoferrin was originally discovered in yeast (called MRS3/MRS416) and in a mutant zebrafish.17 Interestingly, mutations in mitoferrin result in a clinical disorder that is very similar to erythropoietic protoporphyria caused by ferrochelatase mutations.17

Although many tissues express TFR1 at low levels, relatively few cell types are strictly dependent on the transferrin cycle for iron uptake. Targeted disruption of the Tfr1 gene in mice demonstrated that most tissues develop normally without Tfr1, but erythroid precursors, early lymphoid cells, and neuroepithelial cells require Tfr1 for differentiation.18,19 The likely role of TFR1 in erythropoiesis is obvious—the transferrin cycle serves to concentrate iron in the vicinity of DMT1 to maximize iron assimilation for hemoglobin production. However, it is less clear why lymphopoiesis and neurodevelopment should require TFR1.

In the past it was assumed that iron assimilated by erythroid precursors was incorporated into hemoglobin, remaining within the cells until erythrocyte senescence. Recently, however, Quigley and colleagues20 have described a heme exporter, FLVCR, which appears to be necessary for normal erythroid development. They hypothesize that erythroblasts need to have a pop-off valve for extra heme to avoid its toxicity. Targeted disruption of the mouse gene encoding FLVCR demonstrated the importance of this protein in vivo.21 FLVCR-null mice had a failure of definitive erythropoiesis, resulting in fetal demise. Interestingly, the fetuses had craniofacial and limb deformities suggestive of Diamond-Blackfan anemia. When the FLVCR gene was inactivated after birth the animals developed severe, macrocytic anemia, implying that heme export is important for normal erythropoiesis.

Regulation of intracellular iron homeostasis

Intracellular iron homeostasis is maintained, at least in part, through a very elegant posttranscriptional regulatory mechanism. In 1987, investigators observed that conserved sequences in the 5′ untranslated regions (UTRs) of both H- and L-ferritin mRNAs were needed to control a ready but quiescent pool of ferritin mRNA in the cell, which could quickly be mobilized to produce ferritin protein when iron was abundant.22,23 Thermodynamic predictions indicated that the UTR sequences could form stable RNA hairpins with a characteristic secondary structure, termed iron responsive (or regulatory) elements (IREs).24 Soon afterward it was shown that cytoplasmic proteins, now known as iron regulatory proteins (IRPs, formerly IREBPs), recognize and bind to the IREs.2528

The 2 known IRPs share sequence homology but have distinctive properties. At the time of its discovery, IRP1 was recognized to bear strong similarity to aconitase, a mitochondrial enzyme of the tricarboxylic acid cycle. Remarkably, IRP1 also has aconitase activity, making it a prime candidate for a previously described cytoplasmic aconitase.29,30 But the aconitase and IRE-binding activities are mutually exclusive, providing a clue to a clever regulatory switch. Similar to a number of other iron-containing proteins, IRP1 incorporates an iron-sulfur cluster (4Fe•4S). The iron-sulfur cluster forms when iron is abundant, but disassembles when iron is scarce. Haile and Rouault showed that the aconitase activity of IRP1 is present only when the iron-sulfur cluster is complete; when it is not, IRP1 acts as an RNA binding protein, recognizing IREs.31 IRP2, on the other hand, does not incorporate an iron-sulfur cluster. Rather, its activity is regulated at the level of protein stability. Under low iron conditions IRP2 accumulates, but when iron is abundant it triggers IRP2 degradation.3236 It is still not entirely clear why it is necessary to have 2 IRPs, but recent observations suggest that the 2 may respond differently over the physiologically relevant range of oxygen tensions.37 They may also have somewhat different target selectivity among IRE-containing mRNAs.

The ferritin IRE is located just upstream of the start codon for protein translation. Muckenthaler and colleagues showed that IRP binding sterically blocks recruitment of the small ribosomal subunit to the initiation complex, thus preventing translation.38 As a result, ferritin protein production is abrogated under low iron circumstances when the small amount of intracellular iron is needed for cellular functions. On the other hand, when iron is abundant, translational repression is relieved and newly made ferritin subunits assemble to provide iron storage capacity.

The IRE/IRP regulatory system is also used to control expression of other proteins. The best studied is TFR1, which has multiple IREs in the 3′ UTR of its mRNA.39 In this case, IRP regulation operates in a very different fashion. Under low iron conditions, IRP binding has no direct effect on translation, but rather it protects the TFR1 mRNA from endonucleolytic cleavage and consequent degradation. When iron is abundant, nucleases attack A-U rich mRNA sequences adjacent to the IREs and destabilize TFR1 mRNA. Thus, more TFR1 can be produced when cells are in need of iron, but TFR1 expression is interrupted when cells are iron replete.

Other mRNAs encoding important proteins of iron metabolism have been shown to have 5′ IREs (eg, ferroportin, aminolevulinic acid synthase) or 3′ IREs (eg, DMT1), though their regulation by the IRE/IRP system has not been thoroughly studied.40

Perhaps surprisingly, targeted disruption of the IRP1 gene in mice produces no apparent phenotypic abnormalities.41 In contrast, targeted disruption of IRP2 leads to a disorder of iron homeostasis characterized by microcytic, hypochromic anemia,42,43 and, at least in one laboratory, a late onset neurodegenerative disorder.42,44,45 When genes encoding both proteins are inactivated, the compound mutant mice die early in embryonic development, establishing the overall importance of these proteins in vivo.

Spontaneous IRE mutations have been described in human patients and in mice.4648 Beaumont and colleagues48 showed that disruption of the L-ferritin IRE results in hyperferritinemia-cataract disease, with prominent ocular findings and elevated serum ferritin but no evidence of disturbed iron homeostasis. Disruption of the H-ferritin IRE in one Japanese family was associated with a familial iron overload disorder.49 Interestingly, a mutation that prevents formation of the mouse ferroportin IRE causes an unusual and complex disorder of iron homeostasis, underscoring the significance of this IRE in vivo.50

Intestinal iron absorption

In nontransfused individuals, iron enters the body exclusively through the diet. Because there is no regulated excretion of iron through the liver or kidneys, iron balance is primarily controlled at the level of intestinal absorption. Elegant ferrokinetic studies carried out in the middle of the last century gave important physiologic insights into human iron absorption and distribution51 but a molecular understanding of iron absorption came decades later (and is still not complete). When we and others began efforts to find intestinal iron transporters in the mid-1990s the available clues were not particularly helpful: (1) the transferrin cycle was known to have no direct role in intestinal iron absorption, (2) mammalian iron transport appeared to be mechanistically distinct from that of bacteria and single-celled eukaryotes, and (3) ATPase copper transporters, discovered several years earlier, showed no affinity for iron. Protein purification had been attempted for decades without success. In spite of these obstacles and entirely by chance, the first mammalian transmembrane iron transporter was discovered simultaneously in 2 laboratories, located within a city block of each other in Boston, using singularly modern techniques.12,13 Ours was one of those labs, and this marked our entrée into the field of iron biology. Our approach was to take advantage of well-characterized mouse strains that carried spontaneous mutations perturbing iron homeostasis. At the time, 6 strains had been identified; all are now understood in molecular detail.14 One in particular, microcytic anemia (mk), had been carefully studied and shown to have a defect in intestinal iron absorption.52

Iron absorption takes place in the proximal portion of the duodenum (Figure 1), where polarized cells are arranged in fingerlike villi that protrude into the intestinal lumen to maximize absorptive surface area. Each individual absorptive cell, or enterocyte, has a microvillous brush border at the apical (luminal) surface. Most dietary nonheme iron is in the ferric (Fe3+) form. It must be reduced to ferrous (Fe2+) iron, either chemically or through the action of a brush border ferrireductase such as duodenal cytochrome B (CYBRD1, also known as DCYTB), a cytochrome B561 homolog that may use ascorbic acid as a cofactor.53 CYBRD1 was one of 2 iron transport–related molecules discovered by McKie through a very productive RNA subtraction approach.53,54 Surprisingly, although Cybrd1 expression is markedly induced in iron-deficient animals, targeted disruption of the murine Cybrd1 gene was not associated with any apparent phenotype in mice fed standard chow.55 Members of the STEAP ferrireductase family are also expressed in the intestine.56 While they are good candidates for enzymatic ferrireductases at the brush border, the roles of CYBRD1 and STEAPs in intestinal iron absorption remain uncertain.

Fe2+ iron enters absorptive enterocytes through DMT1, the same iron transporter used for endosomal transfer in the transferrin cycle. The intestinal form of DMT1 is produced from a different mRNA splice isoform, resulting in an alternate C-terminus of the protein.57,58 Intestinal DMT1 is primarily localized to the apical membrane and to subapical endosomes.59 Protons necessary for metal cotransport are provided by gastric acid flowing into the proximal portion of the duodenum where DMT1 is most highly expressed and likely most active. The requirement for proton cotransport explains why treatment with antacids or H2 histamine blockers interferes with iron absorption. DMT1 expression is dramatically induced in iron deficiency,13 and possibly regulated at a posttranscriptional level by a 3′ IRE present in the splice isoform expressed in intestine.57 DMT1 may also serve as a physiologically significant portal of entry for other divalent metal cations including Mn2+, Co2+, Zn2+, Cu2+, and Pb2+, though its importance has only been definitively established for Fe2+ in vivo.13

The sole mammalian homolog of DMT1, designated NRAMP1 for natural resistance associated macrophage protein 1, was identified by Vidal et al through positional cloning of a mouse locus involved in host defense against intracellular pathogens in mouse macrophages.60 NRAMP1 is expressed in phagosomes of professional phagocytes.61 After DMT1 was shown to serve as a transmembrane metal transporter, functional studies indicated that NRAMP1 had similar activity.62 It has bacteriostatic but not bacteriocidal activity, presumably because it acts to deplete metals from the phagosomes in which microorganisms replicate, thus depriving them of iron and/or manganese. Homologous proteins in yeast,63 flies,64 and zebrafish65 also transport iron and similar divalent cations.

