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1
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Rao ND, Moonesinghe R, Shi L, Adams PC, Jarvik GP, Kowdley KV, Schieve LA, Grosse SD, Dotson WD, Khoury MJ. Association of HFE genotypes with hemochromatosis-related phenotypes in the All of Us research program. GENETICS IN MEDICINE OPEN 2025; 3:101959. [PMID: 40034140 PMCID: PMC11875803 DOI: 10.1016/j.gimo.2024.101959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 03/05/2025]
Abstract
Purpose Type 1 hereditary hemochromatosis (HH) can result in iron overload and liver disease if not detected and treated early. Most cases are found among people homozygous for HFE p.Cys282Tyr variants. Compound heterozygosity with the HFE p.His63Asp variant is associated with disease to a lesser degree. We sought to examine the association of HFE variation with HH-related phenotypes and assess the prevalence of testing and diagnosis of HH using All of Us data. Methods We used data from 133,978 participants with genetic information linked to medical records. For different HFE genotypes, we examined the prevalence of HH diagnosis codes and related biochemical and clinical phenotypes. Results Among participants who were p.Cys282Tyr homozygotes, the prevalence of HH diagnosis codes was 22.6% among males and 15.6% among females. Serum transferrin-iron saturation measures were available only for 31.4% of males and 21.1% of females who were p.Cys282Tyr homozygotes. Liver disease, including cirrhosis or hepatocellular carcinoma, was present more among males who were p.Cys282Tyr homozygotes compared with males with no p.Cys282Tyr or p.His63Asp variants (15.5% vs 8.5%, P = .0001). Of the 71 participants who were p.Cys282Tyr homozygotes with indication of liver disease, 32 (45.1%) did not have a serum transferrin-iron saturation measure, and 37 (52.1%) did not have diagnosis codes for HH. Conclusion Limited serum transferrin-iron saturation measures or HH diagnosis codes among p.Cys282Tyr homozygotes, even those with liver disease, suggests potential undertesting and underdiagnosis of type 1 HH in clinical practice and a need for improved awareness, education, and testing around HH.
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Affiliation(s)
- Nandana D. Rao
- Division of Blood Disorders and Public Health Genomics, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
| | - Ramal Moonesinghe
- Division of Blood Disorders and Public Health Genomics, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
| | - Lu Shi
- Division of Blood Disorders and Public Health Genomics, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
| | - Paul C. Adams
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Gail P. Jarvik
- Departments of Medicine (Medical Genetics) and Genome Sciences, University of Washington Medical Center, Seattle, WA
| | - Kris V. Kowdley
- Department of Hepatology, Liver Institute Northwest, Seattle, WA
| | - Laura A. Schieve
- Division of Blood Disorders and Public Health Genomics, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
| | - Scott D. Grosse
- National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
| | - W. David Dotson
- Division of Blood Disorders and Public Health Genomics, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
| | - Muin J. Khoury
- Division of Blood Disorders and Public Health Genomics, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, GA
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2
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Katsidi EC, Avramidou EV, Ganopoulos I, Barbas E, Doulis A, Triantafyllou A, Aravanopoulos FA. Genetics and epigenetics of Pinus nigra populations with differential exposure to air pollution. FRONTIERS IN PLANT SCIENCE 2023; 14:1139331. [PMID: 37089661 PMCID: PMC10117940 DOI: 10.3389/fpls.2023.1139331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 03/20/2023] [Indexed: 05/03/2023]
Abstract
Forest species in the course of their evolution have experienced several environmental challenges, which since historic times include anthropogenic pollution. The effects of pollution on the genetic and epigenetic diversity in black pine (Pinus nigra) forests were investigated in the Amyntaio - Ptolemais - Kozani Basin, which has been for decades the largest lignite mining and burning center of Greece, with a total installed generating capacity of about 4.5 GW, operating for more than 70 years and resulting in large amounts of primary air pollutant emissions, mainly SO2, NOx and PM10. P. nigra, a biomarker for air pollution and a keystone species of affected natural ecosystems, was examined in terms of phenology (cone and seed parameters), genetics (283 AFLP loci) and epigenetics (606 MSAP epiloci), using two populations (exposed to pollution and control) of the current (mature trees) and future (embryos) stand. It was found that cone, seed, as well as genetic diversity parameters, did not show statistically significant differences between the exposed population and the control. Nevertheless, statistically significant differences were detected at the population epigenetic level. Moreover, there was a further differentiation regarding the intergenerational comparison: while the epigenetic diversity does not substantially change in the two generations assessed in the control population, epigenetic diversity is significantly higher in the embryo population compared to the parental stand in the exposed population. This study sheds a light to genome dynamics in a forest tree population exposed to long term atmospheric pollution burden and stresses the importance of assessing both genetics and epigenetics in biomonitoring applications.
