Abstract 摘要
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.
已知的铁代谢紊乱谱已在过去几年中急剧扩大。识别出 HFE 基因，这是在患有遗传性血色素沉着症的患者中最常见的突变基因，已经实现了分子诊断，并为识别其他基因（如 TFR2）铺平了道路，这些基因在非 HFE 相关的铁超载中起重要作用。显然还有几个其他未知的铁超载疾病基因有待发现。与此同时，通过识别 Fpn1/Ireg1/MTP1、Sfxn1 和 Dcytb，我们对铁运输的理解已经扩展。对弗里德雷希共济失调、铁染色体贫血、无铜血浆蛋白血症和脑铁沉积性神经退行性疾病的研究正在澄清铁在神经系统中的作用。最后，随着已知铁代谢基因数量的增加和各自功能的确定，新的机会已经出现，可以识别铁稳态的遗传修饰因子。
Received June 1, 2001; Accepted June 28, 2001.
收到日期：2001 年 6 月 1 日；接受日期：2001 年 6 月 28 日。
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.
相同的特性使铁对基本生物过程（如氧气和电子的运输）至关重要，同时也使其具有毒性，因为铁可以促进对重要生物结构的氧化损伤。因此，铁稳态必须受到严格调控。维持铁稳态的基因可能促进铁的摄取、储存或排泄，或者调节这些过程中的任何一个。最近，几种遗传疾病为铁代谢基因的功能和调节提供了新的见解。已经确定了参与铁运输、回收和线粒体铁平衡的新基因。此外，小鼠和人类中突变基因型的可变表型表达揭示了遗传修饰因子的存在。
HEMOCHROMATOSIS 血色病
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.
遗传性血色素沉着症是一种常见的常染色体隐性遗传疾病，导致铁过载[详见（1）]。曾经被认为是一种严重程度不同的单一疾病，现在已知是多基因缺陷导致的异质性疾病。1 型血色素沉着症与 HFE 基因突变相关（人类染色体 6p21.3）（2）。铁负荷的进展通常很缓慢，受影响的个体通常直到生命的第五或第六个十年才出现临床症状。最初的症状很微妙，通常包括手指关节疼痛、皮肤色素沉着、疲劳和抑郁。随着铁负荷的进展，受影响的患者会发展出肝病，逐渐从纤维化进展到肝硬化。他们患肝细胞癌的发病率大大增加。心肌病和心律失常可能由于心脏中铁的沉积而发展。内分泌异常很常见，包括性腺功能减退和糖尿病。
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 β2 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.
HFE 蛋白的正常功能尚不清楚。它与 I 类主要组织相容性蛋白有关，因此，它与β2 微球蛋白形成异源二聚体。它不结合铁，也不是铁载体；相反，它似乎是一种调节分子，影响肠道铁吸收的效率。已观察到 HFE 与转铁蛋白受体相关，并减弱细胞对其配体——血浆铁载体转铁蛋白的铁摄取。然而，HFE 和转铁蛋白受体复合物调节体内铁稳态的机制仍在调查中。
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.
大多数 1 型血色素沉着症患者为 HFE 蛋白的编码密码子 282 位点（C282Y）发生半胱氨酸到酪氨酸的独特等位基因纯合子（2）。该突变阻止了形成对 HFE 的高效表达至关重要的分子内二硫键（10, 11），导致蛋白功能部分丧失（12）。在患有遗传性血色素沉着症的患者中，还发现了其他突变和多态性[H63D（2），S65C（13），I105T 和 G93R（14）]，但它们对疾病的贡献尚不明确（10, 12）。尽管 HFE 突变在患有血色素沉着症的个体中很常见，但并非所有患有血色素沉着症的个体都携带 HFE 突变。这导致了发现其他基因的突变也会引起血色素沉着症。
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
2 型血色素沉着症，或青少年血色素沉着症，比 1 型更严重（15）。虽然尚未确定导致该疾病的基因，但它与人类染色体 1q 有关，并被指定为 HFE2（16）。2 型血色素沉着症的特点是铁负荷快速，并在生命的第二个十年内出现临床表现（15）。心脏和内分泌异常主导临床表现，但肝脏疾病可能很重要。由于 2 型血色素沉着症的铁负荷速度超过 1 型血色素沉着症，因此 HFE2 很可能在相同的调节途径中扮演比 HFE 更重要的角色，或者是一个独特且更强大的调节途径的一部分。
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.