Targeted disruption of the murine gene encoding DMT1 confirmed that DMT1 is the primary transmembrane iron transporter bringing dietary nonheme iron into intestinal epithelial cells and mediating iron uptake through the transferrin cycle in erythroid precursors.66 Surprisingly, however, most other cell types do not appear to require DMT1 for iron uptake. This suggests that other transmembrane iron importers exist. Studies of non–transferrin bound iron uptake by cultured cells support this conclusion.6772 However, aside from L-type calcium channels, which have some iron carrying capability,73 no compelling candidates have been identified that transport iron atoms directly into cells. There is a siderophore-like iron uptake pathway mediated by lipocalin-2 (also called NGAL, 24p3) but its physiologic role is not fully worked out.7476

Once inside the intestinal epithelial cell, iron has at least 2 possible fates. A portion remains in the cell for use or storage. This iron is never absorbed into the body; rather, it is lost when enterocytes senesce and are sloughed into the gut lumen. Only iron exported across the basolateral membrane of the enterocyte is absorbed. The basolateral iron transporter, discovered simultaneously by 3 labs, is ferroportin (also called IREG1, MTP1, SLC39A1, and now SLC40A1).54,77,78 Ferroportin is resident on the basolateral membrane, and also found in macrophages involved in recycling iron from the hemoglobin of effete erythrocytes (Figure 1). Targeted disruption of the murine ferroportin gene demonstrated its importance in both sites.79

Although functional studies are incomplete, ferroportin likely transports ferrous ion. Transport is facilitated by multicopper ferroxidases including the abundant serum protein ceruloplasmin and its membrane-bound intestinal homolog hephaestin.8083 Until recently, the ferroxidases were thought to be important simply for oxidizing Fe2+ to load it onto transferrin. However, De Domenico and colleagues have recently shown that ceruloplasmin is required to maintain cell-surface localization of ferroportin.84 This situation is somewhat analogous to iron transport in yeast, where the ferrous iron permease FTR1 (functionally analogous but structurally unrelated to DMT1) requires the multicopper ferroxidase FET3 for correct localization on the cell surface.85,86

Intestinal absorption of nonheme iron is now understood in some detail, but the absorption of heme iron, primarily derived from meats, remains poorly understood. A description of a putative heme importer in 200587 later proved to be incorrect.88 While heme exporter proteins have been described,20,89 it seems likely that most iron dietary heme iron is liberated from protoporphyrin by heme oxygenase to enter a common pathway with dietary nonheme iron before it leaves the absorptive epithelium.

Regulation of iron homeostasis by hepcidin

Although its handling is frequently termed iron “metabolism,” iron itself is not metabolized in a classical sense. Accordingly, human iron disorders are invariably disorders of iron balance or iron distribution. Iron deficiency anemia, hemochromatosis, and the anemia of chronic disease (also known as the anemia of inflammation) are all common examples of this principle, as will be discussed later. Hence, understanding iron homeostasis is critical for understanding these disorders. Conversely, understanding genetic iron disorders (Table 1) has provided important insights into iron homeostasis.

Table 1
Genes involved in inherited human iron disorders

Systemic iron homeostasis involves meticulous control of intestinal iron absorption, effective utilization of iron for erythropoiesis, efficient recycling of iron from effete erythrocytes, and controlled storage of iron by hepatocytes and macrophages (Figure 1). Erythroid iron utilization is primarily determined by the efficiency of transferrin cycle assimilation of serum iron. In contrast, intestinal absorption, iron recycling, and iron storage are controlled systemically and coordinately. In this context, we now know that hepcidin, a peptide hormone produced in the liver, has primary responsibility for modulating iron availability to meet iron needs.

Discovered independently by 3 laboratories and first reported in 2000 and 2001, hepcidin is a 25-amino-acid protein produced by processing of a larger precursor.9092 Although it bears resemblance to defensin peptides involved in innate immunity, its primary function appears to be regulation of iron homeostasis through a mechanism that was elegantly elucidated by Kaplan, Nemeth, Ganz, De Domenico, and their coworkers. Hepcidin binds to cell-surface ferroportin, triggering its tyrosine phosphorylation, internalization, and ubiquitin-mediated degradation in lysosomes.93,94 By removing ferroportin from the plasma membrane, hepcidin shuts off cellular iron export. This is particularly important in the intestine, where inactivation of basolateral ferroportin leads to retention of iron in the intestinal epithelium, and in iron-recycling macrophages of the reticuloendothelial system, where inactivation of ferroportin interrupts release of iron recovered from senescent red cells (Figure 2A). Both events have the same consequence—decreased serum iron. Interestingly, the importance of controlling basolateral transfer to effect regulation of intestinal iron absorption was initially postulated by Crosby and Conrad more than 40 years before the mechanism was elucidated.95

Figure 2
Hepcidin and hemochromatosis. (A) The activity of hepcidin is depicted, showing ferroportin as a target both on enterocytes and macrophages. Hepcidin binds to ferroportin triggering its internalization and lysosomal degradation. (B) Three classes of hemochromatosis ...

Hepcidin is primarily made in hepatocytes, and secreted into the circulation. The liver acts as a clearinghouse for a variety of signals affecting iron homeostasis. Because of its small size, hepcidin is probably filtered by the kidneys on the first pass. It has been detected and quantitated in urine samples,91,96 and, with more difficulty, in serum.97 Its rapid excretion implies that most regulation of serum hepcidin levels occurs at the level of production. Proteolytic processing of the prohormone is carried out by furin in a relatively unregulated manner.98 In contrast, hepcidin transcription is tightly regulated over a very wide dynamic range.

Initially, murine hepcidin mRNA was shown to be elevated in response to iron overload92 and decreased in response to iron deficiency.99,100 The functional effects of altered hepcidin expression in vivo were apparent when Nicolas, Lesbordes-Brion, and colleagues showed that inactivation of the hepcidin gene in mice was associated with severe iron overload.101,102 Conversely, transgenic overexpression of hepcidin resulted in iron deficiency.103,104 In addition, the amount of hepcidin mRNA in liver cells is decreased in response to hypoxia and ineffective erythropoiesis (overlapping with the response to iron deficiency)99,105 and induced in response to treatment with lipopolysaccharide or by inflammation of other etiologies.92,99 These responses all make sense: when erythropoiesis needs to accelerate, interruption of hepcidin expression results in increased iron availability. In contrast, induction of hepcidin in inflammation and consequent iron sequestration augments innate immune defenses against invading pathogens.106

Current information about the hepcidin promoter indicates that it is relatively compact, as it must be to avoid encroaching on a closely neighboring gene encoding USF2. The most proximal region is highly conserved across mammalian species.107 A consensus STAT3 binding site has been shown to mediate the induction of hepcidin in inflammation, through a signaling pathway triggered by interleukin-6.107,108 The von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) system also appears to control hepcidin expression, with HIF1α acting as a repressor when it binds to the hepcidin promoter.109 Potential binding sites for C/EBPα, USF2, HNF4α, p53 and other widely expressed transcription factors have also been identified in the hepcidin promoter, but it is not yet clear what roles, if any, they have in regulation of hepcidin expression in vivo.110112

Signaling through the bone morphogenetic protein (BMP)/SMAD pathway is the most powerful mechanism known to activate hepcidin transcription. This surprising connection between BMPs and hepcidin was initially discovered through 2 independent avenues of research. In the course of their general studies of cellular signaling, Wang and colleagues inactivated the gene encoding an essential SMAD protein, SMAD4, exclusively in hepatocytes.113 To their surprise, the dominant phenotype that resulted was severe hemochromatosis, similar to that seen in mice lacking hepcidin. In parallel, Babitt and colleagues studied hemojuvelin, a protein mutated in patients with severe, early onset “juvenile hemochromatosis.”114 They showed that hemojuvelin acts as a BMP coreceptor to stimulate hepcidin transcription. Both groups demonstrated that treatment of hepatic cells with BMPs stimulated hepcidin expression, in a manner dependent on the presence of SMAD4,113 BMPs, and hemojuvelin.114

It seems likely that activated SMADs bind directly to the hepcidin promoter in response to BMP signaling. However, in contrast to some other transcription factors, consensus sites for SMAD binding are highly variable and difficult to predict by sequence analysis alone. Truksa et al have localized putative BMP-responsive elements in the hepcidin promoter,115 but it is still uncertain exactly how BMP transcriptional regulation occurs. Nonetheless, BMP treatment is a potent stimulus for hepcidin expression both in cultured cells113,114,116,117 and in animals.117


Our understanding of hepcidin regulation has been greatly enhanced through efforts to understand hemochromatosis, a genetic iron overload disorder. Described as “bronze diabetes” by Trousseau in 1865,118 hemochromatosis was not known to be an iron disorder until well into the 20th century.119 It was one of the first genetic diseases to be linked to a discrete chromosomal position, through the groundbreaking work of Simon, an astute French physician-scientist who found that hemochromatosis patients were disproportionately likely to have particular HLA haplotypes.120 Two decades later that insight led to the identification of HFE (originally called HLA-H), the gene mutated in the large majority of patients with hemochromatosis.121 The positional cloning of HFE by a now-defunct biotechnology company was a tour de force, and one of the landmark accomplishments of the middle years of the human genome project.