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Affiliation(s)
- Elissavet Ch. Katsidi
- Laboratory of Forest Genetics & Tree Breeding, Faculty of Agriculture, Forestry & Environmental Science, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelia V. Avramidou
- Laboratory of Forest Genetics & Tree Breeding, Faculty of Agriculture, Forestry & Environmental Science, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioannis Ganopoulos
- Laboratory of Forest Genetics & Tree Breeding, Faculty of Agriculture, Forestry & Environmental Science, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelos Barbas
- Laboratory of Forest Genetics & Tree Breeding, Faculty of Agriculture, Forestry & Environmental Science, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Doulis
- Laboratory of Plant Biotechnology – Genomic Resources, Hellenic Agricultural Organization DEMETER, Institute of Viticulture, Floriculture and Vegetable Crops, Heraklion, Greece
| | - Athanasios Triantafyllou
- Laboratory of Atmospheric Pollution and Environmental Physics (LALEP), Faculty of Engineering, University of Western Macedonia, Kozani, Greece
| | - Filippos A. Aravanopoulos
- Laboratory of Forest Genetics & Tree Breeding, Faculty of Agriculture, Forestry & Environmental Science, Aristotle University of Thessaloniki, Thessaloniki, Greece
- *Correspondence: Filippos A. Aravanopoulos,
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3
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Affiliation(s)
- John K Olynyk
- From the Department of Gastroenterology and Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, and the School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA (J.K.O.); and the Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, QLD (G.A.R.) - all in Australia
| | - Grant A Ramm
- From the Department of Gastroenterology and Hepatology, Fiona Stanley Fremantle Hospital Group, Murdoch, and the School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA (J.K.O.); and the Hepatic Fibrosis Group, QIMR Berghofer Medical Research Institute, Herston, QLD (G.A.R.) - all in Australia
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4
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Hino K, Yanatori I, Hara Y, Nishina S. Iron and liver cancer: an inseparable connection. FEBS J 2022; 289:7810-7829. [PMID: 34543507 DOI: 10.1111/febs.16208] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 08/17/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023]
Abstract
Iron is an essential element for all organisms. Iron-containing proteins play critical roles in cellular functions. The biological importance of iron is largely attributable to its chemical properties as a transitional metal. However, an excess of 'free' reactive iron damages the macromolecular components of cells and cellular DNA through the production of harmful free radicals. On the contrary, most of the body's excess iron is stored in the liver. Not only hereditary haemochromatosis but also some liver diseases with mild-to-moderate hepatic iron accumulation, such as chronic hepatitis C, alcoholic liver disease and nonalcoholic steatohepatitis, are associated with a high risk for liver cancer development. These findings have attracted attention to the causative and promotive roles of iron in the development of liver cancer. In the last decade, accumulating evidence regarding molecules regulating iron metabolism or iron-related cell death programmes such as ferroptosis has shed light on the relationship between hepatic iron accumulation and hepatocarcinogenesis. In this review, we briefly present the current molecular understanding of iron regulation in the liver. Next, we describe the mechanisms underlying dysregulated iron metabolism depending on the aetiology of liver diseases. Finally, we discuss the causative and promotive roles of iron in cancer development.
