Human Molecular Genetics, 2001, Vol. 10, No. 20 2181-2186
© 2001 Oxford University Press
Recent advances in disorders of iron metabolism: mutations, mechanisms and modifiers
1Division of Hematology/Oncology, Children’s Hospital, Department of Pediatrics, Harvard Medical School, 2Division of Hematology/Oncology, Brigham and Women’s Hospital and 3Howard Hughes Medical Institute, Boston, MA 02115, USA
Received June 1, 2001; Accepted June 28, 2001.
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ABSTRACT |
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 TOP ABSTRACT HEMOCHROMATOSISFRIEDREICH’S ATAXIA AND...ACERULOPLASMINEMIA AND...MODIFIERSCONCLUSIONSNOTE ADDED IN PROOFREFERENCES |
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The spectrum of known disorders of iron metabolism has expanded dramatically over the past few years. Identification of HFE, the gene most commonly mutated in patients with hereditary hemochromatosis, has allowed molecular diagnosis and paved the way for identification of other genes, such as TFR2, that are important in non-HFE-associated iron overload. There are clearly several other, unidentified, iron overload disease genes yet to be found. In parallel, our understanding of iron transport has expanded through identification of Fpn1/Ireg1/MTP1, Sfxn1 and Dcytb. Ongoing studies of Friedreich’s ataxia, sideroblastic anemia, aceruloplasminemia and neurodegeneration with brain-iron accumulation are clarifying the role for iron in the nervous system. Finally, as the number of known iron metabolic genes increases and their respective functions are ascertained, new opportunities have arisen to identify genetic modifiers of iron homeostasis.
The same properties that make iron essential for basic biological processes such as transport of oxygen and electrons also make it toxic, because iron can promote oxidative damage to vital biological structures. Iron homeostasis must, therefore, be tightly regulated. Genes that maintain iron homeostasis may facilitate iron uptake, storage or egress, or the regulation of any of these processes. Recently, several genetic diseases have given new insights into the function and regulation of genes of iron metabolism. New genes have been identified that are involved in iron transport, recycling and mitochondrial iron balance. Furthermore, variable phenotypic expression of mutant genotypes in mice and man is revealing the presence of genetic modifiers.
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HEMOCHROMATOSIS |
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Hereditary hemochromatosis is a common autosomal recessive disorder that results in iron overload [for review see (1)]. What was once thought to be a singular disease with varying degrees of severity is now known to be heterogeneous, resulting from defects in multiple genes. Type 1 hemochromatosis is associated with mutations in the HFE gene (human chromosome 6p21.3) (2). The progression of iron loading is usually slow, and affected individuals often do not present with clinical signs or symptoms until the fifth or sixth decade of life. The initial symptoms are subtle, and often include pain in the joints of the fingers, skin hyperpigmentation, fatigue and depression. As iron loading proceeds, affected patients develop liver disease, gradually progressing from fibrosis to cirrhosis. They have a greatly increased incidence of hepatocellular carcinoma. Cardiomyopathy and arrhythmias may develop from deposition of iron in the heart. Endocrine abnormalities are common, including hypogonadism and diabetes.
The normal function of the HFE protein is not understood. It is related to class I major histocompatability proteins, and, accordingly, it forms a heterodimer with ß2 microglobulin (2). It does not bind iron and it is not an iron transporter; rather, it appears to be a regulatory molecule that influences the efficiency of intestinal iron absorption. HFE has been observed to associate with the transferrin receptor (3–5) and to attenuate cellular iron uptake from its ligand, the plasma iron carrier transferrin (6–9). However, the mechanism by which the HFE and transferrin receptor complex modulates body iron homeostasis remains under investigation.
The majority of type 1 hemochromatosis patients are homozygous for a unique allele containing a cysteine to tyrosine conversion at codon 282 (C282Y) of the HFE protein (2). This mutation prevents the formation of an intramolecular disulfide bond that is critical for efficient expression of HFE (10,11), and results in a partial loss of protein function (12). Other mutations and polymorphisms [H63D (2), S65C (13), I105T and G93R (14)] have been identified in patients with hereditary hemochromatosis, but their contributions to the disease are not well understood (10,12). Despite the prevalence of HFE mutations in individuals with hemochromatosis, not all individuals with hemochromatosis carry mutations in HFE. This has led to the identification of other genes that, when mutated, also cause hemochromatosis.