As is often the case, however, the situation is more complex than originally appreciated. We now know that HFE is one of several genes that can be mutated in hemochromatosis. Furthermore, penetrance of HFE hemochromatosis is incomplete, and only a fraction of affected patients have clinical disease, presumably due to both genetic and environmental modifiers.122 Several modifier gene candidates have been explored and, in some cases, verified.123135 Not surprisingly, heterozygous mutations in other hemochromatosis-associated genes can exacerbate the clinical course for patients who are also homozygous for HFE mutations.

Like hemojuvelin, both HFE and transferrin receptor-2 (TFR2, another hemochromatosis-associated protein) are inferred to be involved in regulation of hepcidin expression. Human patients with mutations in the genes encoding hemojuvelin, HFE, or TFR2 have inappropriately low urinary hepcidin levels for their overall body iron status.136139 As a consequence, intestinal iron absorption and macrophage iron release are not properly controlled, leading to iron overload, increased serum iron, and iron deposition in the liver, heart, and endocrine tissues. Similarly, mouse models of hemochromatosis developed through targeted disruption of any of these 3 genes have diminished hepcidin mRNA in their livers.140144 While this is strong evidence that all 3 proteins are involved in hepcidin regulation, the roles of HFE and TFR2 are not as well understood as that of hemojuvelin.

HFE is an atypical major histocompatibility class I–like molecule that forms a heterodimer with β2-microglobulin but is incapable of binding a small peptide.145 Soon after its discovery, HFE was shown to interact with TFR1 to form a protein-protein complex.145147 Initially, its role in iron homeostasis was thought to involve perturbation of the transferrin cycle, either in hepatocytes or in intestinal epithelial cells (reviewed in Roy and Enns148). However, more recent results suggest a different scenario: that TFR1 regulates HFE activity and inhibits HFE by sequestering it.149 Because TF and HFE compete for binding to TFR1, displacement of HFE from TFR1 by TF may be a means to activate HFE to signal through an as-yet-unknown mechanism to increase hepcidin transcription.

TFR2 probably fits into this scenario in some intimate way. Mutations in TFR2 are much less common than mutations in HFE, but the clinical disease can be indistinguishable.133 Like TFR1, TFR2 interacts with HFE to form a stable protein complex.150 However, as shown by Chen and Enns, HFE does not bind to homologous portions of TFR1 and TFR2.151 Although TFR2 is 43% homologous to TFR1 in its extracellular domain, it does not take up diferric-TF efficiently.152 Rather, its primary function seems to be to interpret body iron status. Amounts of TFR2 protein increase in response to iron-saturated transferrin.151,153155 Taking this into account, we have proposed a model in which TFR2 escorts HFE away from TFR1 when the serum iron level (reflected in the transferrin saturation) is elevated.149,150 The implication of this model is that HFE and TFR2 collaborate in a signaling complex that acts to augment hepcidin expression. These proteins may be part of a larger BMP signaling complex along with hemojuvelin (P.J. Schmidt, F.W. Huang, and N.C.A., unpublished results).

Hemochromatosis can also result from mutations in the gene encoding ferroportin, the target of hepcidin activity. The first mutations in ferroportin were discovered simultaneously by Montosi et al156 and Njajou et al157 in families with iron overload segregating in an autosomal dominant pattern. Many other mutations have been reported subsequently. Initially there was disagreement about the clinical presentation: some patients seemed to have macrophage-predominant iron loading and occasional anemia, while others had clinical features indistinguishable from HFE hemochromatosis. Strikingly, all ferroportin mutations caused missense changes, rather than truncations or frameshifts. Furthermore, knockout mice heterozygous for a null ferroportin allele had no significant iron phenotype, and did not seem to model the human disease.79

These issues were resolved by the discovery that there are 2 broad categories of ferroportin mutations.158,159 Missense mutations that affected the subcellular localization or transporter function of ferroportin (“loss-of-function”) were associated with macrophage iron loading but few, if any, sequelae resembling classical hemochromatosis. In contrast, missense mutations that rendered ferroportin insensitive to regulation by hepcidin (“gain-of-function”) caused hemochromatosis. The fact that both types of mutations have autosomal dominant patterns of clinical expression can be reconciled by the conclusion that ferroportin polypeptides assemble into homo-multimers.158 Recently, a mouse model of the disease associated with loss-of-function ferroportin mutations, flatiron, was identified through a positional cloning effort.160

There are not many precedents for inactivating and activating mutations in one gene causing 2 different diseases. Accordingly, there is no consensus yet on nomenclature for these disorders. It has been suggested that the condition associated with loss-of-function mutations should be called “ferroportin disease” and the condition associated with gain-of-function mutations should be called type IV hemochromatosis. The classification scheme is blurred, however, by the fact that some mutations appear to have features of both types.

Thus, based on our current understanding, the molecular pathogenesis of hemochromatosis can be divided into 3 classes (Figure 2B). First, mutations in the hepcidin gene itself (called HAMP) cause hemochromatosis by preventing the production of functional hepcidin protein.161 Second, mutations in the genes encoding HFE (HFE), TFR2 (TFR2), and hemojuvelin (HFE2) inactivate signaling pathways that normally up-regulate hepcidin expression. Finally, mutations in the gene encoding ferroportin (SLC40A1) can cause hemochromatosis by rendering the transporter insensitive to hepcidin regulation.158,162

Iron deficiency anemia

Iron deficiency anemia continues to be a major public health problem worldwide, with an estimated 3 billion people affected. Arguably, the first thorough descriptions of iron deficiency and its treatment involved chlorosis, a perplexing condition due at least in large part to iron deficiency anemia that was diagnosed between the Middle Ages and the end of the Victorian era in the 1920s. It is remarkable to think that some of the founders of ASH may have seen patients with this disorder. Sydenham, in 1681, recognized that chlorosis could be cured by “the effects of steel.”163 Ferrous sulfate pills, still a mainstay for treatment of iron deficiency, have been in use for nearly 2 centuries.164 The efficacy of iron treatment was formally established in a classic experiment carried out by Castle. He proved that the active substance was iron when he administered parenteral iron and showed a proportionate rise in hemoglobin in patients with hypochromic anemia.165

The vast majority of cases of iron deficiency are acquired, resulting from blood loss (eg, from intestinal parasitosis), from insufficient dietary iron intake, or both. Young children and menstruating women are disproportionately affected because their iron status is marginal to begin with. Recently it was rediscovered that infection with H pylori, even in the absence of significant bleeding, can lead to profound iron deficiency anemia that is poorly responsive to oral iron therapy. This disorder is typically seen in young women, is associated with gastric atrophy, and can be associated with other autoimmune phenomena.166,167 As pointed out by Hershko and colleagues,168 this constellation of findings was reported a century ago by Faber169 and further described by Wintrobe and Beebe.170 Eradication of H pylori infection can lead to correction of the anemia.167

It is now recognized that rare genetic defects can also cause iron deficiency anemia. Mutations in the genes encoding DMT1 (SLC11A2) and glutaredoxin 5 (GLRX5) are associated with autosomal recessive hypochromic, microcytic anemia.171,172 Interestingly, the clinical phenotype of patients with DMT1 mutations differs slightly from the corresponding mouse model, mk.12 The human patients have similar blood films and erythrocyte abnormalities, but also have hepatic iron overload that is not fully explained by their transfusion histories.172176 Perhaps less surprising, the clinical phenotype of a unique patient carrying a GLRX5 mutation also differs somewhat from an earlier animal model with a deletion of that gene, the shiraz zebrafish.177

Two forms of genetic iron deficiency anemia are associated with iron overload outside of the erythron. Deficiency of serum transferrin, due to mutations in the TF gene itself,178,179 interrupts iron delivery to erythroid precursors, triggering a massive but futile increase in intestinal iron absorption and consequent tissue iron deposition. This disorder, hypotransferrinemia (also called atransferrinemia), has been observed in both human patients and in mice.180183 Through a different mechanism, deficiency of another major plasma protein, cerulopasmin, also causes mild iron deficiency anemia associated with iron accumulation in the liver and brain.184 As reported by Harris and colleagues,184 iron deficiency results from lack of ferroxidase activity needed to mobilize iron from storage. Although both of these disorders are rare, each can be confused with hemochromatosis if the entire clinical picture is not taken into account.

We and others have observed that some patients have congenital, iron-refractory, iron-deficiency anemia (IRIDA) that cannot be explained by mutations in the genes encoding DMT1, GLRX5, TF, or ceruloplasmin.185190 These individuals appear to have a defect in cellular iron export,191 but the disorder has an autosomal recessive pattern of inheritance and no mutations have been detected in ferroportin or in the regulatory regions of the hepcidin gene.190 An important clue to the etiology of IRIDA came recently when Ernest Beutler and his son Bruce identified Tmprss6, encoding matriptase-2, as the gene mutated in a novel mouse mutant, Mask.192

In addition to a bizarre hair pattern that led to the strain name, Mask mice have severe iron deficiency anemia attributable to elevated hepcidin expression. Matriptase-2 is a type II transmembrane serine protease of unknown function, which is expressed at high levels in the liver. The mechanism through which matriptase-2 regulates hepcidin expression has not yet been determined. We asked whether mutations in the human ortholog, TMPRSS6, might cause IRIDA. We had been collecting DNA samples from IRIDA patients since I first saw a young boy with this disorder in 1996. Every patient who fit our strict criteria for IRIDA carried inactivating mutations in TMPRSS6 that could explain the disease.190,192 Further studies will be needed to determine the prevalence of this rare disorder, and to evaluate the possibility that less severe mutations increase susceptibility to common, acquired iron deficiency anemia.

