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Heilmeier U, Burghardt AJ, Tse JJ, Kapoor P, Stok KS, Manske S, Voll RE, Schett G, Finzel S. Analysis of Hand Joint Space Morphology in Women and Men with Hereditary Hemochromatosis. Calcif Tissue Int 2023; 112:440-451. [PMID: 36738308 PMCID: PMC10025180 DOI: 10.1007/s00223-022-01050-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 11/25/2022] [Indexed: 02/05/2023]
Abstract
Hereditary hemochromatosis (HH) causes unbalanced iron deposition in many organs including the joints leading to severe cartilage loss and bone damage in the metacarpophalangeal joints (MCPJ). High-resolution peripheral quantitative computed tomography (HR-pQCT) and its joint space width (JSW) quantification algorithm quantifies in vivo 3D joint morphology. We therefore aimed to (i) determine feasibility and performance of the JSW algorithm in HH, (ii) quantify joint space morphology, and (iii) investigate the relationship between morphological and clinical parameters in HH. Here, we performed an exploratory study on 24 HH patients and sex- and age-matched controls using HR-pQCT imaging of MCPJ. Mineralized bone structure was automatically segmented from the grayscale image data and periosteal surface bone masks and joint space masks were generated. Mean, minimal, and maximal joint space width (JSW; JSW.MIN; JSW.MAX), JSW heterogeneity (JSW.SD), JSW asymmetry (JSW.AS), and joint space volume (JSV) were computed. Demographics and, for HH patients, disease-specific parameters were recorded. Segmentation of JS was very good with 79.7% of MCPJs successfully segmented at first attempt and 20.3% requiring semi-manual correction. HH men showed larger JSV at all MCPs (+ 25.4% < JSV < + 41.8%, p < 0.05), larger JSW.MAX at MCP 3-4 (+ 14%, 0.006 < p < 0.062), and wider JSW (+ 13%, p = 0.043) at MCP 4 relative to HH women. Compared to controls, both HH men and HH women showed larger JSW.AS and smaller JSW.MIN at all MCP levels, reaching significance for HH men at MCP 2 and 3 (JSW.AS: + 323% < JSW.AS < + 359%, 0.020 < p < 0.043; JSW.MIN: - 216% < JSW.MIN < - 225%, p < 0.043), and for women at MCP 3 (JSW.AS: + 180%, p = 0.025; JSW.MIN: - 41.8%, p = 0.022). Time since HH diagnosis was correlated positively with MCP 4 JSW.AS and JSW.SD (0.463 < ρ < 0.499, p < 0.040), and the number of phlebotomies since diagnosis was correlated with JSW.SD at all MCPs (0.432 < ρ < 0.535, p < 0.050). HR-pQCT-based JSW quantification in MCPJ of HH patients is feasible, performs well even in narrow JS, and allows to define the microstructural joint burden of HH.
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Affiliation(s)
- Ursula Heilmeier
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg - Medical Center, Hugstetterstraße 55, 79106, Freiburg, Germany.
- Musculoskeletal Quantitative Imaging Research Group, University of California San Francisco, 185 Berry Street, San Francisco, CA, 94158, USA.
| | - Andrew J Burghardt
- Department of Radiology and Biomedical Imaging, University of California San Francisco, 185 Berry Street, San Francisco, CA, 94158, USA
| | - Justin J Tse
- Department of Radiology, Cumming School of Medicine, McCaig Institute for Bone and Joint Health, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada
| | - Puneet Kapoor
- Musculoskeletal Quantitative Imaging Research Group, University of California San Francisco, 185 Berry Street, San Francisco, CA, 94158, USA
| | - Kathryn S Stok
- Department of Biomedical Engineering, The University of Melbourne, Parkville, VIC, Australia
| | - Sarah Manske
- Department of Radiology, Cumming School of Medicine, McCaig Institute for Bone and Joint Health, University of Calgary, 3280 Hospital Drive NW, Calgary, AB, T2N 4Z6, Canada
| | - Reinhard E Voll
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg - Medical Center, Hugstetterstraße 55, 79106, Freiburg, Germany
| | - Georg Schett
- Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Stephanie Finzel
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg - Medical Center, Hugstetterstraße 55, 79106, Freiburg, Germany
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Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease. Blood 2018; 132:101-110. [PMID: 29743178 DOI: 10.1182/blood-2018-02-830562] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Accepted: 05/03/2018] [Indexed: 12/15/2022] Open
Abstract
The clinical progression of HFE-related hereditary hemochromatosis (HH) and its phenotypic variability has been well studied. Less is known about the natural history of non-HFE HH caused by mutations in the HJV, HAMP, or TFR2 genes. The purpose of this study was to compare the phenotypic and clinical presentations of hepcidin-deficient forms of HH. A literature review of all published cases of genetically confirmed HJV, HAMP, and TFR2 HH was performed. Phenotypic and clinical data from a total of 156 patients with non-HFE HH was extracted from 53 publications and compared with data from 984 patients with HFE-p.C282Y homozygous HH from the QIMR Berghofer Hemochromatosis Database. Analyses confirmed that non-HFE forms of HH have an earlier age of onset and a more severe clinical course than HFE HH. HJV and HAMP HH are phenotypically and clinically very similar and have the most severe presentation, with cardiomyopathy and hypogonadism being particularly prevalent findings. TFR2 HH is more intermediate in its age of onset and severity. All clinical outcomes analyzed were more prevalent in the juvenile forms of HH, with the exception of arthritis and arthropathy, which were more commonly seen in HFE HH. This is the first comprehensive analysis comparing the different phenotypic and clinical aspects of the genetic forms of HH, and the results will be valuable for the differential diagnosis and management of these conditions. Importantly, our analyses indicate that factors other than iron overload may be contributing to joint pathology in patients with HFE HH.
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Abstract
Haemochromatosis is defined as systemic iron overload of genetic origin, caused by a reduction in the concentration of the iron regulatory hormone hepcidin, or a reduction in hepcidin-ferroportin binding. Hepcidin regulates the activity of ferroportin, which is the only identified cellular iron exporter. The most common form of haemochromatosis is due to homozygous mutations (specifically, the C282Y mutation) in HFE, which encodes hereditary haemochromatosis protein. Non-HFE forms of haemochromatosis due to mutations in HAMP, HJV or TFR2 are much rarer. Mutations in SLC40A1 (also known as FPN1; encoding ferroportin) that prevent hepcidin-ferroportin binding also cause haemochromatosis. Cellular iron excess in HFE and non-HFE forms of haemochromatosis is caused by increased concentrations of plasma iron, which can lead to the accumulation of iron in parenchymal cells, particularly hepatocytes, pancreatic cells and cardiomyocytes. Diagnosis is noninvasive and includes clinical examination, assessment of plasma iron parameters, imaging and genetic testing. The mainstay therapy is phlebotomy, although iron chelation can be used in some patients. Hepcidin supplementation might be an innovative future approach.