3 型血色素沉着症在表型上与 HFE 相关的血色素沉着症无法区分，与 TFR2 基因突变相关（17）。该基因座编码转铁蛋白受体 2（人类染色体 7q22）（18），这是一种与转铁蛋白受体细胞外结构域具有显著同源性的蛋白质。与转铁蛋白受体类似，转铁蛋白受体 2 可以结合转铁蛋白，但其亲和力远低于其同源蛋白，目前尚不清楚转铁蛋白受体 2 是否在体内参与双铁转铁蛋白的摄取（18, 19）。转铁蛋白受体 2 mRNA 在肝脏中表达最高（18），但与转铁蛋白受体不同，转铁蛋白受体 2 的表达不会对细胞铁状态的变化做出反应（20）。转铁蛋白受体 2 在铁负荷病理发生中的确切作用仍未知。最近的生化证据表明，3 型血色素沉着症可能与 HFE 途径不同，因为与转铁蛋白受体不同（3, 4），转铁蛋白受体 2 在体外不会与 HFE 蛋白形成稳定复合物（21）。 HFE、HFE2 和 TfR2 是否参与重叠或完全独立的遗传途径，还有待进一步研究。
FRIEDREICH’S ATAXIA AND SIDEROBLASTIC ANEMIA
弗里德雷希共济失调和铁粒幼细胞性贫血
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.
Friedreich 氏共济失调症（FRDA）和铁粒幼细胞性贫血代表了两种突出显示线粒体铁运输和稳态重要性的疾病。FRDA 是一种神经退行性疾病，其特征是脊髓和脊神经节感觉神经元的丧失[详见（22）]。患者表现出线粒体铁超载的证据（23）和铁硫簇酶活性的丧失（24）。他们经常死于心肌病。大多数 FRDA 病例是由于 FRDA 基因（人类染色体 9q13）内含子中三核苷酸重复扩增（25）导致 frataxin mRNA 和蛋白表达减少（26）。然而，在少数病例中也已发现点突变。
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.
Frataxin 定位于线粒体（27-29）。当 Frataxin 水平下降，如在 FRDA 中的情况，铁在线粒体内积累，导致氧化应激增加和含铁硫簇蛋白活性降低。尽管小鼠 Frataxin 的完全敲除是胚胎致死的（30），但最近发展的 FRDA 条件敲除小鼠模型表明，线粒体铁积累的影响在不同细胞类型中有所不同（31）。已生成两个模型：缺乏神经元中 Frataxin 的小鼠和缺乏条纹肌中 Frataxin 的小鼠。这两种小鼠都复制了人类疾病的特征。
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.
氧化损伤被认为是 FRDA 中神经元丢失的诱因。酵母实验表明，铁被重新分配到 Yfh（酵母铁蛋白同源物）缺乏的酵母线粒体中，这种铁积累先于氧化损伤发生，这表明铁积累更有可能是导致酵母线粒体氧化损伤的原因，而不是结果（32）。最近，已解析了铁蛋白蛋白的晶体结构（33）。铁蛋白与铁储存蛋白铁蛋白具有结构相似性，这表明铁蛋白可能通过维持铁储存或促进其高效周转来调节线粒体铁离子平衡。未来的实验将确定铁蛋白是否参与线粒体铁储存和排出、铁硫簇生物合成或铁硫簇转运。
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, δ-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.