Anemia of chronic disease

The anemia of chronic disease (also called anemia of inflammation) is an acquired disorder of iron homeostasis (reviewed in Roy and Andrews193). A common explanation for anemia in chronically ill patients, anemia of chronic disease was largely a diagnosis of exclusion in the past. Elegantly described by Cartwright in a classic review,194 this condition may be associated with infection, malignancy, organ failure, trauma, or other causes of inflammation. The anemia is typically mild to moderate, and erythrocytes may not show any stigmata of iron deficiency. But the underlying iron etiology is evident: macrophages that normally recycle iron are found to sequester it, intestinal iron absorption is interrupted, and erythroid precursors respond very rapidly when iron-transferrin is made available. An association with proinflammatory cytokines has been suspected for some time,195 but was not well understood until recently.

Studying an unusual group of patients, we developed an hypothesis to explain the anemia of chronic disease, which has subsequently been validated by others.196 Treated survivors of glycogen storage disease type 1a frequently develop benign hepatic adenomas in early adulthood. With Weinstein, Roy, and colleagues, we observed that these patients also develop anemia resembling the anemia of chronic disease, the severity of which correlates directly with the extent of tumor burden.100 We found that the hepatocyte-like cells of the adenomas expressed very high levels of hepcidin100 and speculated that our results could be generalized—that induction of hepcidin expression in response to inflammation might explain the anemia of chronic disease. Subsequent studies by Nemeth and colleagues96,197 strongly supported our hypothesis, and it is now widely accepted.

In a sense, anemia of chronic disease is the phenotypic opposite of hemochromatosis. Expression of hepcidin that is inappropriately high for body iron status results in interruption of intestinal iron absorption and iron recycling. Consequently, decreased serum iron is available for erythropoiesis. Accordingly, Roy and colleagues have developed a transgenic mouse model expressing hepcidin, which shows that most consistent features of the anemia of chronic disease can be attributed to increased hepcidin expression.104 Our recent discovery that IRIDA is also caused by inappropriately high hepcidin expression suggests that IRIDA and the anemia of chronic disease should have common clinical features. While this is true in some regards, one striking difference is that IRIDA is associated with severe microcytosis, whereas the anemia of chronic disease is typically normocytic. Mice expressing a hepcidin transgene are microcytic, similar to IRIDA.104 I speculate that the normocytic erythrocytes in the anemia of chronic disease result from the combination of iron insufficiency and an as-yet-unexplained tendency to macrocytosis. For example, it is plausible that folate homeostasis is also perturbed in response to inflammation.

Conclusions and future directions

Iron biology is a vast field and, necessarily, there are important areas that I have neglected in this review. These include mitochondrial iron metabolism, heme metabolism, brain iron accumulation in neurodegenerative disorders, Fe•S cluster formation, therapeutic chelation, classical ferrokinetics, microbial iron metabolism, and others. Focusing on physiology more than biochemistry, I have not given due attention to recent structural characterizations of TFR1, HFE, or IRP1 alone and in interactions with the molecules they bind to.145,198200 My choice of topics should not be viewed as a judgment of what is most important; rather, it simply reflects my areas of expertise and a focus on diseases that have only recently become understood. Looking ahead, it is fun to speculate on what we will learn in the next round of discoveries in iron biology. In my opinion, any wish list has to focus on the iron disorders that affect our patients—in the final analysis, they are why most of us have chosen to work in this area.

First, I think there will be a new surge of interest in iron deficiency. We are in an unprecedented position to understand the genome/environment interactions that make some people particularly susceptible to iron deficiency. Among these interactions, we should soon understand why infection with H pylori causes profound iron deficiency that cannot be explained by blood loss or failed iron absorption. We will understand the “erythroid regulator” that communicates body iron needs to liver hepatocytes producing hepcidin, allowing for mobilization of all available iron when erythropoiesis accelerates. New understanding of iron biology may have therapeutic benefits as well. Perhaps it will lead to novel methods for oral iron repletion, allowing it to be accomplished in days, rather than months. If this becomes possible, it will have enormous implications around the globe. Finally, pica, an enigmatic but almost pathognomonic symptom of severe iron deficiency, may provide clues to help us understand the intricate links between nutrition and behavior.

Second, we still have more to learn about primary iron overload disorders. Mutations in the 5 genes currently associated with hemochromatosis probably do not account for all patients with the disease. There is likely to be at least one additional gene yet to be identified. Even when the list is complete, we will need a better understanding of genetic modifiers to fully understand why clinical presentations vary dramatically. Knowledge of the full genetic landscape of hemochromatosis may lead to new approaches to replace blood-letting (phlebotomy), a treatment that was introduced almost a decade before ASH was founded. Because phlebotomy is cheap, easy, safe, and effective, it will be difficult to supplant. But considering how responsive hepcidin expression is to a variety of stimuli, it is quite possible that a safe and effective drug currently used for a different purpose might turn out to have unexpected hepcidin-inducing activity, solving the problem. Finally, although we have made great strides in understanding hemochromatosis in individuals of European descent, we remain largely ignorant of the causes and manifestations of iron overload in individuals of African descent, in spite of the apparent prevalence of the condition in that population.201210

Transfusional iron overload is relatively well understood. In my opinion, the goal in coming years should be to use biology, rather than chemistry, to treat it. By that I mean that detailed knowledge of iron homeostasis will suggest new therapeutic opportunities to deliberately remove iron from the body, even though there is no natural excretion pathway through the liver or kidneys. Deliberate manipulation of iron loss through the gut epithelium or through the kidneys are 2 possible approaches.

Our understanding of the anemia of chronic disease has progressed enormously over the past few years. As we refine our understanding of hepcidin-related manifestations and other manifestations, it should become possible to stratify this disorder according to causes and effects. Undoubtedly there will be new treatment strategies based on our understanding of the biology of the anemia of chronic disease. It is quite likely that this understanding will also lead to a better appreciation of the molecular pathology of the anemia of aging.

A better understanding of iron homeostasis may also enhance treatments for other disorders. We still have much to learn about iron homeostasis in solid tumors, and about possible roles for lipocalin-2 and its receptor76 in malignant transformation. Iron deposition is a hallmark of many neurodegenerative disorders,211 and manipulating iron distribution in the central nervous system may become an important therapeutic approach. Similarly, iron-depleting strategies may someday be used to alter innate immunity and to enhance host defense against invading pathogens. I would venture that a better understanding of iron biology will reap benefits for virtually every field of medicine, keeping our students and fellows busy for decades to come.


I would like to thank colleagues in the field of iron biology who generously welcomed me into their world 12 years ago, and in particular Mark Fleming, a long-term collaborator who gave me a strong push to get into it. I feel quite privileged to work in a field that has benefited so much from the diversity of its investigators: iron biology is a truly international pursuit that has developed from the efforts of scientists in Europe, Australia, Asia, Africa, and the Americas; fruitful approaches have ranged from traditional biochemistry to modern mouse genetics to clinical measurements and everything in between. Like me, many others have stumbled into iron biology, often proclaiming that they will just do a bit of work and then return to their home field, but almost always deciding to stay. Their fresh perspectives have made the field even more exciting, and more welcoming to young scientists. Finally, I have had far more than my share of luck in working with outstanding students, postdoctoral fellows, and technicians in my own laboratory. I owe them a great deal for having made this journey so rewarding and so much fun.

The work in my laboratory is currently supported by National Institutes of Health R01 grants HL051057, DK066373, and DK053813, as well as a grant from the Roche Foundation for Anemia Research.



figure zh80100819790003

Nancy C. Andrews My first exposure to hematology was “Hemo the Magnificent,” a 1957 education film from Bell Science that made blood come alive (literally). Hemo was half red and half blue. My earliest hematology experiments, in high school, were with blue blood. I was fascinated by the fact that the hemocyanin-containing blood of the horseshoe crab coagulates when exposed to tiny amounts of endotoxin. I convinced some friends to drive an old VW bus from Syracuse to Cape Cod to collect the creatures. I returned with 30 horseshoe crabs, which I kept in saltwater tanks in my bedroom. A biology professor at Syracuse University allowed me to work in her lab to try to figure out why the crab blood clotted. Several days a week I walked to the university after school, carrying my research subject in a plastic bucket. I got scooped on the project, but did learn some basic lab techniques that have stuck with me 35 years later.

I went to Yale College hoping to become a scientist. I was lucky to meet Joan Steitz, then a young professor at the forefront of the emerging field of molecular biology. Her lab was a bold and exciting place. There I witnessed the discovery of snurps—ribonucleoprotein particles that are now known to play several fundamental roles in cell biology. Snurps were revealed using sera from patients with autoimmune disorders to immunoprecipitate autoantigens from cell lysates. It was a very clever approach, and it taught me how major advances could come from looking at human disease (and blood) in a novel way—a lesson that has served me well.

I probably would not have gone to medical school if it weren't for the MD-PhD students who orbited around Joan's lab. I ended up in the MD-PhD program at Harvard and did my PhD thesis work with Nobel laureate David Baltimore at MIT. Hematology and cancer were big at MIT at that time. Both Sam Lux and David Nathan passed through on mini-sabbaticals, working with Harvey Lodish, David Housman, and others. Once again I was in the right place at the right time; the MIT Biology Department was a remarkable incubator for scientific talent in the early 1980s. An astounding number of future scientific leaders spent time there as students, postdocs, or visiting scientists. I was in the Baltimore lab when the Whitehead Institute was born, with David as its founding director. It was fun to watch, and it probably inspired my own foray into administration 2 decades later.