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Affiliation(s)
- Pierre Brissot
- INSERM, Univ. Rennes, INRA, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1241, F-35000 Rennes, France
| | - Antonello Pietrangelo
- Division of Internal Medicine 2 and Center for Haemochromatosis, University Hospital of Modena, Modena, Italy
| | - Paul C. Adams
- Department of Medicine, University of Western Ontario, London, Ontario, Canada
| | - Barbara de Graaff
- Menzies Institute for Medical Research, University of Tasmania, Tasmania, Australia
| | | | - Olivier Loréal
- INSERM, Univ. Rennes, INRA, Institut NUMECAN (Nutrition Metabolisms and Cancer) UMR_A 1341, UMR_S 1241, F-35000 Rennes, France
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Laursen AH, Bjerrum OW, Friis-Hansen L, Hansen TO, Marott JL, Magnussen K. Causes of iron overload in blood donors - a clinical study. Vox Sang 2017; 113:110-119. [PMID: 29230833 DOI: 10.1111/vox.12619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 10/31/2017] [Accepted: 11/04/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND OBJECTIVES Despite the obligate iron loss from blood donation, some donors present with hyperferritinaemia that can result from a wide range of acute and chronic conditions including hereditary haemochromatosis (HH). The objective of our study was to investigate the causes of hyperferritinaemia in the blood donor population and explore the value of extensive HH mutational analyses. MATERIALS AND METHODS Forty-nine consecutive donors (f = 6, m = 43) were included prospectively from the Capital Regional Blood Center. Inclusion criteria were a single ferritin value >1000 μg/l or repeated hyperferritinaemia with at least one value >500 μg/l. All donors were questioned about their medical history and underwent a physical examination, biochemical investigations and next-generation sequencing of HH-related genes, including the HFE gene, the haemojuvelin gene (HFE2/HJV), the hepcidin gene (HAMP), the ferroportin 1 gene (SLC40A1) and the transferrin receptor 2 gene (TFR2). RESULTS Forty of 49 donors were mutation positive with a combined 69 mutations, 54 of which were located in the HFE gene. There were 11 mutations in the TFR2 gene, two mutations in the HFE2 gene and two mutations in the HAMP gene. Only four donors had apparent alternative causes of hyperferritinaemia. CONCLUSION HH-related mutations were the most frequent cause of hyperferritinaemia in a Danish blood donor population, and it appears that several different HH-genotypes can contribute to hyperferritinaemia. HH screening in blood donors with high ferritin levels could be warranted. HH-related iron overload should not in itself result in donor ineligibility.
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Affiliation(s)
- A H Laursen
- Department of Haematology, Rigshospitalet, Copenhagen, Denmark
| | - O W Bjerrum
- Department of Haematology, Rigshospitalet, Copenhagen, Denmark
| | - L Friis-Hansen
- Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Biochemistry, Nordsjaellands Hospital, Hillerod, Denmark
| | - T O Hansen
- Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark
| | - J L Marott
- The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen, Denmark
| | - K Magnussen
- Blood Centre Lab, Hvidovre Hospital, Hvidovre, Denmark.,Department of Immunology and Transfusion Medicine, Sorlandet hospital Kristiansand, Kristiansand, Norway
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Achi H, Moukalled N, Mahfouz R, Piperno A, Taher A. Novel mutation in the Transferrin receptor-2 in a patient with Hereditary Hemochromatosis type 3. Meta Gene 2017. [DOI: 10.1016/j.mgene.2017.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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McLaren CE, Emond MJ, Subramaniam VN, Phatak PD, Barton JC, Adams PC, Goh JB, McDonald CJ, Powell LW, Gurrin LC, Allen KJ, Nickerson DA, Louie T, Ramm GA, Anderson GJ, McLaren GD. Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload. Hepatology 2015; 62:429-39. [PMID: 25605615 PMCID: PMC4508230 DOI: 10.1002/hep.27711] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 01/13/2015] [Indexed: 12/12/2022]
Abstract
UNLABELLED To identify polymorphisms associated with variability of iron overload severity in HFE-associated hemochromatosis, we performed exome sequencing of DNA from 35 male HFE C282Y homozygotes with either markedly increased iron stores (n = 22; cases) or with normal or mildly increased iron stores (n = 13; controls). The 35 participants, residents of the United States, Canada, and Australia, reported no or light alcohol consumption. Sequencing data included 82,068 single-nucleotide variants, and 10,337 genes were tested for a difference between cases and controls. A variant in the GNPAT gene showed the most significant association with severe iron overload (P = 3 × 10(-6) ; P = 0.033 by the likelihood ratio test after correction for multiple comparisons). Sixteen of twenty-two participants with severe iron overload had glyceronephosphate O-acyltransferase (GNPAT) polymorphism p.D519G (rs11558492; 15 heterozygotes, one homozygote). No control participant had this polymorphism. To examine functional consequences of GNPAT deficiency, we performed small interfering RNA-based knockdown of GNPAT in the human liver-derived cell line, HepG2/C3A. This knockdown resulted in a >17-fold decrease in expression of the messenger RNA encoding the iron-regulatory hormone, hepcidin. CONCLUSION GNPAT p.D519G is associated with a high-iron phenotype in HFE C282Y homozygotes and may participate in hepcidin regulation.
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Affiliation(s)
| | - Mary J. Emond
- Department of Biostatistics, University of Washington, Seattle, WA
| | - V. Nathan Subramaniam
- QIMR Berghofer Medical Research Institute, Brisbane, Australia,Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia
| | | | | | - Paul C. Adams
- Department of Medicine, London Health Sciences Centre, London, ON, Canada
| | - Justin B. Goh
- QIMR Berghofer Medical Research Institute, Brisbane, Australia,Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia
| | | | - Lawrie W. Powell
- QIMR Berghofer Medical Research Institute, Brisbane, Australia,Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia,Royal Brisbane & Women’s Hospital, Brisbane, Australia
| | - Lyle C. Gurrin
- Centre for MEGA Epidemiology, The University of Melbourne, Melbourne, Australia
| | | | | | - Tin Louie
- Department of Biostatistics, University of Washington, Seattle, WA
| | - Grant A. Ramm
- QIMR Berghofer Medical Research Institute, Brisbane, Australia,Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia
| | - Gregory J. Anderson
- QIMR Berghofer Medical Research Institute, Brisbane, Australia,School of Medicine and School of Chemistry and Molecular Bioscience, University of Queensland
| | - Gordon D. McLaren
- Department of Veterans Affairs Long Beach Healthcare System, Long Beach, CA,Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA
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Worthen CA, Enns CA. The role of hepatic transferrin receptor 2 in the regulation of iron homeostasis in the body. Front Pharmacol 2014; 5:34. [PMID: 24639653 PMCID: PMC3944196 DOI: 10.3389/fphar.2014.00034] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Accepted: 02/18/2014] [Indexed: 12/22/2022] Open
Abstract
Fine-tuning of body iron is required to prevent diseases such as iron-overload and anemia. The putative iron sensor, transferrin receptor 2 (TfR2), is expressed in the liver and mutations in this protein result in the iron-overload disease Type III hereditary hemochromatosis (HH). With the loss of functional TfR2, the liver produces about 2-fold less of the peptide hormone hepcidin, which is responsible for negatively regulating iron uptake from the diet. This reduction in hepcidin expression leads to the slow accumulation of iron in the liver, heart, joints, and pancreas and subsequent cirrhosis, heart disease, arthritis, and diabetes. TfR2 can bind iron-loaded transferrin (Tf) in the bloodstream, and hepatocytes treated with Tf respond with a 2-fold increase in hepcidin expression through stimulation of the bone morphogenetic protein (BMP)-signaling pathway. Loss of functional TfR2 or its binding partner, the original HH protein, results in a loss of this transferrin-sensitivity. While much is known about the trafficking and regulation of TfR2, the mechanism of its transferrin-sensitivity through the BMP-signaling pathway is still not known.
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Affiliation(s)
- Christal A Worthen
- Department of Cell and Developmental Biology, Oregon Health and Science University Portland, OR, USA
| | - Caroline A Enns
- Department of Cell and Developmental Biology, Oregon Health and Science University Portland, OR, USA
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8
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TFR2-related hereditary hemochromatosis as a frequent cause of primary iron overload in patients from Central-Southern Italy. Blood Cells Mol Dis 2014; 52:83-7. [DOI: 10.1016/j.bcmd.2013.08.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 07/23/2013] [Indexed: 11/21/2022]
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Brissot P, Bardou-Jacquet E, Troadec MB, Mosser A, Island ML, Detivaud L, Loréal O, Jouanolle AM. Molecular diagnosis of genetic iron-overload disorders. Expert Rev Mol Diagn 2014; 10:755-63. [DOI: 10.1586/erm.10.55] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Shi Y, Lian Y, Zhou L, Huang L, Zhang X, Guo H, Wu T, Cheng L, He M. Association between genetic variations in TFR2 gene and coronary heart disease in Chinese: a case-control study. J Cardiovasc Med (Hagerstown) 2013; 15:397-401. [PMID: 23751596 DOI: 10.2459/jcm.0b013e32836206f3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
AIMS Studies indicated that body iron stores were associated with coronary heart disease (CHD). Type 2 transferrin receptor (TFR2) participates in cellular iron overload and is related to cardiovascular disease. No studies investigated the associations between variants in TFR2 gene and CHD risk. METHODS We sought to investigate this association in a Chinese Han population and performed a case-control study recruiting 1264 CHD patients and 1264 age and sex frequency matched controls. TaqMan single nucleotide polymorphisms (SNP) allelic discrimination was used to examine genotypes of the tagging single nucleotide polymorphisms (tagSNPs) of TFR2. The plasma ferritin levels were measured by ELISA. RESULTS We did not find significant associations between variants of TFR2 gene (including tagSNPs rs2075674 and rs7385804) and the risk of CHD. After adjustment for the conventional risk factors of CHD, such as smoking and age, the results did not materially alter. Interaction analyses indicated that there were no significant interactions between conventional risk factors of CHD and these two tagSNPs on CHD risk. Among different genotypes of these two tagSNPs, no significant differences in plasma ferritin levels were found. CONCLUSION In summary, the variants of rs2075674 and rs7385804 in TFR2 gene were not associated with CHD risk in a Chinese Han population.
