HAMP gene mutation c.208T>C (p.C70R) identified in an Italian patient with severe hereditary hemochromatosis
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Abstract:
Hepcidin is a recently identified hormone peptide involved in regulation of iron homeostasis. HAMP gene mutations have been described to date in five families with iron overload. We have identified the c.208T>C (p.C70R) mutation in the HAMP gene in a patient affected by a severe form of hereditary hemochromatosis. The variant, occurring in a highly conserved amino acid, disrupts one of the 4 intramolecular disulphide bonds present in hepcidin molecules of all vertebrates, and is presumably able to destabilize the peptide structure. The investigated patient was also found to harbor a heterozygous HFE c.845G>A (p.C282Y) mutation that may have contributed in increasing his iron burden.Keywords:
HAMP
Hereditary hemochromatosis
世袭 hemochromatosis (HH ) 被饮食的铁的长期的亢奋的吸收引起。在织物实质的房间以内的过量铁的进步累积可以导致严重机关损坏。HH 的最流行的类型在 HFE 基因被连接到变化，编码一个不正常的主要组织适合性建筑群一级分子。立即在它在 1996 的发现以后， hemochromatosis 蛋白质 HFE 被显示身体上与转铁蛋白受体 1 交往(TfR1 ) 并且在房间损害 transferrin 固定的铁的举起。然而，这些调查结果没提供 HFE 变化与全身的铁超载联系的线索。HH 的所有形式源于 hepcidin 表示的错误规定，这以后被建立。从由支持铁出口商 ferroportin 的降级的十二指肠的 enterocytes 和网状内皮组织的巨噬细胞的这导出肝的传播肽荷尔蒙控制铁流出。与 HH 的动物模型一起的最近的研究揭开 hepatocyte 熨传感器和 hepcidin 的在上游的管理者的 HFE 的一个关键角色。因此， hepatocyte HFE 为发信号到 hepcidin 是不可缺少的，大概作为更大的察觉到铁的建筑群的成分。一个工作模型要求当蛋白质 TfR1 一定时， HFE 的发信号的活动是 silenced。血浆转铁蛋白的铁浸透的增加从通常认为的察觉到铁的建筑群的 HFE 和汇编导致 TfR1 的排水量。这样，由 hepatocyte 的铁举起被翻译成在 hepcidin 的规定上面，增强肝是为全身的铁动态平衡的主要规章的地点的概念，并且不仅仅一个铁存储仓库。
Hereditary hemochromatosis
Ferroportin
Transferrin receptor
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Ferroportin
Hereditary hemochromatosis
HAMP
Pathogenesis
Transferrin receptor
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Patients with hereditary hemochromatosis (HC) may present a plenty of clinical symptoms, thus are referred to various specialists and may prone a significant diagnostic dillema. The molecular basis of hemochromatosis is more complex than expected. In 1996 HFE gene was identified and its main mutations (C282Y and H63D) were described as well as their high frequency in population of European descent. Them: Most patients with clinical symptoms of hemochromatosis are homozygous for C282Y but it is also clear that some families are linked to rarer conditions, named non-HFE hemochromatosis. Between 2000-2004 other genes involved in iron homeostasis were intensively studied, leading to recognition of hepcidin (HAMP) - the most important iron hormone, hemojuvelin (HJV), transferin receptor 2 (TfR2) and ferroportin. Recent findings led to novel hypothesis on potential digenic modes of inheritance or the involvement of modifier genes. Hepcidin plays a central role in mobilization of iron, HFE, TfR2 and HJV playing a modulating role in its production, related to the body's iron status. It has also been demonstrated that HAMP negatively regulates cellular iron efflux by affecting the ferroportin cell surface availability. The result of such a wide investigations is OMIM classification of hereditaty hemochromatosis, typing four types of the disease.
