Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis
Antonella RoettoGeorge PapanikolaouMarianna PolitouFederica AlbertiDomenico GirelliJohn ChristakisDimitris LoukopoulosClara Camaschella
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HAMP
Hereditary hemochromatosis
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HAMP
Hereditary hemochromatosis
Pathogenesis
Liver disease
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Hereditary hemochromatosis (HHC) is a rare autosomal recessive disorder. We recruited a consanguineous Chinese family including the proband with HHC and other four members without HHC. Using whole-exome sequencing, we identified two homozygous mutations (c.G18C [p.Q6H] and c.GC962_963AA [p.C321X]) in the hemojuvelin gene (HJV) in the proband with HHC. No mutation was found in other four previously identified HHC related genes, HAMP, TFR2, FPN and HFE. The functional impact of p.Q6H mutation is weak whereas p.C321X, a premature termination mutation, results in a truncated HJV protein, which lacks the glycosylphosphatidylinositol (GPI) anchor domain. In addition to the mutations in HJV, other 12 homozygous mutations were identified in this patient. However, none of these mutations showed strong damaging impact and the mutated genes are not related to iron metabolism. Our in-house data further demonstrated that p.C321X is absent in the general Chinese population, suggesting that the homozygous mutation p.C321X in HJV is causative in the patient with HHC. Accordingly, all of the four members without HHC from the same family carried wild-type alleles or heterozygous mutations, but not the homozygous mutation in this site. Thus, we found for the first time that the homozygous mutation p.C321X in HJV can result in HHC, which will help genetic diagnosis and prenatal counseling for HHC.
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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.
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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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Hereditary hemochromatosis
Ferroportin
Pathogenesis
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HAMP
Hereditary hemochromatosis
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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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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
Ferroportin
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HAMP
Ferroportin
Hereditary hemochromatosis
Transferrin saturation
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HAMP
Hereditary hemochromatosis
Ferroportin
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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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Ferroportin
Hereditary hemochromatosis
Pathogenesis
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