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Affiliation(s)
- Ying Shi
- aInstitute of Occupational Medicine and the Ministry of Education Key Lab of Environment and Health bDepartment of Cardiology, Union Hospital, Huazhong University of Science and Technology cDepartment of Cardiology, the People's Hospital of Guangxi Zhuang Autonomous Region, China
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Santos PCJDL, Dinardo CL, Cançado RD, Schettert IT, Krieger JE, Pereira AC. Non-HFE hemochromatosis. Rev Bras Hematol Hemoter 2012; 34:311-6. [PMID: 23049448 PMCID: PMC3460409 DOI: 10.5581/1516-8484.20120079] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 07/10/2012] [Indexed: 12/15/2022] Open
Abstract
Hereditary hemochromatosis (HH) is an autosomal recessive disorder classically related to HFE mutations. However, since 1996, it is known that HFE mutations explain about 80% of HH cases, with the remaining around 20% denominated non-HFE hemochromatosis. Nowadays, four main genes are implicated in the pathophysiology of clinical syndromes classified as non-HFE hemochromatosis: hemojuvelin (HJV, type 2Ajuvenile HH), hepcidin (HAMP, type 2B juvenile HH), transferrin receptor 2 (TFR2, type 3 HH) and ferroportin (SLC40A1, type 4 HH). The aim of this review is to explore molecular, clinical and management aspects of non-HFE hemochromatosis.
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12
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Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis. Gene 2012; 508:15-20. [PMID: 22890139 DOI: 10.1016/j.gene.2012.07.069] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2012] [Accepted: 07/30/2012] [Indexed: 01/29/2023]
Abstract
Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c.845G>A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HFE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A (p.A376D) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype.
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Siddique A, Kowdley KV. Review article: the iron overload syndromes. Aliment Pharmacol Ther 2012; 35:876-93. [PMID: 22385471 DOI: 10.1111/j.1365-2036.2012.05051.x] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 06/26/2011] [Accepted: 02/08/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Iron overload syndromes encompass a wide range of hereditary and acquired conditions. Major developments in the field of genetics and the discovery of hepcidin as a central regulator of iron homeostasis have greatly increased our understanding of the pathophysiology of iron overload syndromes. AIM To review advances in iron regulation and iron overload syndrome with special emphasis on hereditary haemochromatosis, the prototype iron overload syndrome. METHODS A PubMed search using words such as 'iron overload', 'hemochromatosis', 'HFE', 'Non-HFE', 'secondary iron overload' was undertaken. RESULTS Iron overload is associated with significant morbidity and mortality. Sensitive diagnostic tests and effective therapy are widely available and can prevent complications associated with iron accumulation in end- organs. Therapeutic phlebotomy remains the cornerstone of therapy for removal of excess body iron, but novel therapeutic agents including oral iron chelators have been developed for iron overload associated with anaemia. CONCLUSIONS Iron overload disorders are common. Inexpensive screening tests as well as confirmatory diagnostic tests are widely available. Increased awareness of the causes and importance of early diagnosis and knowledge of the appropriate use of genetic testing are encouraged. The availability of novel treatments should increase therapeutic options for patients with iron overload disorders.
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Affiliation(s)
- A Siddique
- Department of Hepatology, Virginia Mason Medical Center, Seattle, WA, USA.
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14
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Molecular diagnostic and pathogenesis of hereditary hemochromatosis. Int J Mol Sci 2012; 13:1497-1511. [PMID: 22408404 PMCID: PMC3291973 DOI: 10.3390/ijms13021497] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2011] [Revised: 01/12/2012] [Accepted: 01/13/2012] [Indexed: 12/15/2022] Open
Abstract
Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by enhanced intestinal absorption of dietary iron. Without therapeutic intervention, iron overload leads to multiple organ damage such as liver cirrhosis, cardiomyopathy, diabetes, arthritis, hypogonadism and skin pigmentation. Most HH patients carry HFE mutant genotypes: homozygosity for p.Cys282Tyr or p.Cys282Tyr/p.His63Asp compound heterozygosity. In addition to HFE gene, mutations in the genes that encode hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1) have been associated with regulation of iron homeostasis and development of HH. The aim of this review was to identify the main gene mutations involved in the pathogenesis of type 1, 2, 3 and 4 HH and their genetic testing indication. HFE testing for the two main mutations (p.Cys282Tyr and p.His63Asp) should be performed in all patients with primary iron overload and unexplained increased transferrin saturation and/or serum ferritin values. The evaluation of the HJV p.Gly320Val mutation must be the molecular test of choice in suspected patients with juvenile hemochromatosis with less than 30 years and cardiac or endocrine manifestations. In conclusion, HH is an example that genetic testing can, in addition to performing the differential diagnostic with secondary iron overload, lead to more adequate and faster treatment.
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Hereditary hemochromatosis: Mutations in genes involved in iron homeostasis in Brazilian patients. Blood Cells Mol Dis 2011; 46:302-7. [DOI: 10.1016/j.bcmd.2011.02.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Revised: 02/11/2011] [Accepted: 02/17/2011] [Indexed: 12/29/2022]
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Factors influencing disease phenotype and penetrance in HFE haemochromatosis. Hum Genet 2010; 128:233-48. [DOI: 10.1007/s00439-010-0852-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Accepted: 06/16/2010] [Indexed: 01/24/2023]
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17
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Santos PCJL, Cançado RD, Terada CT, Rostelato S, Gonzales I, Hirata RDC, Hirata MH, Chiattone CS, Guerra-Shinohara EM. HFE gene mutations and iron status of Brazilian blood donors. Braz J Med Biol Res 2009; 43:107-14. [PMID: 20027482 DOI: 10.1590/s0100-879x2009007500031] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Accepted: 12/04/2009] [Indexed: 12/15/2022] Open
Abstract
Mutations of the HFE and TFR2 genes have been associated with iron overload. HFE and TFR2 mutations were assessed in blood donors, and the relationship with iron status was evaluated. Subjects (N = 542) were recruited at the Hemocentro da Santa Casa de São Paulo, São Paulo, Brazil. Iron status was not influenced by HFE mutations in women and was independent of blood donation frequency. In contrast, men carrying the HFE 282CY genotype had lower total iron-binding capacity (TIBC) than HFE 282CC genotype carriers. Men who donated blood for the first time and were carriers of the HFE 282CY genotype had higher transferrin saturation values and lower TIBC concentrations than those with the homozygous wild genotype for the HFE C282Y mutation. Moreover, in this group of blood donors, carriers of HFE 63DD plus 63HD genotypes had higher serum ferritin values than those with the homozygous wild genotype for HFE H63D mutation. Multiple linear regression analysis showed that HFE 282CY leads to a 17.21% increase (P = 0.018) and a 83.65% decrease (P = 0.007) in transferrin saturation and TIBC, respectively. In addition, serum ferritin is influenced by age (3.91%, P = 0.001) and the HFE 63HD plus DD genotype (55.84%, P = 0.021). In conclusion, the HFE 282Y and 65C alleles were rare, while the HFE 63D allele was frequent in Brazilian blood donors. The HFE C282Y and H63D mutations were associated with alterations in iron status in blood donors in a gender-dependent manner.