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Affiliation(s)
- Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - Izumi Yanatori
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Japan
| | - Yuichi Hara
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - Sohji Nishina
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
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5
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Zoller H, Schaefer B, Vanclooster A, Griffiths B, Bardou-Jacquet E, Corradini E, Porto G, Ryan J, Cornberg M. EASL Clinical Practice Guidelines on haemochromatosis. J Hepatol 2022; 77:479-502. [PMID: 35662478 DOI: 10.1016/j.jhep.2022.03.033] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 03/29/2022] [Indexed: 12/15/2022]
Abstract
Haemochromatosis is characterised by elevated transferrin saturation (TSAT) and progressive iron loading that mainly affects the liver. Early diagnosis and treatment by phlebotomy can prevent cirrhosis, hepatocellular carcinoma, diabetes, arthropathy and other complications. In patients homozygous for p.Cys282Tyr in HFE, provisional iron overload based on serum iron parameters (TSAT >45% and ferritin >200 μg/L in females and TSAT >50% and ferritin >300 μg/L in males and postmenopausal women) is sufficient to diagnose haemochromatosis. In patients with high TSAT and elevated ferritin but other HFE genotypes, diagnosis requires the presence of hepatic iron overload on MRI or liver biopsy. The stage of liver fibrosis and other end-organ damage should be carefully assessed at diagnosis because they determine disease management. Patients with advanced fibrosis should be included in a screening programme for hepatocellular carcinoma. Treatment targets for phlebotomy are ferritin <50 μg/L during the induction phase and <100 μg/L during the maintenance phase.
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6
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Fisher AL, Babitt JL. Coordination of iron homeostasis by bone morphogenetic proteins: Current understanding and unanswered questions. Dev Dyn 2022; 251:26-46. [PMID: 33993583 PMCID: PMC8594283 DOI: 10.1002/dvdy.372] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/15/2021] [Accepted: 05/07/2021] [Indexed: 01/19/2023] Open
Abstract
Iron homeostasis is tightly regulated to balance the iron requirement for erythropoiesis and other vital cellular functions, while preventing cellular injury from iron excess. The liver hormone hepcidin is the master regulator of systemic iron balance by controlling the degradation and function of the sole known mammalian iron exporter ferroportin. Liver hepcidin expression is coordinately regulated by several signals that indicate the need for more or less iron, including plasma and tissue iron levels, inflammation, and erythropoietic drive. Most of these signals regulate hepcidin expression by modulating the activity of the bone morphogenetic protein (BMP)-SMAD pathway, which controls hepcidin transcription. Genetic disorders of iron overload and iron deficiency have identified several hepatocyte membrane proteins that play a critical role in mediating the BMP-SMAD and hepcidin regulatory response to iron. However, the precise molecular mechanisms by which serum and tissue iron levels are sensed to regulate BMP ligand production and promote the physical and/or functional interaction of these proteins to modulate SMAD signaling and hepcidin expression remain uncertain. This critical commentary will focus on the current understanding and key unanswered questions regarding how the liver senses iron levels to regulate BMP-SMAD signaling and thereby hepcidin expression to control systemic iron homeostasis.
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Affiliation(s)
| | - Jodie L Babitt
- Corresponding author: Jodie L Babitt, Division of Nephrology, Program in Membrane Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Mailing address: 185 Cambridge St., CPZN-8208, Boston, MA 02114. Telephone: +1 (617) 643-3181.