Type 2 hemochromatosis, or juvenile hemochromatosis, is more severe than type 1 (15). While the gene responsible for this disease has not been identified, it is linked to human chromosome 1q and has been designated HFE2 (16). Type 2 hemochromatosis is characterized by rapid iron loading and clinical presentation within the second decade of life (15). Cardiac and endocrine abnormalities dominate the clinical picture, but liver disease may be significant. Because the rate of iron loading in type 2 hemochromatosis exceeds that of type 1 hemochromatosis, it is likely that HFE2 either plays a more important role than HFE within the same regulatory pathway, or is part of a distinct and more potent regulatory pathway.1
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Type 3 hemochromatosis, which is phenotypically indistinguishable from HFE-associated hemochromatosis, is associated with mutations in TFR2 (17). This locus encodes transferrin receptor 2 (human chromosome 7q22) (18), a protein that shares significant homology with the extracellular domain of the transferrin receptor. Like the transferrin receptor, transferrin receptor 2 can bind transferrin, but it does so with much lower affinity than its homolog, and it is uncertain whether transferrin receptor 2 serves in the uptake of diferric transferrin in vivo (18,19). Transferrin receptor 2 mRNA expression is highest in the liver (18) but, unlike the transferrin receptor, transferrin receptor 2 expression does not respond to changes in cellular iron status (20). The exact role of transferrin receptor 2 in the pathogenesis of iron loading is still unknown. Recent biochemical evidence suggests that type 3 hemochromatosis may be distinct from the HFE pathway because, unlike the transferrin receptor (3,4), transferrin receptor 2 does not form a stable complex with the HFE protein in vitro (21). Whether HFE, HFE2 and TfR2 participate in overlapping or completely independent genetic pathways awaits further investigation.
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FRIEDREICH’S ATAXIA AND SIDEROBLASTIC ANEMIA |
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TOPABSTRACTHEMOCHROMATOSISFRIEDREICH’S ATAXIA AND...ACERULOPLASMINEMIA AND...MODIFIERSCONCLUSIONSNOTE ADDED IN PROOFREFERENCES |
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Friedreich’s ataxia (FRDA) and sideroblastic anemia represent two diseases that highlight the importance of mitochondrial iron transport and homeostasis. FRDA is a neurodegenerative disease characterized by loss of sensory neurons in the spinal cord and dorsal root ganglia [for review see (22)]. Patients show evidence of mitochondrial iron overload (23) and a loss of activity of iron–sulfur cluster-containing enzymes (24). They frequently die from cardiomyopathy. The majority of FRDA cases result from the expansion of triple nucleotide repeats within an intron of the FRDA gene (human chromosome 9q13) (25) leading to reduced expression of frataxin mRNA and protein (26). However, point mutations have also been identified in a small number of cases.
Frataxin is localized to the mitochondrion (27–29). When frataxin levels decrease, as is the case in FRDA, iron accumulates within mitochondria, leading to increased oxidative stress and decreased activity of iron–sulfur cluster-containing proteins. Although a complete knockout of murine frataxin is embryonic lethal (30), recently developed conditional knockout mouse models of FRDA suggest that the effects of mitochondrial iron accumulation vary among different cell types (31). Two models have been generated: mice that lack frataxin in neurons and mice that lack frataxin in striated muscle. Both of these mice recapitulate features of the human disease.
Oxidative damage is thought to precipitate the neuron loss in FRDA. Experiments in yeast show that iron is redistributed to the mitochondria of Yfh (yeast frataxin homolog)-deficient yeast and that this iron accumulation precedes oxidative damage, arguing that iron accumulation is more likely to be the cause of oxidative damage to the yeast mitochondrion than the result (32). Recently, the crystal structure of the frataxin protein was solved (33). Frataxin shows structural similarity to the iron storage protein ferritin, suggesting that frataxin might mediate mitochondrial iron homeostasis by maintaining iron stores or facilitating their efficient turnover. Future experiments will determine whether frataxin is involved in mitochondrial iron storage and egress, iron–sulfur cluster biogenesis or iron–sulfur cluster transport.