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Affiliation(s)
- P C J L Santos
- Departamento de Análises Clínicas e Toxicológicas, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP, Brasil
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Gan EK, Trinder D, Ayonrinde OT, Olynyk JK. Genetics of hereditary hemochromatosis: a clinical perspective. Expert Rev Endocrinol Metab 2009; 4:225-239. [PMID: 30743791 DOI: 10.1586/eem.09.9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Hereditary hemochromatosis due to homozygosity for the C282Y mutation in the HFE gene product is the most common autosomal recessive genetic disorder in populations of northern European descent, where it attains a maximum prevalence of approximately one in 200. Cross-sectional and longitudinal studies have revealed that clinically significant iron-overload disease develops in at least 28% of male and 1% of female HFE C282Y homozygotes. The relatively low clinical penetrance is largely unexplained. Current evidence suggests a limited role for digenic inheritance of mutations in iron homeostasis genes in modifying the penetrance of hemochromatosis. Male gender is a strong genetic factor, promoting expression of clinical disease. Dietary intake of alcohol and noncitrus fruit may also act as important environmental modifiers of penetrance. With genetic analyses becoming simpler to perform, new genetic modifiers of hepatic iron loading and liver fibrogenesis are likely to be forthcoming.
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Affiliation(s)
- Eng K Gan
- a School of Medicine & Pharmacology, Fremantle Hospital, PO Box 480, Fremantle 6959, WA, Australia.
| | - Debbie Trinder
- b School of Medicine & Pharmacology, Fremantle Hospital, PO Box 480, Fremantle 6959, WA, Australia.
| | - Oyekoya T Ayonrinde
- c School of Medicine & Pharmacology, Fremantle Hospital, PO Box 480, Fremantle 6959, WA, Australia.
| | - John K Olynyk
- d Professor, School of Medicine & Pharmacology, Fremantle Hospital, PO Box 480, Fremantle 6959, WA, Australia.
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Bittencourt PL, Marin MLC, Couto CA, Cançado ELR, Carrilho FJ, Goldberg AC. Analysis of HFE and non-HFE gene mutations in Brazilian patients with hemochromatosis. Clinics (Sao Paulo) 2009; 64:837-41. [PMID: 19759876 PMCID: PMC2745139 DOI: 10.1590/s1807-59322009000900003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2009] [Accepted: 06/01/2009] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Approximately one-half of Brazilian patients with hereditary hemochromatosis (HH) are neither homozygous for the C282Y mutation nor compound heterozygous for the H63D and C282Y mutations that are associated with HH in Caucasians. Other mutations have been described in the HFE gene as well as in genes involved in iron metabolism, such as transferrin receptor 2 (TfR2) and ferroportin 1 (SCL40A1). AIMS To evaluate the role of HFE, TfR2 and SCL40A1 mutations in Brazilian subjects with HH. PATIENTS AND METHODS Nineteen male subjects (median age 42 [range: 20-72] years) with HH were evaluated using the Haemochromatosis StripAssay A. This assay is capable of detecting twelve HFE mutations, which are V53M, V59M, H63D, H63H, S65C, Q127H, P160delC, E168Q, E168X, W169X, C282Y and Q283, four TfR2 mutations, which are E60X, M172K, Y250X, AVAQ594-597del, and two SCL40A1 mutations, which are N144H and V162del. RESULTS In our cohort, nine (47%) patients were homozygous for the C282Y mutation, two (11%) were heterozygous for the H63D mutation, and one each (5%) was either heterozygous for C282Y or compound heterozygous for C282Y and H63D. No other mutations in the HFE, TfR2 or SCL40A1 genes were observed in the studied patients. CONCLUSIONS One-third of Brazilian subjects with the classical phenotype of HH do not carry HFE or other mutations that are currently associated with the disease in Caucasians. This observation suggests a role for other yet unknown mutations in the aforementioned genes or in other genes involved in iron homeostasis in the pathogenesis of HH in Brazil.
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20
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Mendes AI, Ferro A, Martins R, Picanço I, Gomes S, Cerqueira R, Correia M, Nunes AR, Esteves J, Fleming R, Faustino P. Non-classical hereditary hemochromatosis in Portugal: novel mutations identified in iron metabolism-related genes. Ann Hematol 2008; 88:229-34. [PMID: 18762941 DOI: 10.1007/s00277-008-0572-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2008] [Accepted: 07/21/2008] [Indexed: 12/01/2022]
Abstract
The most frequent genotype associated with Hereditary hemochromatosis is the homozygosity for C282Y, a common HFE mutation. However, other mutations in HFE, transferrin receptor 2 (TFR2), hemojuvelin (HJV) and hepcidin (HAMP) genes, have also been reported in association with this pathology. A mutational analysis of these genes was carried out in 215 Portuguese iron-overloaded individuals previously characterized as non-C282Y or non-H63D homozygous and non-compound heterozygous. The aim was to determine the influence of these genes in the development of iron overload phenotypes in our population. Regarding HFE, some known mutations were found, as S65C and E277K. In addition, three novel missense mutations (L46W, D129N and Y230F) and one nonsense mutation (Y138X) were identified. In TFR2, besides the I238M polymorphism and the rare IVS5 -9T-->A mutation, a novel missense mutation was detected (F280L). Concerning HAMP, the deleterious mutation 5'UTR -25G-->A was found once, associated with Juvenile Hemochromatosis. In HJV, the A310G polymorphism, the novel E275E silent alteration and the novel putative splicing mutation (IVS2 +395C-->G) were identified. In conclusion, only a few number of mutations which can be linked to iron overload was found, revealing their modest contribution for the development of this phenotype in our population, and suggesting that their screening in routine diagnosis is not cost-effective.
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Affiliation(s)
- Ana Isabel Mendes
- Human Genetics Centre, National Institute of Health Dr. Ricardo Jorge, Lisbon, Portugal
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21
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Abstract
Following the discovery of the HFE gene in 1996 and its linkage to the iron overload disorder hereditary hemochromatosis (HH) there have been profound developments in our understanding of the pathogenesis of the biochemical and clinical manifestations of a number of iron overload disorders. This article provides an update of recent developments and key issues relating to iron homeostasis and inherited disorders of iron overload, with emphasis on HFE-related HH, and is based on the content of the American Association for the Study of Liver Diseases Single-Topic Conference entitled "Hemochromatosis: What has Happened After HFE?" which was held at the Emory Convention Center in Atlanta, September 7-9, 2007.
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Affiliation(s)
- John K Olynyk
- School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Fremantle, Western Australia, Australia.
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22
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Nelson JE, Kowdley KV. Non-HFE hemochromatosis: genetics, pathogenesis, and clinical management. Curr Gastroenterol Rep 2008; 7:71-80. [PMID: 15701302 DOI: 10.1007/s11894-005-0069-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Recent advances in our understanding of iron metabolism and the epidemiology of iron overload disorders have shown that hereditary forms of hemochromatosis can result from mutations in several iron metabolism genes other than HFE, including Hamp, HJV, TFR2, and SCL40A. These "non-HFE" forms of hemochromatosis are much rarer than HFE-related hemochromatosis but exhibit a similar phenotype, and with the exception of ferroportin disease, a similar pattern of inheritance and parenchymal iron accumulation. Therefore, these diseases can be thought of as variant forms of a primary hepatic iron overload syndrome; thus, a unified approach can be used for evaluation and diagnosis. Management generally consists of periodic phlebotomies until iron is depleted.