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7
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Verbrugge SAJ, Alhusen JA, Kempin S, Pillon NJ, Rozman J, Wackerhage H, Kleinert M. Genes controlling skeletal muscle glucose uptake and their regulation by endurance and resistance exercise. J Cell Biochem 2021; 123:202-214. [PMID: 34812516 DOI: 10.1002/jcb.30179] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 10/27/2021] [Accepted: 11/04/2021] [Indexed: 12/25/2022]
Abstract
Exercise improves the insulin sensitivity of glucose uptake in skeletal muscle. Due to that, exercise has become a cornerstone treatment for type 2 diabetes mellitus (T2DM). The mechanisms by which exercise improves skeletal muscle insulin sensitivity are, however, incompletely understood. We conducted a systematic review to identify all genes whose gain or loss of function alters skeletal muscle glucose uptake. We subsequently cross-referenced these genes with recently generated data sets on exercise-induced gene expression and signaling. Our search revealed 176 muscle glucose-uptake genes, meaning that their genetic manipulation altered glucose uptake in skeletal muscle. Notably, exercise regulates the expression or phosphorylation of more than 50% of the glucose-uptake genes or their protein products. This included many genes that previously have not been associated with exercise-induced insulin sensitivity. Interestingly, endurance and resistance exercise triggered some common but mostly unique changes in expression and phosphorylation of glucose-uptake genes or their protein products. Collectively, our work provides a resource of potentially new molecular effectors that play a role in the incompletely understood regulation of muscle insulin sensitivity by exercise.
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Affiliation(s)
- Sander A J Verbrugge
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München, Neuherberg, Germany.,Exercise Biology Group, Department for Sport and Health Sciences, Technical University of Munich, Munich, Germany
| | - Julia A Alhusen
- Molecular Endocrinology, Institute for Diabetes and Cancer (IDC), Helmholtz Zentrum Munich, Helmholtz Diabetes Center (HMGU), Munich, Germany
| | - Shimon Kempin
- Exercise Biology Group, Department for Sport and Health Sciences, Technical University of Munich, Munich, Germany
| | - Nicolas J Pillon
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Jan Rozman
- Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic
| | - Henning Wackerhage
- Exercise Biology Group, Department for Sport and Health Sciences, Technical University of Munich, Munich, Germany
| | - Maximilian Kleinert
- Muscle Physiology and Metabolism Group, German Institute of Human Nutrition, Potsdam - Rehbrücke, Nuthetal, Germany.,Department of Nutrition, Exercise and Sports, Faculty of Science, Section of Molecular Physiology, University of Copenhagen, Copenhagen, Denmark
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8
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Wang EW, Trojano ML, Lewis MM, Du G, Chen H, Brown GL, Jellen LC, Song I, Neely E, Kong L, Connor JR, Huang X. HFE H63D Limits Nigral Vulnerability to Paraquat in Agricultural Workers. Toxicol Sci 2021; 181:47-57. [PMID: 33739421 DOI: 10.1093/toxsci/kfab020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Paraquat is an herbicide whose use is associated with Parkinson's disease (PD), a neurodegenerative disorder marked by neuron loss in the substantia nigra pars compacta (SNc). We recently observed that the murine homolog to the human H63D variant of the homeostatic iron regulator (HFE) may decrease paraquat-associated nigral neurotoxicity in mice. The present study examined the potential influence of H63D on paraquat-associated neurotoxicity in humans. Twenty-eight paraquat-exposed workers were identified from exposure histories and compared with 41 unexposed controls. HFE genotypes, and serum iron and transferrin were measured from blood samples. MRI was used to assess the SNc transverse relaxation rate (R2*), a marker for iron, and diffusion tensor imaging scalars of fractional anisotropy (FA) and mean diffusivity, markers of microstructural integrity. Twenty-seven subjects (9 exposed and 18 controls) were H63D heterozygous. After adjusting for age and use of other PD-associated pesticides and solvents, serum iron and transferrin were higher in exposed H63D carriers than in unexposed carriers and HFE wildtypes. SNc R2* was lower in exposed H63D carriers than in unexposed carriers, whereas SNc FA was lower in exposed HFE wildtypes than in either unexposed HFE wildtypes or exposed H63D carriers. Serum iron and SNc FA measures correlated positively among exposed, but not unexposed, subjects. These data suggest that H63D heterozygosity is associated with lower neurotoxicity presumptively linked to paraquat. Future studies with larger cohorts are warranted to replicate these findings and examine potential underlying mechanisms, especially given the high prevalence of the H63D allele in humans.