I formally entered hematology in 1989 as a fellow at Children's Hospital Boston and Dana-Farber Cancer Institute. I was interested in red cells and chose Stuart Orkin's lab for my fellowship research. There I took advantage of my previous biochemistry experience (dating back to the horseshoe crab days) to purify and clone a hematopoietic-specific transcription factor, NF-E2. It was a huge job, requiring thousands of liters of cultured cells to get enough material, but it worked in the end.

I might have continued working on NF-E2 if it weren't for several circumstances that lured me into iron biology. Most important among these were meeting Mark Fleming, then a Harvard medical student, and becoming an investigator of the Howard Hughes Medical Institute. Mark, now a long-time collaborator, convinced me to share his curiosity about the pathophysiology of hemochromatosis. HHMI provided the unrestricted funding I needed to move into a completely new area of science.

Although I have less time for the lab now than I once did, I still love science. I've been fortunate to have helped make a few important discoveries over the years. But even more satisfying, I've had a part in teaching, advising, and mentoring an amazing group of students, postdocs, and technicians. It is great fun to watch them develop their own careers and follow their own imaginations.


Contribution: N.C.A. wrote the paper.

Conflict-of-interest disclosure: The author declares no competing financial interests.

Correspondence: Nancy C. Andrews, Duke University School of Medicine, DUMC 2927, Durham, NC 27710; e-mail: ude.ekud@swerdna.ycnan.