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Affiliation(s)
- James E Nelson
- Department of Medicine, Division of Gastroenterology, University of Washington Medical Center, 1959 NE Pacific Street, Box 356424, Seattle, WA 98195, USA
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23
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Wallace DF, Summerville L, Crampton EM, Subramaniam VN. Defective trafficking and localization of mutated transferrin receptor 2: implications for type 3 hereditary hemochromatosis. Am J Physiol Cell Physiol 2008; 294:C383-90. [DOI: 10.1152/ajpcell.00492.2007] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Transferrin receptor 2 (TfR2), a homologue of transferrin receptor 1 (TfR1), is a key molecule involved in the regulation of iron homeostasis. Mutations in TfR2 result in iron overload with similar features to HFE-associated hereditary hemochromatosis. The precise role of TfR2 in iron metabolism and the functional consequences of disease-causing mutations have not been fully determined. We have expressed wild-type and various mutant forms of TfR2 that are associated with human disease in a mouse liver cell line. Intracellular and surface analysis shows that all the TfR2 mutations analyzed cause the intracellular retention of the protein in the endoplasmic reticulum, whereas the wild-type protein is expressed in endocytic structures and at the cell surface. Our results indicate that the majority of mutations that cause type 3 hereditary hemochromatosis are a consequence of the defective localization of the protein.
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24
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Ayonrinde OT, Milward EA, Chua ACG, Trinder D, Olynyk JK. Clinical Perspectives on Hereditary Hemochromatosis. Crit Rev Clin Lab Sci 2008; 45:451-84. [DOI: 10.1080/10408360802335716] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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25
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Swinkels DW, Venselaar H, Wiegerinck ET, Bakker E, Joosten I, Jaspers CAJJ, Vasmel WL, Breuning MH. A novel (Leu183Pro-)mutation in the HFE-gene co-inherited with the Cys282Tyr mutation in two unrelated Dutch hemochromatosis patients. Blood Cells Mol Dis 2007; 40:334-8. [PMID: 18042412 DOI: 10.1016/j.bcmd.2007.10.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2007] [Revised: 10/10/2007] [Accepted: 10/11/2007] [Indexed: 11/28/2022]
Abstract
We describe a novel heterozygous mutation in exon 3 of the HFE-gene that was co-inherited with Cys282Tyr in two unrelated Dutch men both presenting a classical form of hereditary hemochromatosis. Heterozygosity for this mutation was also found in one out of 100 healthy controls of Dutch descent. This c.548T>C mutation converts a leucine to a proline residue at position 183 in the alpha2-helix of the HFE-protein (Leu183Pro). Standard bioinformatics analysis shows that the mutation is likely to disturb the HFE interaction with TfR1. This disrupting role of the mutation in the iron regulatory pathway is further corroborated by the familial co-occurrence of the observed compound heterozygosity with increased serum iron parameters. Haplotype analysis strongly suggests that this novel mutation arose from a common ancestor in the distant past. These findings may have implications for HFE-testing of iron overloaded heterozygous Cys282Tyr-patients of Northern European origin and their relatives.
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Affiliation(s)
- Dorine W Swinkels
- Department of Clinical Chemistry, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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26
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Abstract
Non-HFE hereditary haemochromatosis (HH) refers to a genetically heterogeneous group of iron overload disorders that are unlinked to mutations in the HFE gene. The four main types of non-HFE HH are caused by mutations in the hemojuvelin, hepcidin, transferrin receptor 2 and ferroportin genes. Juvenile haemochromatosis is an autosomal recessive disorder and can be caused by mutations in either hemojuvelin or hepcidin. An adult onset form of HH similar to HFE-HH is caused by homozygosity for mutations in transferrin receptor 2. The autosomal dominant iron overload disorder ferroportin disease is caused by mutations in the iron exporter ferroportin. The clinical characteristics and molecular basis of the various types of non-HFE haemochromatosis are reviewed. The study of these disorders and the molecules involved has been invaluable in improving our understanding of the mechanisms involved in the regulation of iron metabolism.
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Affiliation(s)
- Daniel-F Wallace
- Membrane Transport Laboratory, The Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, QLD 4006 Australia
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27
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Abstract
Fe homeostasis is maintained by regulation of Fe absorption to balance largely unregulated body Fe losses. The majority of human subjects maintain relatively constant Fe stores; however, Fe deficiency and Fe overload are common conditions. Fe overload is frequently associated with mutations in genes of Fe metabolism. The present paper summarises present knowledge of these mutations as well as indicating other genes that animal studies have implicated as candidates for influencing body Fe stores.
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Affiliation(s)
- Johanne McGregor
- Division of Life Sciences, King's College London, London SE1 9NN, UK
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28
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Abstract
AbstractOur knowledge of mammalian iron metabolism has advanced dramatically over recent years. Iron is an essential element for virtually all living organisms. Its intestinal absorption and accurate cellular regulation is strictly required to ensure the coordinated synthesis of the numerous iron-containing proteins involved in key metabolic processes, while avoiding the uptake of excess iron that can lead to organ damage. A range of different proteins exist to ensure this fine control within the various tissues of the body. Among these proteins, transferrin receptor (TFR2) seems to play a key role in the regulation of iron homeostasis. Disabling mutations in TFR2 are responsible for type 3 hereditary hemochromatosis (Type 3 HH). This review describes the biological properties of this membrane receptor, with a particular emphasis paid to the structure, function and cellular localization. Although much information has been garnered on TFR2, further efforts are needed to elucidate its function in the context of the iron regulatory network.
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29
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Drake SF, Morgan EH, Herbison CE, Delima R, Graham RM, Chua ACG, Leedman PJ, Fleming RE, Bacon BR, Olynyk JK, Trinder D. Iron absorption and hepatic iron uptake are increased in a transferrin receptor 2 (Y245X) mutant mouse model of hemochromatosis type 3. Am J Physiol Gastrointest Liver Physiol 2007; 292:G323-8. [PMID: 16935854 DOI: 10.1152/ajpgi.00278.2006] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hereditary hemochromatosis type 3 is an iron (Fe)-overload disorder caused by mutations in transferrin receptor 2 (TfR2). TfR2 is expressed highly in the liver and regulates Fe metabolism. The aim of this study was to investigate duodenal Fe absorption and hepatic Fe uptake in a TfR2 (Y245X) mutant mouse model of hereditary hemochromatosis type 3. Duodenal Fe absorption and hepatic Fe uptake were measured in vivo by 59Fe-labeled ascorbate in TfR2 mutant mice, wild-type mice, and Fe-loaded wild-type mice (2% dietary carbonyl Fe). Gene expression was measured by real-time RT-PCR. Liver nonheme Fe concentration increased progressively with age in TfR2 mutant mice compared with wild-type mice. Fe absorption (both duodenal Fe uptake and transfer) was increased in TfR2 mutant mice compared with wild-type mice. Likewise, expression of genes participating in duodenal Fe uptake (Dcytb, DMT1) and transfer (ferroportin) were increased in TfR2 mutant mice. Nearly all of the absorbed Fe was taken up rapidly by the liver. Despite hepatic Fe loading, hepcidin expression was decreased in TfR2 mutant mice compared with wild-type mice. Even when compared with Fe-loaded wild-type mice, TfR2 mutant mice had increased Fe absorption, increased duodenal Fe transport gene expression, increased liver Fe uptake, and decreased liver hepcidin expression. In conclusion, despite systemic Fe loading, Fe absorption and liver Fe uptake were increased in TfR2 mutant mice in association with decreased expression of hepcidin. These findings support a model in which TfR2 is a sensor of Fe status and regulates duodenal Fe absorption and liver Fe uptake.
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Affiliation(s)
- S F Drake
- School of Medicine and Pharmacology, Fremantle Hospital, University of Western Australia, PO Box 480, Fremantle, 6959, WA, Australia
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30
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Lambert LA, Mitchell SL. Molecular Evolution of the Transferrin Receptor/Glutamate Carboxypeptidase II Family. J Mol Evol 2006; 64:113-28. [PMID: 17160644 DOI: 10.1007/s00239-006-0137-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2006] [Accepted: 10/03/2006] [Indexed: 02/07/2023]
Abstract
The transferrin receptor family is represented by at least seven different homologous proteins in primates. Transferrin receptor (TfR1) is a type II membrane glycoprotein that, as a cell surface homodimer, binds iron-loaded transferrin as part of the process of iron transfer and uptake. Other family members include transferrin receptor 2 (TfR2), glutamate carboxypeptidase II (GCP2 or PSMA), N-acetylated alpha-linked acidic dipeptidase-like protein (NLDL), N-acetylated alpha-linked acidic dipeptidase 2 (NAALAD2), and prostate-specific membrane antigen-like protein (PMSAL/GCPIII). We compared 86 different sequences from 24 different species, from mammals to fungi. Through this comparison, we have identified several highly conserved residues specific to each family not previously associated with clinical mutations. The evolutionary history of the TfR/GCP2 family shows repeated episodes of duplications consistent with recent theories that nondispensable, slowly evolving genes are more likely to form multiple gene families.