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Affiliation(s)
- Ernest W Wang
- Department of Neurology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Max L Trojano
- Department of Neurology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Mechelle M Lewis
- Department of Neurology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.,Department of Pharmacology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Guangwei Du
- Department of Neurology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Hairong Chen
- Department of Neurology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Gregory L Brown
- Department of Neurology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Leslie C Jellen
- Department of Neurology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Insung Song
- Department of Neurosurgery, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Elizabeth Neely
- Department of Neurosurgery, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Lan Kong
- Department of Public Health Sciences, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - James R Connor
- Department of Neurosurgery, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Xuemei Huang
- Department of Neurology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.,Department of Pharmacology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.,Department of Neurosurgery, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.,Department of Radiology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA.,Department of Kinesiology, Pennsylvania State Health-Milton S. Hershey Medical Center, Hershey, Pennsylvania 17033, USA
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9
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Jha V, Pal R, Kumar D, Mukhopadhyay S. ESAT-6 Protein of Mycobacterium tuberculosis Increases Holotransferrin-Mediated Iron Uptake in Macrophages by Downregulating Surface Hemochromatosis Protein HFE. THE JOURNAL OF IMMUNOLOGY 2020; 205:3095-3106. [PMID: 33148716 DOI: 10.4049/jimmunol.1801357] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 10/01/2020] [Indexed: 11/19/2022]
Abstract
Iron is an essential element for Mycobacterium tuberculosis; it has at least 40 enzymes that require iron as a cofactor. Accessibility of iron at the phagosomal surface inside macrophage is crucial for survival and virulence of M. tuberculosis ESAT-6, a 6-kDa-secreted protein of region of difference 1, is known to play a crucial role in virulence and pathogenesis of M. tuberculosis In our earlier study, we demonstrated that ESAT-6 protein interacts with β-2-microglobulin (β2M) and affects class I Ag presentation through sequestration of β2M inside endoplasmic reticulum, which contributes toward inhibition of MHC class I:β2M:peptide complex formation. The 6 aa at C-terminal region of ESAT-6 are essential for ESAT6:β2M interaction. β2M is essential for proper folding of HFE, CD1, and MHC class I and their surface expression. It is known that M. tuberculosis recruit holotransferrin at the surface of the phagosome. But the upstream mechanism by which it modulates holotransferrin-mediated iron uptake at the surface of macrophage is not well understood. In the current study, we report that interaction of the ESAT-6 protein with β2M causes downregulation of surface HFE, a protein regulating iron homeostasis via interacting with transferrin receptor 1 (TFR1). We found that ESAT-6:β2M interaction leads to sequestration of HFE in endoplasmic reticulum, causing poorer surface expression of HFE and HFE:TFR1 complex (nonfunctional TFR1) in peritoneal macrophages from C57BL/6 mice, resulting in increased holotransferrin-mediated iron uptake in these macrophages. These studies suggest that M. tuberculosis probably targets the ESAT-6 protein to increase iron uptake.