Sideroblastic anemia is another disorder associated with aberrant mitochondrial iron homeostasis. Although the genetic defects leading to sideroblastic anemia are heterogeneous, they all affect the efficiency of heme production within erythroblast mitochondria, leading to iron-overloaded mitochondria that form a characteristic ring around the cell nucleus. There are two forms of X-linked sideroblastic anemia, distinguished by the presence or absence of ataxia. Mutations in ALAS2 (human chromosome Xp11.21) (34) reduce the efficiency of a critical enzyme in the heme biosynthetic pathway, 
-aminolevulinic acid synthetase (35). Many patients respond to pharmacological doses of pyridoxine, a co-factor for ALAS2. Sideroflexin 1, a novel gene encoding a mitochondrial membrane protein, has recently been identified because it is mutated in mice with siderocytic anemia (36). The striking similarity between mice lacking sideroflexin and mice deprived of pyridoxine (37) suggests that sideroflexin might facilitate transport of pyridoxine or another ALAS2 cofactor into the mitochondrion, but this has not yet been shown experimentally.
ABC-7 (human chromosome Xq13.1–q13.3) (38) is a gene mutated in X-linked sideroblastic anemia with ataxia. Individuals with mutations in ABC-7 present with hypochromic, microcytic anemia, ringed sideroblasts and non-progressive spinocerebellar ataxia (39,40). The functions of ABC-7, and its connection to sideroblastic anemia, have not been definitively established. However, experiments in mutant yeast cells have shown that ABC-7 can substitute for a homologous protein, Atm1p, which is involved in transport of iron–sulfur clusters from their site of synthesis in mitochondria to the cytoplasm (41). The link between iron–sulfur cluster biogenesis and ataxia in Friedreich’s ataxia and sideroblastic anemia with ataxia offers clues to the role of iron metabolic genes in the control of neuronal cell survival and function, but the mechanisms remain uncertain.
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ACERULOPLASMINEMIA AND NEURODEGENERATION WITH BRAIN-IRON ACCUMULATION-1 |
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Aceruloplasminemia is an autosomal recessive disease of iron overload that results from loss of function mutations in the ceruloplasmin (Cp) gene (human chromosome 3q23–q24) (42–45). While the iron overload associated with hemochromatosis results from increased iron absorption, the iron overload associated with aceruloplasminemia results from aberrant iron distribution. Ceruloplasmin is a serum protein and a multi-copper oxidase [for review see (46)]. Without this serum oxidase activity, iron cannot be efficiently recycled from storage sites in the liver and a seemingly paradoxical constellation of iron-related symptoms develops. Serum ferritin is elevated, but serum iron remains low because iron is not efficiently loaded onto transferrin. Iron accumulates in the parenchymal and reticuloendothelial cells of the liver and pancreas, but anemia results because iron is not efficiently delivered to red blood cell precursors. Ceruloplasmin must not be essential for export of iron from all cells of the body because dietary iron can still cross the intestine to enter the blood of individuals with aceruloplasminemia. This is probably due to the copper oxidase activity of the sla gene product, hephaestin (human chromosome Xq11–q12) (47), which has significant homology to ceruloplasmin in its structure and presumed function.
In addition to anemia and parenchymal iron overload, aceruloplasminemia also results in retinal degeneration, cerebellar ataxia and dementia. These neurological symptoms are not usually associated with either primary or secondary iron overload. Contrasted with the iron accumulation in dorsal root ganglia of individuals with Friedreich’s ataxia, the ataxia associated with aceruloplasminemia is probably the result of iron accumulation in the basal ganglia of the brain.1
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Neurodegeneration with brain-iron accumulation-1 [NBIA-1, previously referred to as Hallervorden–Spatz disease (human chromosome 20p12.3–13) (48)] is another genetic disorder that results in the accumulation of iron in the brain. In the case of NBIA-1, young patients present with progressive dementia and muscle rigidity. Iron accumulation occurs in the substantia nigra and globus pallidus (49). The different locations for brain iron deposition associated with these different neurological disorders suggest that there are multiple genes governing the distribution of iron in the brain and nervous system. Additionally, the lack of brain iron accumulation in Friedreich’s ataxia suggests that the iron regulatory pathways of the brain are still different from those of the peripheral nervous system. Finally, the lack of brain iron accumulation in hemochromatosis or secondary iron overload implicates particular control mechanisms for the brain.