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Affiliation(s)
- Lisa Ann Lambert
- Department of Biology, Chatham College, Woodland Road, Pittsburgh, PA 15232, USA.
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31
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Huang XP, O'Brien PJ, Templeton DM. Mitochondrial involvement in genetically determined transition metal toxicity. Chem Biol Interact 2006; 163:68-76. [PMID: 16797509 DOI: 10.1016/j.cbi.2006.05.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2006] [Revised: 05/11/2006] [Accepted: 05/11/2006] [Indexed: 02/03/2023]
Abstract
Iron that is not specifically chaperoned through its essential functional pathways is damaging to biological systems, in major part by catalyzing the production of reactive oxygen species. Iron serves in several essential roles in the mitochondrion, as an essential cofactor for certain enzymes of electron transport, and through its involvement in the assembly of iron-sulfur clusters and iron-porphyrin (heme) complexes, both processes occurring in the mitochondrion. Therefore, there are mechanisms that deliver iron specifically to mitochondria, although these are not well understood. Under normal circumstances the mitochondrion has levels of stored iron that are higher than other organelles, though lower than in cytosol, while in some disorders of iron metabolism, mitochondrial iron levels exceed those in the cytosol. Under these circumstances of excess iron, protective mechanisms are overwhelmed and mitochondrial damage ensues. This may take the form of acute oxidative stress with structural damage and functional impairment, but also may result in long-term damage to the mitochondrial genome. This review discusses the evidence that mitochondria do indeed accumulate iron in several genetic disorders, and are a direct target for iron toxicity when it is present in excess. We then consider two classes of genetic disorders involving iron and the mitochondrion. The first include defects in genes directly regulating mitochondrial iron metabolism that lead to Friedreich's ataxia and the various sideroblastic anemias, with excessive mitochondrial iron accumulation. Under the second class, we discuss various primary hemochromatoses that lead to direct mitochondrial damage, with reference to mutations in genes encoding HFE, hepcidin, hemojuvelin, transferrin receptor-2, ferroportin, transferrin, and ceruloplasmin.
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Affiliation(s)
- Xi-Ping Huang
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 1 King's College Circle, Toronto, Ont. M5S 1A8, Canada
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32
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Abstract
In recent years, the number of proteins implicated in iron homeostasis has increased dramatically, and genetic causes have apparently been identified for the major disorders associated with tissue iron overload. These dramatic steps forward have transformed the way we look at iron-related disorders, particularly hemochromatosis. This review presents a concept of this disease that is based on this new knowledge and stems from the idea that, beyond their genetic diversities, all known hemochromatoses originate from the same metabolic error, the genetic disruption of human tendency for circulatory iron constancy. Hepcidin, the iron hormone, seems to hold a central pathogenic place in hemochromatosis, similar to insulin in diabetes: Genetically determined lack of hepcidin synthesis or activity may cause the disease.
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Affiliation(s)
- Antonello Pietrangelo
- Department of Internal Medicine, Center for Hemochromatosis, University of Modena and Reggio Emilia, Policlinico, 41100 Modena, Italy.
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33
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Khusainova RI, Khusnutdinova NN, Khusnutdinova EK. Analysis of the hemochromatosis gene (HFE) mutations, C282Y and H63D, in the populations of Central Asia. RUSS J GENET+ 2006. [DOI: 10.1134/s102279540603015x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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34
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Lee PL, Barton JC. Hemochromatosis and severe iron overload associated with compound heterozygosity for TFR2 R455Q and two novel mutations TFR2 R396X and G792R. Acta Haematol 2006; 115:102-5. [PMID: 16424658 DOI: 10.1159/000089474] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2005] [Accepted: 04/25/2005] [Indexed: 01/08/2023]
Abstract
We report three mutations of transferrin receptor 2 (TFR2)--R396X (exon 9; nt 1186C-->T), R455Q (exon 10; nt 1364G-->A) and G792R (exon 18; nt 2374G-->A)--in a man of Scottish descent with hemochromatosis and severe iron overload. He was also heterozygous for the common HFE H63D polymorphism. The patient did not have coding region mutations in HAMP, FPN1, HJV or ALAS2. We conclude that this patient represents another example of hemochromatosis due to mutations of the gene encoding transferrin receptor 2.
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Affiliation(s)
- Pauline L Lee
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
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35
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Abstract
The molecular basis of haemochromatosis has proved more complex than expected. After the 1996 identification of the main causative gene HFE and confirmation that most patients were homozygous for the founder C282Y mutation, it became clear that some families were linked to rarer conditions, first named 'non-HFE haemochromatosis'. The genetics of these less common forms was intensively studied between 2000 and 2004, leading to the recognition of haemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin-related haemochromatosis, and opening the way for novel hypotheses such as those related to digenic modes of inheritance or the involvement of modifier genes. Molecular studies of rare haemochromatosis disorders have contributed to our understanding of iron homeostasis. In turn, recent findings from studies of knockout mice and functional studies have confirmed that HAMP plays a central role in mobilization of iron, shown that HFE, TFR2 and HJV modulate HAMP production according to the body's iron status, and demonstrated that HAMP negatively regulates cellular iron efflux by affecting the ferroportin cell surface availability. These data shed new light on the pathophysiology of all types of haemochromatosis, and offer novel opportunities to comment on phenotypic differences and distinguish mutations.
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36
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Morris TJ, Litvinova MM, Ralston D, Mattman A, Holmes D, Lockitch G. A novel ferroportin mutation in a Canadian family with autosomal dominant hemochromatosis. Blood Cells Mol Dis 2005; 35:309-14. [PMID: 16111902 DOI: 10.1016/j.bcmd.2005.07.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2005] [Accepted: 07/18/2005] [Indexed: 12/19/2022]
Abstract
We report a new mutation, Asn185Asp, in exon 6 of the ferroportin gene (FPN1) in 15 members of three successive generations of a Canadian family of Scandinavian origin with autosomal dominant hemochromatosis. Hyperferritinemia with low transferrin saturation was noted in younger family members, seven of whom were aged 20 years or less at the time of diagnosis. In those individuals first diagnosed with hemochromatosis in later life, marked hyperferritinemia was accompanied by high transferrin saturation. In contrast to the phenotype of high ferritin with low saturation first reported for ferroportin disease, this family demonstrates a phenotype of iron indices that varies with age.
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Affiliation(s)
- Tara J Morris
- Department of Pathology and Laboratory Medicine, Children's and Women's Health Centre of British Columbia, 4480 Oak Street, Vancouver, Canada BC V6H3V4
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37
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Abstract
Mutations in the hepcidin gene HAMP and the hemojuvelin gene HJV have recently been shown to result in juvenile haemochromatosis (JH). Hepcidin is an antimicrobial peptide that plays a key role in regulating intestinal iron absorption. Hepcidin levels are reduced in patients with haemochromatosis due to mutations in the HFE and HJV genes. Digenic inheritance of mutations in HFE and HAMP can result in either JH or hereditary haemochromatosis (HH) depending upon the severity of the mutation in HAMP. Here we review these findings and discuss how understanding the different types of haemochromatosis and our increasing knowledge of iron metabolism may help to elucidate the host's response to infection.