1. Finch CA, Harker LA, Cook JD. Kinetics of the formed elements of human blood. Blood. 1977;50:699–707. [PubMed]
2. Josephs HW. Absorption of iron as a problem in human physiology; a critical review. Blood. 1958;13:1–54. [PubMed]
3. Laufberger V. Sur la cristallisation de la ferritine. Soc Chim Biol. 1937;19:1575–1582.
4. Schade AL, Caroline L. An iron-binding component in human blood plasma. Science. 1946;104:340–341. [PubMed]
5. Harrison PM, Fischbach FA, Hoy TG, Haggis GH. Ferric oxyhydroxide core of ferritin. Nature. 1967;216:1188–1190. [PubMed]
6. Munro HN. Back to basics: an evolutionary odyssey with reflections on the nutrition research of tomorrow. Annu Rev Nutr. 1986;6:1–12. [PubMed]
7. Chen TT, Li L, Chung DH, et al. TIM-2 is expressed on B cells and in liver and kidney and is a receptor for H-ferritin endocytosis. J Exp Med. 2005;202:955–965. [PMC free article] [PubMed]
8. Wixom RL, Prutkin L, Munro HN. Hemosiderin: nature, formation and significance. Int Rev Exp Pathol. 1980;22:193. [PubMed]
9. Martin AW, Huebers E, Huebers H, Webb J, Finch CA. A mono-sited transferrin from a representative deuterostome: the ascidian Pyura stolonifera (subphylum Urochordata). Blood. 1984;64:1047–1052. [PubMed]
10. Ohgami RS, Campagna DR, Greer EL, et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat Genet. 2005;37:1264–1269. [PMC free article] [PubMed]
11. Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC. Nramp2 is mutated in the anemic Belgrade 11. (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci U S A. 1998;95:1148–1153. [PMC free article] [PubMed]
12. Fleming MD, Trenor CC, 3rd, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16:383–386. [PubMed]
13. Gunshin H, Mackenzie B, Berger UV, et al. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388:482–488. [PubMed]
14. Andrews NC. Iron homeostasis: insights from genetics and animal models. Nat Rev Genet. 2000;1:208–217. [PubMed]
15. Sacher A, Cohen A, Nelson N. Properties of the mammalian and yeast metal-ion transporters DCT1 and Smf1p expressed in Xenopus laevis oocytes. J Exp Biol. 2001;204:1053–1061. [PubMed]
16. Foury F, Roganti T. Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain. J Biol Chem. 2002;277:24475–24483. [PubMed]
17. Shaw GC, Cope JJ, Li L, et al. Mitoferrin is essential for erythroid iron assimilation. Nature. 2006;440:96–100. [PubMed]
18. Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet. 1999;21:396–399. [PubMed]
19. Ned RM, Swat W, Andrews NC. Transferrin receptor 1 is differentially required in lymphocyte development. Blood. 2003;102:3711–3718. [PubMed]
20. Quigley JG, Yang Z, Worthington MT, et al. Identification of a human heme exporter that is essential for erythropoiesis. Cell. 2004;118:757–766. [PubMed]
21. Keel SB, Doty RT, Yang Z, et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science. 2008;319:825–828. [PubMed]
22. Aziz N, Munro HN. Iron regulates ferritin mRNA translation through a segment of its 5′-untranslated region. PNAS. 1987;84:8478. [PMC free article] [PubMed]
23. Hentze MW, Rouault TA, Caughman SW, Dancis A, Harford JB, Klausner RD. A cis-acting element is necessary and sufficient for translational regulation of human ferritin expression in response to iron. Proc Natl Acad Sci U S A. 1987;84:6730–6734. [PMC free article] [PubMed]
24. Casey JL, Hentze MW, Koeller DM, et al. Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. Science. 1988;240:924–928. [PubMed]
25. Caughman SW, Hentze MW, Rouault TA, Harford JB, Klausner RD. The iron-responsive element is the single element responsible for iron-dependent translational regulation of ferritin biosynthesis: evidence for function as the binding site for a translational repressor. J Biol Chem. 1988;263:19048–19052. [PubMed]
26. Hentze MW, Caughman SW, Rouault TA, et al. Identification of the iron-responsive element for the translational regulation of human ferritin mRNA. Science. 1987;238:1570–1573. [PubMed]
27. Leibold EA, Munro HN. Cytoplasmic protein binds in vitro to a highly conserved sequence in the 5′ untranslated region of ferritin heavy- and light-subunit mRNAs. Proc Natl Acad Sci U S A. 1988;85:2171–2175. [PMC free article] [PubMed]
28. Rouault TA, Hentze MW, Caughman SW, Harford JB, Klausner RD. Binding of a cytosolic protein to the iron-responsive element of human ferritin messenger RNA. Science. 1988;241:1207–1210. [PubMed]
29. Hentze MW, Argos P. Homology between IRE-BP, a regulatory RNA-binding protein, aconitase, and isopropylmalate isomerase. Nucleic Acids Res. 1991;19:1739–1740. [PMC free article] [PubMed]
30. Kaptain S, Downey WE, Tang C, et al. A regulated RNA binding protein also possesses aconitase activity. Proc Natl Acad Sci U S A. 1991;88:10109–10113. [PMC free article] [PubMed]
31. Haile DJ, Rouault TA, Tang CK, Chin J, Harford JB, Klausner RD. Reciprocal control of RNA-binding and aconitase activity in the regulation of the iron-responsive element binding protein: role of the iron-sulfur cluster. Proc Natl Acad Sci U S A. 1992;89:7536–7540. [PMC free article] [PubMed]
32. Guo B, Phillips JD, Yu Y, Leibold EA. Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J Biol Chem. 1995;270:21645–21651. [PubMed]
33. Iwai K, Klausner RD, Rouault TA. Requirements for iron-regulated degradation of the RNA binding protein, iron regulatory protein 2. EMBO J. 1995;14:5350–5357. [PMC free article] [PubMed]
34. Iwai K, Drake SK, Wehr NB, et al. Iron-dependent oxidation, ubiquitination, and degradation of iron regulatory protein 2: implications for degradation of oxidized proteins. Proc Natl Acad Sci U S A. 1998;95:4924–4928. [PMC free article] [PubMed]
35. Yamanaka K, Ishikawa H, Megumi Y, et al. Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2. Nat Cell Biol. 2003;5:336–340. [PubMed]
36. Wang J, Chen G, Muckenthaler M, Galy B, Hentze MW, Pantopoulos K. Iron-mediated degradation of IRP2, an unexpected pathway involving a 2-oxoglutarate-dependent oxygenase activity. Mol Cell Biol. 2004;24:954–965. [PMC free article] [PubMed]
37. Meyron-Holtz EG, Ghosh MC, Rouault TA. Mammalian tissue oxygen levels modulate iron-regulatory protein activities in vivo. Science. 2004;306:2087–2090. [PubMed]
38. Muckenthaler M, Gray NK, Hentze MW. IRP-1 binding to ferritin mRNA prevents the recruitment of the small ribosomal subunit by the cap-binding complex eIF4F. Mol Cell. 1998;2:383–388. [PubMed]
39. Casey JL, Koeller DM, Ramin VC, Klausner RD, Harford JB. Iron regulation of transferrin receptor mRNA levels requires iron-responsive elements and a rapid turnover determinant in the 3′ untranslated region of the mRNA. EMBO J. 1989;8:3693–3699. [PMC free article] [PubMed]
40. Leipuviene R, Theil EC. The family of iron responsive RNA structures regulated by changes in cellular iron and oxygen. Cell Mol Life Sci. 2007;64:2945–2955. [PubMed]
41. Meyron-Holtz EG, Ghosh MC, Iwai K, et al. Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J. 2004;23:386–395. [PMC free article] [PubMed]
42. Cooperman SS, Meyron-Holtz EG, Olivierre-Wilson H, Ghosh MC, McConnell JP, Rouault TA. Microcytic anemia, erythropoietic protoporphyria and neurodegeneration in mice with targeted deletion of iron regulatory protein 2. Blood. 2005;106:1084–1091. [PMC free article] [PubMed]
43. Galy B, Ferring D, Minana B, et al. Altered body iron distribution and microcytosis in mice deficient in iron regulatory protein 2 (IRP2). Blood. 2005;106:2580–2589. [PubMed]
44. LaVaute T, Smith S, Cooperman S, et al. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet. 2001;27:209–214. [PubMed]
45. Galy B, Holter SM, Klopstock T, et al. Iron homeostasis in the brain: complete iron regulatory protein 2 deficiency without symptomatic neurodegeneration in the mouse. Nat Genet. 2006;38:967–969. discussion 969–970. [PubMed]
46. Bonneau D, Winter-Fuseau I, Loiseau MN, et al. Bilateral cataract and high serum ferritin: a new dominant genetic disorder? J Med Genet. 1995;32:778–779. [PMC free article] [PubMed]
47. Girelli D, Corrocher R, Bisceglia L, et al. Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the “Verona mutation”). Blood. 1995;86:4050–4053. [PubMed]
48. Beaumont C, Leneuve P, Devaux I, et al. Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinemia and cataract. Nat Genet. 1995;11:444–446. [PubMed]
49. Kato J, Fujikawa K, Kanda M, et al. A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload. Am J Hum Genet. 2001;69:191–197. [PMC free article] [PubMed]
50. Mok H, Jelinek J, Pai S, et al. Disruption of ferroportin 1 regulation causes dynamic alterations in iron homeostasis and erythropoiesis in polycythaemia mice. Development. 2004;131:1859–1868. [PubMed]
51. Finch CA, Deubelbeiss K, Cook JD, et al. Ferrokinetics in man. Medicine (Baltimore) 1970;49:17–53. [PubMed]
52. Russell ES, Nash DJ, Bernstein SE, et al. Characterization and genetic studies of microcytic anemia in house mouse. Blood. 1970;35:838–850. [PubMed]
53. McKie AT, Barrow D, Latunde-Dada GO, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science. 2001;291:1755–1759. [PubMed]
54. McKie AT, Marciani P, Rolfs A, et al. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell. 2000;5:299–309. [PubMed]
55. Gunshin H, Starr CN, Direnzo C, et al. Cybrd1 (duodenal cytochrome b) is not necessary for dietary iron absorption in mice. Blood. 2005;16:16. [PMC free article] [PubMed]
56. Ohgami RS, Campagna DR, McDonald A, Fleming MD. The Steap proteins are metalloreductases. Blood. 2006;108:1388–1394. [PMC free article] [PubMed]
57. Hubert N, Hentze MW. Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc Natl Acad Sci U S A. 2002;99:12345–12350. [PMC free article] [PubMed]
58. Lam-Yuk-Tseung S, Touret N, Grinstein S, Gros P. Carboxyl-terminus determinants of the iron transporter DMT1/SLC11A2 isoform II (-IRE/1B) mediate internalization from the plasma membrane into recycling endosomes. Biochemistry. 2005;44:12149–12159. [PubMed]
59. Canonne-Hergaux F, Gruenheid S, Ponka P, Gros P. Cellular and subcellular localization of the Nramp2 iron transporter in the intestinal brush border and regulation by dietary iron. Blood. 1999;93:4406–4417. [PubMed]
60. Vidal SM, Malo D, Vogan K, Skamene E, Gros P. Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg. Cell. 1993;73:469–485. [PubMed]
61. Gruenheid S, Pinner E, Desjardins M, Gros P. Natural resistance to infection with intracellular pathogens: the Nramp1 protein is recruited to the membrane of the phagosome. J Exp Med. 1997;185:717–730. [PMC free article] [PubMed]
62. Forbes JR, Gros P. Iron, manganese, and cobalt transport by Nramp1 (Slc11a1) and Nramp2 (Slc11a2) expressed at the plasma membrane. Blood. 2003;102:1884–1892. [PubMed]
63. Supek F, Supekova L, Nelson H, Nelson N. A yeast manganese transporter related to the macrophage protein involved in conferring resistance to mycobacteria. Proc Natl Acad Sci U S A. 1996;93:5105–5110. [PMC free article] [PubMed]
64. Rodrigues V, Cheah PY, Ray K, Chia W. Malvolio, the Drosophila homologue of mouse NRAMP-1 (Bcg), is expressed in macrophages and in the nervous system and is required for normal taste behaviour. EMBO J. 1995;14:3007–3020. [PMC free article] [PubMed]
65. Donovan A, Brownlie A, Dorschner MO, et al. The zebrafish mutant gene chardonnay (cdy) encodes divalent metal transporter 1 (DMT1). Blood. 2002;100:4655–4659. [PubMed]