辅酶 B6 治疗许多患者，这是 ALAS2 的辅酶。最近，发现了编码线粒体膜蛋白的新基因 Sideroflexin 1，因为在患有铁粒贫血的小鼠中发生了突变。缺乏 Sideroflexin 的小鼠和缺乏辅酶 B6 的小鼠之间的惊人相似性表明，Sideroflexin 可能有助于将辅酶 B6 或另一种 ALAS2 辅因子转运到线粒体中，但这尚未在实验中得到证实。
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.
ABC-7（人类 X 染色体 Xq13.1–q13.3）（38）是 X 连锁铁粒幼细胞性贫血伴共济失调的突变基因。 ABC-7 基因突变的个体表现为低色素、小细胞性贫血、环状铁粒幼细胞和非进行性脊髓小脑共济失调（39, 40）。 ABC-7 的功能及其与铁粒幼细胞性贫血的关联尚未明确确定。然而，对突变酵母细胞的实验表明，ABC-7 可以替代同源蛋白 Atm1p，后者参与将铁硫簇从线粒体合成位点转运至细胞质（41）。铁硫簇生物合成与弗里德雷希共济失调和伴有共济失调的铁粒幼细胞性贫血中的共济失调之间的联系为铁代谢基因在控制神经元细胞存活和功能中的作用提供了线索，但机制仍不确定。
ACERULOPLASMINEMIA AND NEURODEGENERATION WITH BRAIN-IRON ACCUMULATION-1
铜蓝蛋白血症和脑铁沉积相关的神经退行性疾病-1
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.
铜蓝蛋白血症是一种铁过载的常染色体隐性遗传病，由铜蓝蛋白（Cp）基因（人类染色体 3q23-q24）的功能丧失突变引起（42-45）。虽然与血色病相关的铁过载是由于铁吸收增加，但与铜蓝蛋白血症相关的铁过载是由于铁分布异常。铜蓝蛋白是一种血清蛋白和多铜氧化酶[参见（46）进行审查]。没有这种血清氧化酶活性，铁就无法有效地从肝脏的储存部位回收，导致一系列看似矛盾的与铁相关的症状。血清铁蛋白升高，但血清铁保持较低，因为铁不能有效地装载到转铁蛋白上。铁在肝脏和胰腺的实质细胞和网状内皮细胞中积累，但贫血是因为铁不能有效地输送到红细胞前体细胞。铜蓝蛋白对于从身体所有细胞中输出铁可能并非必不可少，因为膳食铁仍然可以跨越肠道进入铜蓝蛋白血症患者的血液。 这可能是由于 sla 基因产物铜氧化酶活性的影响，赫菲斯汀（人类 X 染色体 Xq11-q12）（47），其在结构和假定功能上与铜蓝蛋白具有显著的同源性。
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
除了贫血和实质性铁过载外，无铜血蛋白血症还会导致视网膜退行、小脑共济失调和痴呆。这些神经症状通常不与原发性或继发性铁过载有关。与弗里德赖希共济失调患者的脊髓后根神经节中的铁积累相比，无铜血蛋白血症相关的共济失调可能是由于大脑基底神经节中的铁积累所致。
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.
神经退行性脑铁沉积症-1（NBIA-1，以前称为哈勒沃登-斯帕兹病（人类 20 号染色体 p12.3-13）（48））是另一种导致大脑铁积累的遗传性疾病。在 NBIA-1 的情况下，年轻患者表现出进行性痴呆和肌肉僵硬。铁积累发生在黑质和球状丘脑（49）中。与这些不同神经疾病相关的大脑铁沉积的不同位置表明，有多个基因控制大脑和神经系统中铁的分布。此外，在费氏共济失调症中缺乏大脑铁沉积表明，大脑的铁调节途径仍然与外周神经系统不同。最后，在血色病或继发性铁过载中缺乏大脑铁沉积暗示了大脑的特定控制机制。
MODIFIERS 修饰语
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, β2 microglobulin deficiency on an HFE–/– background increases iron loading, indicating that another β2 microglobulin-dependent gene product may be involved in iron metabolism (50).