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38
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Abstract
Elucidation of the molecular pathways of iron transport through cells and its control is leading to an understanding of genetic iron loading conditions. The general phenotype of haemochromatosis is iron accumulation in liver parenchymal cells, a raised serum transferrin saturation and ferritin concentration. Four types have been identified: type 1 is the common form and is an autosomal recessive disorder of low penetrance strongly associated with mutations in the HFE gene on chromosome 6(p21.3); type 2 (juvenile haemochromatosis) is autosomal recessive, of high penetrance with causative mutations identified in the HFE2 gene on chromosome 1 (q21) and the HAMP gene on chromosome 19 (q13); type 3 is also autosomal recessive with mutations in the TfR2 gene on chromosome 3 (7q22); type 4 is an autosomal dominant condition with heterozygous mutations in the ferroportin 1 gene. In type 4, iron accumulates in both parenchymal and reticuloendothelial cells and the transferrin saturation may be normal. There are also inherited neurodegenerative conditions associated with iron accumulation. The current research challenges include understanding the central role of the HAMP gene (hepcidin) in controlling iron absorption and the reasons for the variable penetrance in HFE type 1.
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Affiliation(s)
- Mark Worwood
- Department of Haematology, University of Wales College of Medicine, Cardiff CF14 4XN, Wales, UK.
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Cadet E, Perez AS, Capron D, Rochette J. Bases moléculaires des hémochromatoses génétiques. Rev Med Interne 2005; 26:393-402. [PMID: 15893030 DOI: 10.1016/j.revmed.2004.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2004] [Accepted: 09/16/2004] [Indexed: 10/26/2022]
Abstract
PURPOSE Recent discoveries in molecular mechanisms of iron metabolism have changed the classical view of hereditary iron overload conditions. We present natural mutations in newly discovered genes and related phenotypes observed in patients with different form of haemochromatosis. CURRENT KNOWLEDGE AND KEY POINTS Most haemochromatosis patients are homozygous for the C282Y mutation in the HFE gene. Ferroportin, TFR2, hemojuvelin and hepcidin mutations also cause iron overload. Recent data support the hypothesis that haemochromatosis should no longer be considered a monogenic disease but rather an oligogenic disorder. Several results suggest that haemochromatosis could result from digenic inheritance of mutations in HFE and HAMP. FUTURE PROSPECTS AND PROJECTS Other modifier genes probably influence penetrance in C282Y homozygous patients. Such genes could enhance or reduce the phenotypic expression in various iron overload conditions.
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Affiliation(s)
- E Cadet
- Service de génétique moléculaire médicale et UPRES EA 2629, CHU d'Amiens, université de Picardie-Jules-Verne, 3, rue des Louvels, 80036 Amiens cedex, France.
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40
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Aguilar-Martinez P, Schved JF, Brissot P. The evaluation of hyperferritinemia: an updated strategy based on advances in detecting genetic abnormalities. Am J Gastroenterol 2005; 100:1185-94. [PMID: 15842597 DOI: 10.1111/j.1572-0241.2005.40998.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The number of new genes implicated in iron metabolism has dramatically increased during the last few years. Alterations of these genes may cause hyperferritinemia associated or not with iron overload. Correct assignment of the specific disorder of iron metabolism requires the identification of the causative gene mutation. Here, we propose a rational strategy that allows targeting the gene(s) to be screened for a diagnostic purpose. This strategy relies on the age of onset of the disease, the type of clinical symptoms, the biochemical profile (elevated or normal serum transferrin saturation (TfSat)), the presence or not of visceral iron excess, and the mode of inheritance (autosomal recessive or dominant). Then, two main entities can be differentiated: genetic (adult or juvenile) hemochromatosis characterized by elevated TfSat, and hereditary hyperferritinemias where TfSat is normal (or only slightly modified). Adult genetic hemochromatosis (GH) is related mainly to mutations of the HFE gene, and exceptionally to mutations of the TFR2 gene. Juvenile GH is a rare condition related principally to mutations of the HJV gene coding for hemojuvelin, and rarely to mutations of the HAMP gene coding for hepcidin. Hereditary hyperferritinemias are linked to mutations of three genes: the L-ferritin gene responsible for the hereditary hyperferritinemia cataract syndrome (without iron overload), the ferroportin gene leading to a dominant form of iron overload, and the ceruloplasmin (CP) gene corresponding to an iron overload syndrome with neurological symptoms. The proposed strategic approach may change with the identification of other genes involved in iron metabolism.
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Biasiotto G, Roetto A, Daraio F, Polotti A, Gerardi GM, Girelli D, Cremonesi L, Arosio P, Camaschella C. Identification of new mutations of hepcidin and hemojuvelin in patients with HFE C282Y allele. Blood Cells Mol Dis 2005; 33:338-43. [PMID: 15528154 DOI: 10.1016/j.bcmd.2004.08.002] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2004] [Revised: 08/06/2004] [Indexed: 02/09/2023]
Abstract
HFE-hemochromatosis is the most common form of hereditary hemochromatosis. The disorder is associated with the homozygous C282Y mutation and has variable phenotype, being modulated by environmental and genetic factors. Candidate modifier genes are hemojuvelin and hepcidin, which are responsible for juvenile hemochromatosis. We used DHPLC to scan mutations in these genes in a cohort of unrelated patients with C282Y mutation. They consisted of 136 C282Y homozygous, 43 heterozygous, and 42 C282Y/H63D compound heterozygous, plus 62 controls subjects. Mutations and polymorphisms were found in 16 patients and 4 controls. Abnormally high indices of iron status were found in subjects C282Y/H63D heterozygous for the N196K hemojuvelin mutation and the -72C > T hepcidin substitution. The already described G71D mutation of hepcidin did not induce evident modification of the C282Y/H63D phenotype. The data show that heterozygous mutations of the hemojuvelin gene contribute like those of hepcidin to the phenotypic heterogeneity of hemochromatosis. However, they are rare and explain only a minor portion of the variable penetrance of the disorder.
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Affiliation(s)
- Giorgio Biasiotto
- Dipartimento Materno Infantile e Tecnologie Biomediche, Università di Brescia, A.O. Spedali Civili, Brescia, Italy
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42
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Lorenz M, Kletzmayr J, Huber A, Hörl WH, Sunder-Plassmann G, Födinger M. Iron overload in kidney transplants: Prospective analysis of biochemical and genetic markers. Kidney Int 2005; 67:691-7. [PMID: 15673318 DOI: 10.1111/j.1523-1755.2005.67129.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND The prevalence of iron overload and the influence of mutations in the HFE and TRF2 gene on biochemical markers of iron overload among renal transplant patients is unknown. METHODS Serum iron, ferritin, transferrin saturation (TSAT), and liver function parameters were analyzed in a cohort of 438 renal transplants. In patients with iron overload, the time course of biochemical markers of iron status as well as the influence of iron loading mutations was investigated during a time period of 5 years. RESULTS Of 438 renal transplant patients 41 (9.4%) presented with an iron loading phenotype (TSAT above 40% and/or ferritin above 800 ng/mL). Mutations in the HFE gene were present in 12 of 33 (36.3%) patients with iron overload. Among these one patient was homozygous for HFE C282Y, and two patients were compound heterozygous for HFE C282Y/H63D. No individual tested positive for nine other mutations in HFE as well as theTRF2 Y250X mutation. Over time we observed a decrease of mean iron and ferritin levels, and of mean TSAT in our study sample. In patients with mutations in HFE this decrease was less pronounced as compared to patients without mutations. We found an independent positive association between the presence of mutations in HFE and serum alanine-aminotransferase levels at follow-up (P= 0.003). CONCLUSION Our study demonstrates that iron overload is frequently present in renal transplant patients and shows a continuous decrease over time. This decrease is possibly impaired by the HFE C282Y and HFE H63D mutations. Furthermore, mutations in HFE may influence liver function as reflected by increased alanine-aminotransferase concentrations.