66. Gunshin H, Fujiwara Y, Custodio AO, Direnzo C, Robine S, Andrews NC. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J Clin Invest. 2005;115:1258–1266. [PMC free article] [PubMed]
67. Barisani D, Berg CL, Wessling-Resnick M, Gollan JL. Evidence for a low Km transporter for non-transferrin-bound iron in isolated rat hepatocytes. Am J Physiol. 1995;269:G570–576. [PubMed]
68. Inman RS, Coughlan MM, Wessling-Resnick M. Extracellular ferrireductase activity of K562 cells is coupled to transferrin-independent iron transport. Biochemistry. 1994;33:11850–11857. [PubMed]
69. Kaplan J, Jordan I, Sturrock A. Regulation of the transferrin-independent iron transport system in cultured cells. J Biol Chem. 1991;266:2997–3004. [PubMed]
70. Parkes JG, Randell EW, Olivieri NF, Templeton DM. Modulation by iron loading and chelation of the uptake of non-transferrin-bound iron by human liver cells. Biochim Biophys Acta. 1995;1243:373–380. [PubMed]
71. Randell EW, Parkes JG, Olivieri NF, Templeton DM. Uptake of non-transferrin bound iron by both reductive and non-reductive processes is modulated by intracellular iron. J Biol Chem. 1994;269:16046–16053. [PubMed]
72. Sturrock A, Alexander J, Lamb J, Craven CM, Kaplan J. Characterization of a transferrin-independent uptake system for iron in HeLa cells. J Biol Chem. 1990;265:3139–3145. [PubMed]
73. Oudit GY, Sun H, Trivieri MG, et al. L-type Ca(2+) channels provide a major pathway for iron entry into cardiomyocytes in iron-overload cardiomyopathy. Nat Med. 2003;9:1187–1194. [PubMed]
74. Goetz DH, Holmes MA, Borregaard N, Bluhm ME, Raymond KN, Strong RK. The neutrophil lipocalin NGAL is a bacteriostatic agent that interferes with siderophore-mediated iron acquisition. Mol Cell. 2002;10:1033–1043. [PubMed]
75. Yang J, Goetz D, Li JY, et al. An iron delivery pathway mediated by a lipocalin. Mol Cell. 2002;10:1045–1056. [PubMed]
76. Devireddy LR, Gazin C, Zhu X, Green MR. A cell-surface receptor for lipocalin 24p3 selectively mediates apoptosis and iron uptake. Cell. 2005;123:1293–1305. [PubMed]
77. Abboud S, Haile DJ. A novel mammalian iron-regulated protein involved in intracellular iron metabolism. J Biol Chem. 2000;275:19906–19912. [PubMed]
78. Donovan A, Brownlie A, Zhou Y, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403:776–781. [PubMed]
79. Donovan A, Lima CA, Pinkus JL, et al. The iron exporter ferroportin/Slc40a1 is essential for iron homeostasis. Cell Metab. 2005;1:191–200. [PubMed]
80. Osaki S, Johnson DA. Mobilization of liver iron by ferroxidase (ceruloplasmin). J Biol Chem. 1969;244:5757–5758. [PubMed]
81. Osaki S, Johnson DA, Frieden E. The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem. 1966;241:2746–2751. [PubMed]
82. Roeser HP, Lee GR, Nacht S, Cartwright GE. The role of ceruloplasmin in iron metabolism. J Clin Invest. 1970;49:2408–2417. [PMC free article] [PubMed]
83. Vulpe CD, Kuo YM, Murphy TL, et al. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat Genet. 1999;21:195–199. [PubMed]
84. De Domenico I, Ward DM, di Patti MC, et al. Ferroxidase activity is required for the stability of cell surface ferroportin in cells expressing GPI-ceruloplasmin. EMBO J. 2007;26:2823–2831. [PMC free article] [PubMed]
85. Askwith C, Eide D, Van Ho A, et al. The FET3 gene of S. cerevisiae encodes a multicopper oxidase required for ferrous iron uptake. Cell. 1994;76:403–410. [PubMed]
86. Stearman R, Yuan DS, Yamaguchi-Iwai Y, Klausner RD, Dancis A. A permease-oxidase complex involved in high-affinity iron uptake in yeast. Science. 1996;271:1552–1557. [PubMed]
87. Shayeghi M, Latunde-Dada GO, Oakhill JS, et al. Identification of an intestinal heme transporter. Cell. 2005;122:789–801. [PubMed]
88. Qiu A, Jansen M, Sakaris A, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell. 2006;127:917–928. [PubMed]
89. Krishnamurthy P, Ross DD, Nakanishi T, et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem. 2004;279:24218–24225. [PubMed]
90. Krause A, Neitz S, Magert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000;480:147–150. [PubMed]
91. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276:7806–7810. [PubMed]
92. Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 2001;276:7811–7819. [PubMed]
93. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090–2093. [PubMed]
94. De Domenico I, Ward DM, Langelier C, et al. The molecular mechanism of hepcidin-mediated ferroportin down-regulation. Mol Biol Cell. 2007;18:2569–2578. [PMC free article] [PubMed]
95. Conrad ME, Crosby WH. Intestinal mucosal mechanisms controlling iron absorption. Blood. 1963;22:406–415. [PubMed]
96. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 2003;101:2461–2463. [PubMed]
97. Kemna EH, Tjalsma H, Podust VN, Swinkels DW. Mass spectrometry-based hepcidin measurements in serum and urine: analytical aspects and clinical implications. Clin Chem. 2007;53:620–628. [PubMed]
98. Valore EV, Ganz T. Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis. 2008;40:132–138. [PMC free article] [PubMed]
99. Nicolas G, Chauvet C, Viatte L, et al. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest. 2002;110:1037–1044. [PMC free article] [PubMed]
100. Weinstein DA, Roy CN, Fleming MD, Loda MF, Wolfsdorf JI, Andrews NC. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood. 2002;100:3776–3781. [PubMed]
101. Nicolas G, Bennoun M, Devaux I, et al. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc Natl Acad Sci U S A. 2001;98:8780–8785. [PMC free article] [PubMed]
102. Lesbordes-Brion JC, Viatte L, Bennoun M, et al. Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis. Blood. 2006;108:1402–1405. [PubMed]
103. Nicolas G, Bennoun M, Porteu A, et al. Severe iron deficiency anemia in transgenic mice expressing liver hepcidin. Proc Natl Acad Sci U S A. 2002;99:4596–4601. [PMC free article] [PubMed]
104. Roy CN, Mak HH, Akpan I, Losyev G, Zurakowski D, Andrews NC. Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. Blood. 2007;109:4038–4044. [PMC free article] [PubMed]
105. Adamsky K, Weizer O, Amariglio N, et al. Decreased hepcidin mRNA expression in thalassemic mice. Br J Haematol. 2004;124:123–124. [PubMed]
106. Ganz T. Hepcidin—a peptide hormone at the interface of innate immunity and iron metabolism. Curr Top Microbiol Immunol. 2006;306:183–198. [PubMed]
107. Wrighting DM, Andrews NC. Interleukin-6 induces hepcidin expression through STAT3. Blood. 2006;108:3204–3209. [PMC free article] [PubMed]
108. Verga Falzacappa MV, Vujic Spasic M, Kessler R, Stolte J, Hentze MW, Muckenthaler MU. STAT3 mediates hepatic hepcidin expression and its inflammatory stimulation. Blood. 2007;109:353–358. [PubMed]
109. Peyssonnaux C, Zinkernagel AS, Schuepbach RA, et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest. 2007;117:1926–1932. [PMC free article] [PubMed]
110. Courselaud B, Pigeon C, Inoue Y, et al. C/EBPalpha regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism: cross-talk between C/EBP pathway and iron metabolism. J Biol Chem. 2002;277:41163–41170. [PubMed]
111. Bayele HK, McArdle H, Srai SK. Cis and trans regulation of hepcidin expression by upstream stimulatory factor. Blood. 2006;108:4237–4245. [PubMed]
112. Weizer-Stern O, Adamsky K, Margalit O, et al. Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53. Br J Haematol. 2007;138:253–262. [PubMed]
113. Wang RH, Li C, Xu X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2:399–409. [PubMed]
114. Babitt JL, Huang FW, Wrighting DM, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38:531–539. [PubMed]
115. Truksa J, Peng H, Lee P, Beutler E. Different regulatory elements are required for response of hepcidin to interleukin-6 and bone morphogenetic proteins 4 and 9. Br J Haematol. 2007;139:138–147. [PubMed]
116. Truksa J, Peng H, Lee P, Beutler E. Bone morphogenetic proteins 2, 4, and 9 stimulate murine hepcidin 1 expression independently of Hfe, transferrin receptor 2 (Tfr2), and IL-6. Proc Natl Acad Sci U S A. 2006;103:10289–10293. [PMC free article] [PubMed]
117. Babitt JL, Huang FW, Xia Y, Sidis Y, Andrews NC, Lin HY. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance. J Clin Invest. 2007;117:1933–1939. [PMC free article] [PubMed]
118. Trousseau A. Glycosurie; diabete sucre. Clinique medicale de l'Hotel-Dieu de Paris. 1865;2:663–698.
119. Sheldon JH. London, United Kingdom: Oxford University Press; 1935. Haemochromatosis.
120. Simon M, Bourel M, Fauchet R, Genetet B. Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut. 1976;17:332–334. [PMC free article] [PubMed]
121. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13:399–408. [PubMed]
122. Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358:221–230. [PubMed]
123. Levy JE, Montross LK, Andrews NC. Genes that modify the hemochromatosis phenotype in mice. J Clin Invest. 2000;105:1209–1216. [PMC free article] [PubMed]
124. Sachot S, Moirand R, Jouanolle AM, et al. Low penetrant hemochromatosis phenotype in eight families: no evidence of modifiers in the MHC region. Blood Cells Mol Dis. 2001;27:518–529. [PubMed]
125. Sproule TJ, Jazwinska EC, Britton RS, et al. Naturally variant autosomal and sex-linked loci determine the severity of iron overload in beta 2-microglobulin-deficient mice. Proc Natl Acad Sci U S A. 2001;98:5170–5174. [PMC free article] [PubMed]
126. Cardoso EM, Macedo MG, Rohrlich P, et al. Increased hepatic iron in mice lacking classical MHC class I molecules. Blood. 2002;100:4239–4241. [PubMed]
127. Bensaid M, Fruchon S, Mazeres C, Bahram S, Roth MP, Coppin H. Multigenic control of hepatic iron loading in a murine model of hemochromatosis. Gastroenterology. 2004;126:1400–1408. [PubMed]
128. Biasiotto G, Roetto A, Daraio F, et al. Identification of new mutations of hepcidin and hemojuvelin in patients with HFE C282Y allele. Blood Cells Mol Dis. 2004;33:338–343. [PubMed]
129. Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood. 2004;103:2835–2840. [PubMed]
130. Le Gac G, Scotet V, Ka C, et al. The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet. 2004;13:1913–1918. [PubMed]
131. Nicolas G, Andrews NC, Kahn A, Vaulont S. Hepcidin, a candidate modifier of the hemochromatosis phenotype in mice. Blood. 2004;103:2841–2843. [PubMed]
132. Tolosano E, Fagoonee S, Garuti C, et al. Haptoglobin modifies the hemochromatosis phenotype in mice. Blood. 2004;105:3353–3355. [PubMed]
133. Camaschella C. Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders. Blood. 2005;106:3710–3717. [PubMed]
134. Merryweather-Clarke AT, Cadet E, Bomford A, et al. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet. 2003;12:2241–2247. [PubMed]
135. Wang F, Paradkar PN, Custodio AO, et al. Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice. Nat Genet. 2007;39:1025–1032. [PubMed]
136. Bridle KR, Frazer DM, Wilkins SJ, et al. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet. 2003;361:669–673. [PubMed]
137. Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2 hemochromatosis. Blood. 2005;105:1803–1806. [PubMed]
138. Papanikolaou G, Samuels ME, Ludwig EH, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36:77–82. [PubMed]
139. Papanikolaou G, Tzilianos M, Christakis JI, et al. Hepcidin in iron overload disorders. Blood. 2005;105:4103–4105. [PMC free article] [PubMed]