很明显，我们尚未确定所有参与铁运输和代谢的基因。然而，表征哺乳动物铁稳态的下一步将涉及至少部分地识别已经确定的铁代谢紊乱表型的基因。在血色病小鼠模型中的研究表明，DMT1 和 hephaestin 都是由 HFE 调节的铁摄取途径的一部分，这表明这两种蛋白质中的轻微突变会改善或加重血色病表型。此外，在 HFE 背景下β2 微球蛋白缺乏会增加铁负荷，表明另一种β2 微球蛋白依赖的基因产物可能参与铁代谢。
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.
三个新鉴定的铁运输基因，Fpn1/Ireg1/MTP1（人类染色体 2q32）（51），Dcytb 和 CD163（人类染色体 12p13.3）（52）也是铁代谢紊乱的遗传修饰因子的候选基因。Fpn1/Ireg1/MTP1 是脊椎动物中首次发现的跨膜铁外流转运蛋白（53-55）。其推测功能是从包括胎盘合胞体、肠上皮细胞、肝细胞和巨噬细胞在内的专门运输和储存细胞向血液输送铁。因此，导致 Fpn1/Ireg1/MTP1 活性差异的轻微突变可能会改变与铁过载相关疾病的严重程度，包括血色病、无铜血浆蛋白血症和皮肤型卟啉病（见下文）。Fpn1/Ireg1/MTP1 中的功能增强突变可能使其成为新生儿或显性血色病的候选基因。Dcytb（56）是在肠粘膜中表达的一种铁还原酶。它可能在将膳食（三价）铁转化为其二价形式以供二价金属离子转运蛋白 DMT1（57,58）运输中发挥重要作用。 与 Fpn1/Ireg1/MTP1 类似，Dcytb 活性的差异可能通过调节铁吸收来改变铁过载病的发病情况。
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.
CD163 是一种在单核细胞和组织巨噬细胞中表达的清道夫受体，最近已被证明是红细胞在循环中溶解时形成的血红蛋白/血红蛋白复合物的受体。 CD163 的变化可能影响网状内皮系统中铁的周转速率，改变全身储存组织中铁的分布以及遗传性血色病和无铜血浆铁过多症等疾病的严重程度。
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.
HFE 本身就是一个遗传修饰因子的例子，因为 HFE 的突变可以影响皮肤型副铁血红素症（PCT）的严重程度。PCT 是与肝脏铁负荷相关的一种光敏性皮肤病。它是由于尿卟啉和部分脱羧卟啉的增加而导致的。该病存在家族性和散发性两种形式。在任何情况下，都观察到肝酶尿卟啉原脱羧酶（URO-D）活性的降低。PCT 的表型严重程度变化很大。通过评估患有 PCT 的个体的表型和基因型，Bulaj 等人能够确定与铁负荷相关的环境和遗传因素，这些因素有助于更严重的 PCT 表型。C282Y HFE 等位基因是这样一个遗传因素。
CONCLUSIONS 结论
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.
铁病基因的鉴定以及表型和基因型的相关性提供了关于维持铁稳态所需调控广度的重要信息。未来，能够鉴定疾病基因及其修饰因子中的特定损伤可能会导致个体化治疗的实现，这种治疗将考虑到疾病的预期严重程度，而不仅仅是潜在缺陷。即使在过去的一年里，已经发现了对铁摄取和排出的基本过程至关重要的新基因。尽管有这些发现，我们仍然缺乏对许多铁代谢紊乱疾病过程的全面理解。毫无疑问，还有许多涉及细胞内铁运输和稳态调节的额外基因等待鉴定。
ACKNOWLEDGEMENTS 致谢
C.N.R. was supported in part by the Hematology Training Grant T32-HL07623-15.
C.N.R. 部分得到了血液学培训基金 T32-HL07623-15 的支持。
NOTE ADDED IN PROOF
证明中添加的注释
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.