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Affiliation(s)
- Matthias Lorenz
- Division of Nephrology and Dialysis, Department of Medicine III, Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Vienna, Vienna, Austria
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43
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Kawabata H, Tong X, Kawanami T, Wano Y, Hirose Y, Sugai S, Koeffler HP. Analyses for binding of the transferrin family of proteins to the transferrin receptor 2. Br J Haematol 2004; 127:464-73. [PMID: 15521925 DOI: 10.1111/j.1365-2141.2004.05224.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Transferrin receptor 2 alpha (TfR2 alpha), the major product of the TfR2 gene, is the second receptor for transferrin (Tf), which can mediate cellular iron uptake in vitro. Homozygous mutations of TfR2 cause haemochromatosis, suggesting that TfR2 alpha may not be a simple iron transporter, but a regulator of iron by identifying iron-Tf. In this study, we analysed the ligand specificity of TfR2 alpha using human transferrin receptor 1 (TfR1) and TfR2 alpha-stably transfected and expressing cells and flow-cytometric techniques. We showed that human TfR2 alpha interacted with both human and bovine Tf, whereas human TfR1 interacted only with human Tf. Neither human TfR1 nor TfR2 alpha interacted with either lactoferrin or melanotransferrin. In addition, by creating point mutations in human TfR2 alpha, the RGD sequence in the extracellular domain of TfR2 alpha was shown to be crucial for Tf-binding. Furthermore, we demonstrated that mutated TfR2 alpha (Y250X), which has been reported in patients with hereditary haemochromatosis, also lost its ability to interact with both human and bovine Tf. Although human TfR1 and TfR2 alpha share an essential structure (RGD) for ligand-binding, they have clearly different ligand specificities, which may be related to the differences in their roles in iron metabolism.
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Affiliation(s)
- Hiroshi Kawabata
- Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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44
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Heeney MM, Andrews NC. Iron homeostasis and inherited iron overload disorders: an overview. Hematol Oncol Clin North Am 2004; 18:1379-403, ix. [PMID: 15511621 DOI: 10.1016/j.hoc.2004.06.018] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Iron is an ubiquitous metal of vital importance to the normal physiologic processes of many organisms. Recent discoveries of mutations in genes that lead to inherited iron overload diseases have advanced the understanding of iron homeostasis in humans. This article provides an overview of the human iron cycle, regulation of iron homeostasis, how perturbations in this homeostasis lead to iron overload disease in adults and children, and strategies for diagnosis of inherited iron overload.
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45
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Mura C, Le Gac G, Jacolot S, Férec C. Transcriptional regulation of the human HFE gene indicates high liver expression and erythropoiesis coregulation. FASEB J 2004; 18:1922-4. [PMID: 15467009 DOI: 10.1096/fj.04-2520fje] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The human HFE gene is clearly involved in hereditary hemochromatosis, a common autosomal recessive genetic disorder of iron homeostasis. However, the precise role of the HFE protein is still undefined. Here, to obtain new insight, we analyzed the transcriptional regulation of HFE gene and defined the functional organization of the HFE promoter. Both in vitro transcription and reporter gene assay in transient transfection evidenced a high liver expression of the HFE mRNA. The 5' end analysis of mRNA showed two major initiation sites localized at -265 and -195 directed by TATA-like sequences and a window of initiation within the -120 to -10 GC-rich region upstream of the first coding nucleotide. Positive cis-regulating elements were characterized within the -1057/-8 region, and a negative one extending upstream (-1485/-1057) was identified. DNase I footprinting analysis and gel shift assay revealed several protein binding sites, and subsequent functional analysis evidenced transactivation of HFE by liver-enriched C/EBPalpha, erythropoietic-specific GATA-1, and ubiquitous Sp1 transcription factors. These data bring some evidence of a role of HFE in the liver and a coregulation with erythropoiesis as other genes involved in iron homeostasis.
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Affiliation(s)
- Catherine Mura
- INSERM U613, Génétique Moléculaire et Génétique Epidémiologique, UBO, 46 rue Félix Le Dantec, Brest 29200, France.
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46
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Robb AD, Ericsson M, Wessling-Resnick M. Transferrin receptor 2 mediates a biphasic pattern of transferrin uptake associated with ligand delivery to multivesicular bodies. Am J Physiol Cell Physiol 2004; 287:C1769-75. [PMID: 15317665 DOI: 10.1152/ajpcell.00337.2004] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The physiological role of transferrin (Tf) receptor 2 (TfR2), a homolog of the well-characterized TfR1, is unclear. Mutations in TfR2 result in hemochromatosis, indicating that this receptor has a unique role in iron metabolism. We report that HepG2 cells, which endogenously express TfR2, display a biphasic pattern of Tf uptake when presented with ligand concentrations up to 2 muM. The apparently nonsaturating pathway of Tf endocytosis resembles TfR1-independent Tf uptake, a process previously characterized in some liver cell types. Exogenous expression of TfR2 but not TfR1 induces a similar biphasic pattern of Tf uptake in HeLa cells, supporting a role for TfR2 in this process. Immunoelectron microscopy reveals that while Tf, TfR1, and TfR2 are localized in the plasma membrane and tubulovesicular endosomes, TfR2 expression is associated with the additional appearance of Tf in multivesicular bodies. These combined results imply that unlike TfR1, which recycles apo-Tf back to the cell surface after the release of iron, TfR2 promotes the intracellular deposition of ligand. Tf delivered by TfR2 does not appear to be degraded, which suggests that its delivery to this organelle may be functionally relevant to the storage of iron in overloaded states.
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Affiliation(s)
- Aeisha D Robb
- Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115, USA
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47
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Beutler L, Beutler E. Hematologically important mutations: iron storage diseases. Blood Cells Mol Dis 2004; 33:40-4. [PMID: 15223009 DOI: 10.1016/j.bcmd.2004.03.002] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2004] [Indexed: 11/19/2022]
Affiliation(s)
- Lisa Beutler
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
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48
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Le Gac G, Mons F, Jacolot S, Scotet V, Férec C, Frébourg T. Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent. Br J Haematol 2004; 125:674-8. [PMID: 15147384 DOI: 10.1111/j.1365-2141.2004.04950.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The molecular basis of hereditary hemochromatosis (HH) is more complex than previously expected. More than 80% of hemochromatosis probands of Northern European descent are homozygous for the C282Y HFE gene mutation. However, five novel non-related-HFE HH forms have now been identified. The transferrin receptor(TFR2)-linked form is inherited in an autosomal recessive pattern and is considered to be an adult-onset syndrome. Until now, it has been associated with five mutations that have only been detected in Japanese and southern European patients. Here, we report the identification of a novel TFR2 nonsense mutation in two related French adolescents. We discuss the phenotype of this sibling pair from precedent biological and clinical findings as well as the expected role of TFR2 in iron homeostasis. Finally, we suggest that iron overload phenotypes associated with mutations in TFR2 may be intermediate between those related to mutations in HFE and those related to mutations in juvenile hemochromatosis genes.
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49
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Affiliation(s)
- Antonello Pietrangelo
- Center for Hemochromatosis and Hereditary Liver Diseases, Department of Internal Medicine, University of Modena and Reggio Emilia Policlinico, Modena, Italy.
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50
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Riva A, Mariani R, Bovo G, Pelucchi S, Arosio C, Salvioni A, Vergani A, Piperno A. Type 3 hemochromatosis and β
-thalassemia trait. Eur J Haematol 2004; 72:370-4. [PMID: 15059075 DOI: 10.1111/j.1600-0609.2004.00230.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Type 3 hemochromatosis is a rare autosomal recessive disorder due to mutations of the TFR2 gene. We describe clinical, biochemical and histopathologic findings of a patient with type 3 hemochromatosis at presentation and during a follow-up of more than 20 yr and we evaluate the effect of an associated beta-thalassemia trait on phenotypic expression. At the age of 33 yr the patient showed a marked iron overload and severe iron-related complications. After removal of 26 g of iron by subcutaneous deferoxamine infusion a marked clinical improvement was observed. Liver biopsies, performed at the age of 34 and 49 yr, indicate that in type 3 hemochromatosis there is a progressive hepatocellular iron accumulation from Rappaport's zone 1-3 and that iron loading in sinusoidal and portal macrophages occurs only in the more advanced stage. As observed in HFE hemochromatosis, the beta-thalassemia trait seems to aggravate the clinical picture of patients lacking TFR2, favoring higher rates of iron accumulation probably by activation of the erythroid iron regulator.
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Affiliation(s)
- Alessia Riva
- Clinica Medica, Azienda Ospedaliera San Gerardo, Università Milano-Bicocca, Via Donizetti 106, 20052 Monza, Italy
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