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<i>Background/Aims:</i> In <i>HFE</i>-related hereditary hemochromatosis an inappropriately low hepatic expression of the iron-regulatory peptide hepcidin (encoded by <i>HAMP</i>) has been suggested to cause iron overload. The aim of the present study was to evaluate whether the hepatic expression of <i>HAMP</i> in relation to iron stores requires <i>HFE</i> or might involve other important iron-related genes including <i>HJV</i> (encoding hemojuvelin) and <i>TFR2 </i>(encoding transferrin receptor-2). <i>Methods:</i> Using quantitative RT-PCR, the iron-dependent hepatic expression patterns of <i>HAMP</i>, <i>HJV</i>, and <i>TFR2</i> were evaluated in human and murine <i>HFE</i>-related hemochromatosis. <i>Results:</i> The overall level of hepatic <i>HAMP</i> expression in human and murine <i>HFE</i>-related hemochromatosis is impaired but can still be modulated by iron stores. Moreover, we demonstrate an <i>HFE</i>-independent correlation between the expression of <i>HAMP</i> and <i>TFR2</i> in mouse and human livers. On the other hand, a strong correlation between the hepatic expression of <i>HAMP</i> and <i>HJV</i> was only found in hemochromatosis patients and <i>Hfe</i>-deficient mice. <i>Conclusion:</i> The central pathogenetic step in <i>HFE</i>-related hemochromatosis is an impaired basal expression of <i>HAMP</i> rather than a lack of <i>HAMP</i> upregulation in response to iron stores. An <i>HFE</i>-independent pathway that seems to involve <i>TFR2</i> and <i>HJV</i> can regulate <i>HAMP</i> expression under conditions of iron overload.
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Remarkable advances in understanding the pathogenesis of hereditary hemochromatosis have been made since 1996, the year in which the HFE gene, which is responsible for the vast majority of cases, was discovered.1 The recognition of the central role of the iron regulatory hormone hepcidin in the pathogenesis of hereditary hemochromatosis has been particularly significant. In addition to HFE, defects in four additional genes have been found to cause hereditary hemochromatosis: hepcidin, transferrin receptor 2 (TFR2), hemojuvelin (HJV), and ferroportin.2 Interestingly, these genes each encode for a protein that affects pathways influencing liver hepcidin synthesis or its interaction with the cellular iron export protein ferroportin. It is now clear that inadequate production of hepcidin or response to it is responsible for the excess dietary iron absorption and excess iron release from macrophages stores, and consequent hyperferremia, which characterize the classical hereditary hemochromatosis phenotype. For clinicians, the challenge is to diagnose hereditary hemochromatosis before this hyperferremia leads to irreversible tissue damage. At the same time the clinician must have ways to distinguish progressive heritable forms of iron overload from increasingly common acquired diseases with only moderately increased iron body stores, such as the metabolic syndrome. This challenge has raised interest in the possibility that recent bench top discoveries might lead to novel bedside laboratory tests. Two publications in this issue of Haematologica are relevant to this possibility.3,4 In one study, serum hepcidin levels were used to characterize the response of patients with HFE- or TFR2-associated hereditary hemochromatosis to an oral iron challenge.3 The other study identifed several clinically significant orphan mutations in the HFE gene.4 The contribution of each of these studies to a better understanding of the pathogenesis of hereditary hemochromatosis and the possible ways they might influence the future diagnostic work-up and monitoring of iron overload disorders are discussed.
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Hemochromatosis is a kind of organ-damaged disease which is caused by iron overload.Many genes related iron metabolism such as HFE,HJV,HAMP,TfR2 are mutated to result in hemochromatosis,and HAMP is the most important gene.HAMP encodes a kind of small peptide called hepcidin which is a negative regulator of iron absorbtion in the small intestine and iron release from macrophages.Decrease of hepcidin content can lead to serum iron load and hemochromatosis.Other genes such as HFE,HJV,TfR2 can affect expression of hepcidin,so hepcidin is a central regulator in hemochromatosis.These researches are very important for understanding of hemochromatosis mechanism and diagnosis and treatment of hemochromatosis.
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Hereditary hemochromatosis
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Hereditary hemochromatosis (HH) is an inherited iron overload disorder characterized by normal iron-driven erythropoiesis and abnormal iron metabolism, leading to excess iron deposited in parenchymal cells of liver, heart, and endocrine glands. Iron hormone, hepcidin, plays a critical role in iron homeostasis through interaction with ferroportin (FPN), a major cellular iron exporter. Hepcidin is encoded by hepcidin antimicrobial peptide (HAMP). Mutations in hepcidin and any genes that regulate the biology of hepcidin, including hemochromatosis genes (HFE), Hemojuvelin (HJV), transferring receptor 2 (TFR2) and FPN, result in hemochromatosis. The identification of hepcidin and its role will provide a better understanding for pathogenesis of HH.
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