Hayflick 和同事（62）于 2001 年 8 月报告了一种新的在 HSS 中发生突变的基因。在经典和非典型 HSS 患者中鉴定出泛酸激酶基因（PANK2）中的无义、错义和移码突变。受影响个体球内丘中半胱氨酸的积累可能导致铁的螯合和隔离。已提出了一种新名称“泛酸激酶相关神经退行性疾病”或 PKAN，用于该疾病。
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
请将函件寄至：美国波士顿长木大道 300 号，儿童医院 Enders 720 血液学部，邮编 02115。电话：+1 617 355 7265；传真：+1 617 734 6791；电子邮件：nancy_andrews@hms.harvard.edu
Figure 1. Functional modifiers of iron metabolism. Several genes have been shown to alter iron transport processes even though they are not iron transporters themselves. Black arrows depict iron flux through general transport pathways. The specific molecular transporters are not depicted and in some cases have not yet been identified. Red arrows represent the observed changes in iron flux through a given pathway that occur when the indicated gene is mutated. (A) HFE is mutated in type 1 hemochromatosis and results in increased iron absorption through the intestine. Hephaestin (heph) is mutated in mice with sex-linked anemia, resulting in decreased transfer of iron from the intestine to the blood, thereby reducing absorption of iron. (B) Ceruloplasmin (Cp) is mutated in aceruloplasminemia, resulting in decreased efficiency of iron egress from the liver and consequent iron overload. Transferrin receptor 2 (TFR2) is hypothesized to alter liver iron homeostasis because it is mutated in type 2 hemochromatosis, but whether it is involved in iron transport to or from the liver is not yet clear. (C) Mutations in Sideroflexin 1 (Sfxn1) and erythroid d-aminoevulinate synthase (ALAS2) are associated with siderocytic and sideroblastic anemias. An inability to efficiently produce and export heme in both of these anemias is coupled with the accumulation of iron in the mitochondria of erythrocyte precursors. ABC-7 encodes a human ortholog of the yeast iron–sulfur cluster transporter, which is mutated in sideroblastic anemia with ataxia, suggesting that ABC-7 (or the iron–sulfur clusters that it transports) may modify heme synthesis or transport. (D) Friedreich’s ataxia results from trinucleotide expansions in FRDA. These mutations are hypothesized to prevent the efficient synthesis or export of iron–sulfur clusters from the mitochondrion.
Genetic iron overload disorders
表 1. 遗传性铁过载疾病
| Disease | Protein | Map position 地图位置 | Phenotype |
| Hemochromatosis (type 1) 血色病（类型 1） | HFE | 6p21.3 | Increased absorption of dietary iron; iron deposition in liver, heart, endocrine tissues 增加膳食铁的吸收；铁在肝脏、心脏、内分泌组织中沉积 |
| Juvenile hemochromatosis (type 2) 青少年血色素沉着症（2 型） | ? | 1q21 | Rapid iron loading with marked deposition in heart, endocrine tissues, liver 心脏、内分泌组织、肝脏中明显沉积的快速铁负荷 |
| Hemochromatosis (type 3) 血色素沉着症（3 型） | TFR2 | 7q22 | Increased absorption of dietary iron; iron deposition in liver, heart, endocrine tissues 增加膳食铁的吸收；铁在肝脏、心脏、内分泌组织中沉积 |
| Friedreich’s ataxia 弗里德雷希氏共济失调 | Frataxin | 9q13 | Mitochondrial iron deposition, ataxia, cardiomyopathy 线粒体铁沉积，共济失调，心肌病 |
| X-linked sideroblastic anemia X 连锁侧索性贫血 | ALAS2 | Xp11.21 | Defective heme biosynthesis, iron deposition in erythroid mitochondria, anemia 血红素生物合成缺陷，红细胞线粒体中铁沉积，贫血 |
| X-linked sideroblastic anemia with ataxia 共济失调 X 连锁侧索性贫血 | ABC-7 | Xq13 | Mild anemia, mitochondrial iron deposition, non-progressive ataxia 轻度贫血，线粒体铁沉积，非进行性共济失调 |