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MODIFIERS |
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It is clear that we have not yet identified all genes involved in iron transport and metabolism. However, the next step in characterizing mammalian iron homeostasis will involve, at least in part, the identification of genes that modify the phenotype of iron metabolic disorders that have already been identified. Studies in a mouse model of hemochromatosis (12) have shown that DMT1 and hephaestin are both part of the pathway of iron uptake that is regulated by HFE, suggesting that mild mutations in either of those proteins would ameliorate or exacerbate the hemochromatosis phenotype. Furthermore, ß2 microglobulin deficiency on an HFE–/– background increases iron loading, indicating that another ß2 microglobulin-dependent gene product may be involved in iron metabolism (50).
Three newly identified genes of iron transport, Fpn1/Ireg1/MTP1 (human chromosome 2q32) (51), Dcytb and CD163 (human chromosome 12p13.3) (52) are also candidates for genetic modifiers of iron metabolic disorders. Fpn1/Ireg1/MTP1 is the first transport protein for transmembrane iron egress identified in vertebrates (53–55). Its putative function is to deliver iron to the blood from specialized transport and storage cells including placental syncytiotrophoblasts, enterocytes, hepatocytes and macrophages. Therefore, mild mutations resulting in differences in the activity of Fpn1/Ireg1/MTP1 may modify the severity of diseases associated with iron overload including hemochromatosis, aceruloplasminemia and porphyria cutanea tarda (see below). A gain of function mutation in Fpn1/Ireg1/MTP1 could make it a candidate for neonatal or dominant hemochromatosis. Dcytb (56) is a ferrireductase expressed in the intestinal mucosa. It is likely to play an important role in converting dietary (ferric) iron to its ferrous form for transport by the divalent metal ion transporter DMT1 (57,58). Like Fpn1/Ireg1/MTP1, differences in the activity of Dcytb may modify diseases of iron overload by modulating iron absorption.
CD163, a scavenger receptor expressed in monocytes and tissue macrophages, has recently been shown to be the receptor for hemoglobin/haptoglobin complexes formed when erythrocytes lyse in the circulation (59). Variations in CD163 might affect the rate of iron turnover in the reticuloendothelial system, modifying both the distribution of iron in storage tissues throughout the body and the severity of diseases such as hereditary hemochromatosis and aceruloplasminemia.
HFE itself is an example of a genetic modifier because mutations in HFE can affect the severity of porphyria cutanea tarda (PCT). PCT is a photosensitive dermatosis associated with hepatic siderosis. It results from increased production of uroporphyrin and partially decarboxylated porphyrins. Both familial and sporadic forms of the disease exist. In either case, a reduction in the activity of a liver enzyme, uroporphyrinogen decarboxylase (URO-D), is observed (60). The phenotypic severity of PCT varies widely. By evaluating the phenotypes and genotypes of individuals with PCT, Bulaj et al. (61) were able to identify environmental and genetic factors associated with iron loading that contributed to a more severe PCT phenotype. The C282Y HFE allele was such a genetic contributor.
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CONCLUSIONS |
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The identification of iron disease genes and correlation of phenotypes and genotypes has provided significant information concerning the breadth of regulation that is required for the maintenance of iron homeostasis. In the future, the ability to identify specific lesions in disease genes and their modifiers is likely to result in individualized treatments that take into account the projected severity of the disease rather than merely the underlying defect. Even within the last year, new genes that are fundamental to the basic processes of iron uptake and egress have been identified. Despite these discoveries, we still lack a full understanding of the disease process in many disorders of iron metabolism. There is no doubt that additional genes involved in intracellular iron transport and the regulation of homeostasis await identification.
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ACKNOWLEDGEMENTS |
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C.N.R. was supported in part by the Hematology Training Grant T32-HL07623-15.
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NOTE ADDED IN PROOF |
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Hayflick and colleagues (62) reported a novel gene mutated in HSS in August 2001. Nonsense, missense and frameshift mutations in the pantothenate kinase gene (PANK2) were identified in classical and atypical HSS patients. The resulting accumulation of cysteine in the globus pallidus of affected individuals may lead to the chelation and sequestration of iron. A new name, ‘pantothenate kinase associated neurodegeneration’ or PKAN, has been proposed for the disease.
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FOOTNOTES |
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+ To whom correspondence should be addressed at: Division of Hematology, Enders 720, Children’s Hospital, 300 Longwood Avenue, Boston, MA 02115, USA. Tel: +1 617 355 7265; Fax: +1 617 734 6791; Email: nancy_andrews@hms.harvard.edu
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