140. Huang FW, Pinkus JL, Pinkus GS, Fleming MD, Andrews NC. A mouse model of juvenile hemochromatosis. J Clin Invest. 2005;115:2187–2191. [PMC free article] [PubMed]
141. Kawabata H, Fleming RE, Gui D, et al. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis. Blood. 2005;105:376–381. [PubMed]
142. Muckenthaler M, Roy CN, Custodio AO, et al. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet. 2003;34:102–107. [PubMed]
143. Nicolas G, Viatte L, Lou DQ, et al. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet. 2003;34:97–101. [PubMed]
144. Niederkofler V, Salie R, Arber S. Hemojuvelin is essential for dietary iron sensing, and its mutation leads to severe iron overload. J Clin Invest. 2005;115:2180–2186. [PMC free article] [PubMed]
145. Lebron JA, Bennett MJ, Vaughn DE, et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998;93:111–123. [PubMed]
146. Feder JN, Penny DM, Irrinki A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A. 1998;95:1472–1477. [PMC free article] [PubMed]
147. Parkkila S, Waheed A, Britton RS, et al. Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis. Proc Natl Acad Sci U S A. 1997;94:13198–13202. [PMC free article] [PubMed]
148. Roy CN, Enns CA. Iron homeostasis: new tales from the crypt. Blood. 2000;96:4020–4027. [PubMed]
149. Schmidt PJ, Toran PT, Giannetti AM, Bjorkman PJ, Andrews NC. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab. 2008;7:205–214. [PMC free article] [PubMed]
150. Goswami T, Andrews NC. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006;281:28494–28498. [PubMed]
151. Chen J, Enns CA. The cytoplasmic domain of transferrin receptor 2 dictates its stability and response to holo-transferrin in Hep3B cells. J Biol Chem. 2007;282:6201–6209. [PubMed]
152. Kawabata H, Yang R, Hirama T, et al. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem. 1999;274:20826–20832. [PubMed]
153. Johnson MB, Chen J, Murchison N, Green FA, Enns CA. Transferrin receptor 2: evidence for ligand-induced stabilization and redirection to a recycling pathway. Mol Biol Cell. 2007;18:743–754. [PMC free article] [PubMed]
154. Robb A, Wessling-Resnick M. Regulation of transferrin receptor 2 protein levels by transferrin. Blood. 2004;104:4294–4299. [PubMed]
155. Johnson MB, Enns CA. Diferric transferrin regulates transferrin receptor 2 protein stability. Blood. 2004;104:4287–4293. [PubMed]
156. Montosi G, Donovan A, Totaro A, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001;108:619–623. [PMC free article] [PubMed]
157. Njajou OT, Vaessen N, Joosse M, et al. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet. 2001;28:213–214. [PubMed]
158. De Domenico I, Ward DM, Nemeth E, et al. The molecular basis of ferroportin-linked hemochromatosis. Proc Natl Acad Sci U S A. 2005;102:8955–8960. [PMC free article] [PubMed]
159. Drakesmith H, Schimanski LM, Ormerod E, et al. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin. Blood. 2005;106:1092–1097. [PubMed]
160. Zohn IE, De Domenico I, Pollock A, et al. The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease. Blood. 2007;109:4174–4180. [PMC free article] [PubMed]
161. Roetto A, Papanikolaou G, Politou M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33:21–22. [PubMed]
162. Schimanski LM, Drakesmith H, Merryweather-Clarke AT, et al. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations. Blood. 2005;105:4096–4102. [PubMed]
163. Beutler E. History of iron in medicine. Blood Cells Mol Dis. 2002;29:297–308. [PubMed]
164. Blaud P. Sur les maladies chlorotiques et sur un mode de traitement specifique dans ces affections. Rev Med Franc Etrang. 1832;45:357–367.
165. Heath CW, Strauss MB, Castle WB. Quantitative aspects of iron deficiency in hypochromic anemia. J Clin Invest. 1932;11:1293–1312. [PMC free article] [PubMed]
166. Carnicer J, Badia R, Argemi J. Helicobacter pylori gastritis and sideropenic refractory anemia. J Pediatr Gastroenterol Nutr. 1997;25:441. [PubMed]
167. Marignani M, Angeletti S, Bordi C, et al. Reversal of long-standing iron deficiency anaemia after eradication of Helicobacter pylori infection. Scand J Gastroenterol. 1997;32:617–622. [PubMed]
168. Hershko C, Patz J, Ronson A. The anemia of achylia gastrica revisited. Blood Cells Mol Dis. 2007;39:178–183. [PubMed]
169. Faber K. Achylia gastrica mit Anamie. Medizinishe Klinik. 1909;5:1310–1325.
170. Wintrobe MM, Beebe RT. Idiopathic hypocrhomic anemia. Medicine. 1933;12:187–243.
171. Camaschella C, Campanella A, De Falco L, et al. The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload. Blood. 2007;110:1353–1358. [PubMed]
172. Mims MP, Guan Y, Pospisilova D, et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood. 2005;105:1337–1342. [PubMed]
173. Priwitzerova M, Nie G, Sheftel AD, Pospisilova D, Divoky V, Ponka P. Functional consequences of the human DMT1 (SLC11A2) mutation on protein expression and iron uptake. Blood. 2005;106:3985–3987. [PubMed]
174. Beaumont C, Delaunay J, Hetet G, Grandchamp B, de Montalembert M, Tchernia G. Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood. 2006;107:4168–4170. [PubMed]
175. Iolascon A, d'Apolito M, Servedio V, Cimmino F, Piga A, Camaschella C. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood. 2006;107:349–354. [PubMed]
176. Lam-Yuk-Tseung S, Camaschella C, Iolascon A, Gros P. A novel R416C mutation in human DMT1 (SLC11A2) displays pleiotropic effects on function and causes microcytic anemia and hepatic iron overload. Blood Cells Mol Dis. 2006;36:347–354. [PubMed]
177. Wingert RA, Galloway JL, Barut B, et al. Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis. Nature. 2005;436:1035–1039. [PubMed]
178. Beutler E, Gelbart T, Lee P, Trevino R, Fernandez MA, Fairbanks VF. Molecular characterization of a case of atransferrinemia. Blood. 2000;96:4071–4074. [PubMed]
179. Trenor CC, 3rd, Campagna DR, Sellers VM, Andrews NC, Fleming MD. The molecular defect in hypotransferrinemic mice. Blood. 2000;96:1113–1118. [PubMed]
180. Heilmeyer L, Keller W, Vivell O, et al. Congenital transferrin deficiency in a seven-year old girl. German Medical Monthly. 1961;86:1745–1751. [PubMed]
181. Goya N, Miyazaki S, Kodate S, Ushio B. A family of congenital atransferrinemia. Blood. 1972;40:239–245. [PubMed]
182. Bernstein SE. Hereditary hypotransferrinemia with hemosiderosis, a murine disorder resembling human atransferrinemia. J Lab Clin Med. 1987;110:690–705. [PubMed]
183. Hamill RL, Woods JC, Cook BA. Congenital atransferrinemia: a case report and review of the literature. Am J Clin Pathol. 1991;96:215–218. [PubMed]
184. Harris ZL, Takahashi Y, Miyajima H, Serizawa M, MacGillivray RT, Gitlin JD. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci U S A. 1995;92:2539–2543. [PMC free article] [PubMed]
185. Buchanan DD, Silburn PA, Chalk JB, Le Couteur DG, Mellick GD. The Cys282Tyr polymorphism in the HFE gene in Australian Parkinson's disease patients. Neurosci Lett. 2002;327:91–94. [PubMed]
186. Hartman KR, Barker JA. Microcytic anemia with iron malabsorption: an inherited disorder of iron metabolism. Am J Hematol. 1996;51:269–275. [PubMed]
187. Parsons SK, Fleming MD, Nathan DG, Andrews NC. Iron deficiency anemia associated with an error of iron metabolism in two siblings: a thirty year follow up. Hematology. 1996;1:65–73.
188. Pearson HA, Lukens JN. Ferrokinetics in the syndrome of familial hypoferremic microcytic anemia with iron malabsorption. J Pediatr Hematol Oncol. 1999;21:412–417. [PubMed]
189. Mayo MM, Samuel SM. Iron deficiency anemia due to a defect in iron metabolism: a case report. Clin Lab Sci. 2001;14:135–138. [PubMed]
190. Finberg KA, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet. 2008 Prepublished on April 13, 2008 as DOI 10.1038/ug.130. [PMC free article] [PubMed]
191. Andrews NC, Fleming MD. Commentary on: ferrokinetics in the syndrome of familial hypoferremic microcytic anemia with iron malabsorption. J Pediatr Hematol Oncol. 1999;21:353–355. [PubMed]
192. Beutler E, Lee P, Gelbart T, et al. The Mask mutation identifies TMPRSS6 as an essential suppressor of hepcidin gene expression, required for normal uptake of dietary iron. [abstract] Blood. 2007;110 Abstract 3.
193. Roy CN, Andrews NC. Anemia of inflammation: the hepcidin link. Curr Opin Hematol. 2005;12:107–111. [PubMed]
194. Cartwright GE. The anemia of chronic disorders. Semin Hematol. 1966;3:351–375. [PubMed]
195. Means RT. Pathogenesis of the anemia of chronic disease: a cytokine-mediated anemia. Stem Cells. 1995;13:32–37. [PubMed]
196. Roy CN, Weinstein DA, Andrews NC. 2002 E. Mead Johnson Award for Research in Pediatrics Lecture: the molecular biology of the anemia of chronic disease: a hypothesis. Pediatr Res. 2003;53:507–512. [PubMed]
197. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271–1276. [PMC free article] [PubMed]
198. Bennett MJ, Lebron JA, Bjorkman PJ. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature. 2000;403:46–53. [PubMed]
199. Lawrence CM, Ray S, Babyonyshev M, Galluser R, Borhani DW, Harrison SC. Crystal structure of the ectodomain of human transferrin receptor. Science. 1999;286:779–782. [PubMed]
200. Walden WE, Selezneva AI, Dupuy J, et al. Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA. Science. 2006;314:1903–1908. [PubMed]
201. MacPhail AP, Derman DP, Bothwell TH, et al. Serum ferritin concentrations in black miners. S Afr Med J. 1979;55:758–760. [PubMed]
202. Gordeuk VR, Boyd RD, Brittenham GM. Dietary iron overload persists in rural sub-Saharan Africa. Lancet. 1986;1:1310–1313. [PubMed]
203. Barton JC, Edwards CQ, Bertoli LF, Shroyer TW, Hudson SL. Iron overload in African Americans. Am J Med. 1995;99:616–623. [PubMed]
204. Wurapa RK, Gordeuk VR, Brittenham GM, Khiyami A, Schechter GP, Edwards CQ. Primary iron overload in African Americans [see comments]. Am J Med. 1996;101:9–18. [PubMed]
205. Moyo VM, Mandishona E, Hasstedt SJ, et al. Evidence of genetic transmission in African iron overload. Blood. 1998;91:1076–1082. [PubMed]
206. Gangaidzo IT, Moyo VM, Saungweme T, et al. Iron overload in urban Africans in the 1990s. Gut. 1999;45:278–283. [PMC free article] [PubMed]
207. Gordeuk VR. African iron overload. Semin Hematol. 2002;39:263–269. [PubMed]
208. Barton JC, Acton RT, Rivers CA, et al. Genotypic and phenotypic heterogeneity of African Americans with primary iron overload. Blood Cells Mol Dis. 2003;31:310–319. [PubMed]
209. Brown KE, Khan CM, Zimmerman MB, Brunt EM. Hepatic iron overload in blacks and whites: a comparative autopsy study. Am J Gastroenterol. 2003;98:1594–1598. [PubMed]
210. Gordeuk VR, Caleffi A, Corradini E, et al. Iron overload in Africans and African-Americans and a common mutation in the SCL40A1 (ferroportin 1) gene. Blood Cells Mol Dis. 2003;31:299–304. [PubMed]
211. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004;5:863–873. [PubMed]
212. Campuzano V, Montermini L, Molto MD, et al. Friedreich's ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion [see comments]. Science. 1996;271:1423–1427. [PubMed]
213. Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25:14–15. [PubMed]

Articles from Blood are provided here courtesy of American Society of Hematology
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...