| Aceruloplasminemia | Cp | 3q23–24 | Mild anemia, liver iron overload, progressive neurodegenerative disease 轻度贫血，肝铁过载，进行性神经退行性疾病 |
| NBIA-1 | ? | 20p1 | Progressive dementia and muscle rigidity 进行性痴呆和肌肉僵硬 |
| Disease | Protein | Map position | Phenotype |
| Hemochromatosis (type 1) | HFE | 6p21.3 | Increased absorption of dietary iron; iron deposition in liver, heart, endocrine tissues |
| Juvenile hemochromatosis (type 2) | ? | 1q21 | Rapid iron loading with marked deposition in heart, endocrine tissues, liver |
| Hemochromatosis (type 3) | TFR2 | 7q22 | Increased absorption of dietary iron; iron deposition in liver, heart, endocrine tissues |
| Friedreich’s ataxia | Frataxin | 9q13 | Mitochondrial iron deposition, ataxia, cardiomyopathy |
| X-linked sideroblastic anemia | ALAS2 | Xp11.21 | Defective heme biosynthesis, iron deposition in erythroid mitochondria, anemia |
| X-linked sideroblastic anemia with ataxia | ABC-7 | Xq13 | Mild anemia, mitochondrial iron deposition, non-progressive ataxia |
| Aceruloplasminemia | Cp | 3q23–24 | Mild anemia, liver iron overload, progressive neurodegenerative disease |
| NBIA-1 | ? | 20p1 | Progressive dementia and muscle rigidity |
Genetic iron overload disorders
| Disease | Protein | Map position | Phenotype |
| Hemochromatosis (type 1) | HFE | 6p21.3 | Increased absorption of dietary iron; iron deposition in liver, heart, endocrine tissues |
| Juvenile hemochromatosis (type 2) | ? | 1q21 | Rapid iron loading with marked deposition in heart, endocrine tissues, liver |
| Hemochromatosis (type 3) | TFR2 | 7q22 | Increased absorption of dietary iron; iron deposition in liver, heart, endocrine tissues |
| Friedreich’s ataxia | Frataxin | 9q13 | Mitochondrial iron deposition, ataxia, cardiomyopathy |
| X-linked sideroblastic anemia | ALAS2 | Xp11.21 | Defective heme biosynthesis, iron deposition in erythroid mitochondria, anemia |
| X-linked sideroblastic anemia with ataxia | ABC-7 | Xq13 | Mild anemia, mitochondrial iron deposition, non-progressive ataxia |
| Aceruloplasminemia | Cp | 3q23–24 | Mild anemia, liver iron overload, progressive neurodegenerative disease |
| NBIA-1 | ? | 20p1 | Progressive dementia and muscle rigidity |
| Disease | Protein | Map position | Phenotype |
| Hemochromatosis (type 1) | HFE | 6p21.3 | Increased absorption of dietary iron; iron deposition in liver, heart, endocrine tissues |
| Juvenile hemochromatosis (type 2) | ? | 1q21 | Rapid iron loading with marked deposition in heart, endocrine tissues, liver |
| Hemochromatosis (type 3) | TFR2 | 7q22 | Increased absorption of dietary iron; iron deposition in liver, heart, endocrine tissues |
| Friedreich’s ataxia | Frataxin | 9q13 | Mitochondrial iron deposition, ataxia, cardiomyopathy |
| X-linked sideroblastic anemia | ALAS2 | Xp11.21 | Defective heme biosynthesis, iron deposition in erythroid mitochondria, anemia |
| X-linked sideroblastic anemia with ataxia | ABC-7 | Xq13 | Mild anemia, mitochondrial iron deposition, non-progressive ataxia |
| Aceruloplasminemia | Cp | 3q23–24 | Mild anemia, liver iron overload, progressive neurodegenerative disease |
| NBIA-1 | ? | 20p1 | Progressive dementia and muscle rigidity |
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