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Affiliation(s)
- Vishwanath Jha
- Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics, Uppal, Hyderabad 500039, Telangana, India.,Graduate Studies, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India; and
| | - Ravi Pal
- Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics, Uppal, Hyderabad 500039, Telangana, India.,Graduate Studies, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India; and
| | - Dhiraj Kumar
- International Centre for Genetic Engineering and Biotechnology, New Delhi 110067, India
| | - Sangita Mukhopadhyay
- Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics, Uppal, Hyderabad 500039, Telangana, India;
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10
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Bönnemann V, Claus M, Butzeck B, Collette D, Bröde P, Golka K, Watzl C. Analysis of Natural Killer cell functions in patients with hereditary hemochromatosis. EXCLI JOURNAL 2020; 19:430-441. [PMID: 32327961 PMCID: PMC7174573 DOI: 10.17179/excli2020-1116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 03/23/2020] [Indexed: 12/13/2022]
Abstract
Hereditary hemochromatosis (HH) is an autosomal-recessive disorder of the iron metabolism. Patients are typically affected by dysregulated iron levels, which can lead to iron accumulation within essential organs, such as liver, heart and pancreas. Furthermore, many HH patients are also afflicted by several immune defects and increased occurrence of autoimmune diseases that are linked to human homeostatic iron regulator protein (HFE) in the immune response. Here we examined immune cell phenotype and function in 21 HH patients compared to 21 healthy controls with a focus on Natural Killer (NK) cells. We observed increased basal and stimulated production of pro-inflammatory cytokines such as IL-1β or IL-18 in HH patients compared to healthy controls. However, we did not find major changes in the phenotype, the amount or the cytotoxic function of NK cells in HH patients. Instead, our data show a general decrease in the total number of granulocytes in HH patients (2774 ± 958 per μl versus 3457 ± 1122 per μl in healthy controls). These data demonstrate that NK cells of HH patients are not significantly affected and that the patients' treatment by regular phlebotomy is sufficient to avoid systemic iron overload and its consequences to the immune system.
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Affiliation(s)
- Vivian Bönnemann
- Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at TU Dortmund, Dortmund, Germany
| | - Maren Claus
- Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at TU Dortmund, Dortmund, Germany
| | - Barbara Butzeck
- Hämochromatose-Vereinigung Deutschland e.V. HVD, European Federation of Associations of Patients with Haemochromatosis EFAPH, Hattingen, Germany
| | - Daniela Collette
- Gemeinschaftspraxis für Hämatologie und Onkologie, Dortmund, Germany
| | - Peter Bröde
- Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at TU Dortmund, Dortmund, Germany
| | - Klaus Golka
- Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at TU Dortmund, Dortmund, Germany
| | - Carsten Watzl
- Department for Immunology, Leibniz Research Centre for Working Environment and Human Factors (IfADo) at TU Dortmund, Dortmund, Germany
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11
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Barton JC, Wiener HH, Acton RT, Adams PC, Eckfeldt JH, Gordeuk VR, Harris EL, McLaren CE, Harrison H, McLaren GD, Reboussin DM. Prevalence of iron deficiency in 62,685 women of seven race/ethnicity groups: The HEIRS Study. PLoS One 2020; 15:e0232125. [PMID: 32324809 PMCID: PMC7179917 DOI: 10.1371/journal.pone.0232125] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Few cross-sectional studies report iron deficiency (ID) prevalence in women of different race/ethnicity and ages in US or Canada. MATERIALS AND METHODS We evaluated screening observations on women who participated between 2001-2003 in a cross-sectional, primary care-based sample of adults ages ≥25 y whose observations were complete: race/ethnicity; age; transferrin saturation; serum ferritin; and HFE p.C282Y and p.H63D alleles. We defined ID using a stringent criterion: combined transferrin saturation <10% and serum ferritin <33.7 pmol/L (<15 μg/L). We compared ID prevalence in women of different race/ethnicity subgrouped by age and determined associations of p.C282Y and p.H63D to ID overall, and to ID in women ages 25-44 y with or without self-reported pregnancy. RESULTS These 62,685 women included 27,079 whites, 17,272 blacks, 8,566 Hispanics, 7,615 Asians, 449 Pacific Islanders, 441 Native Americans, and 1,263 participants of other race/ethnicity. Proportions of women with ID were higher in Hispanics and blacks than whites and Asians. Prevalence of ID was significantly greater in women ages 25-54 y of all race/ethnicity groups than women ages ≥55 y of corresponding race/ethnicity. In women ages ≥55 y, ID prevalence did not differ significantly across race/ethnicity. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy. CONCLUSIONS ID prevalence was greater in Hispanic and black than white and Asian women ages 25-54 y. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy.
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Affiliation(s)
- James C. Barton
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA and Southern Iron Disorders Center, Birmingham, AL, United States of America
| | - Howard H. Wiener
- Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States of America
| | - Ronald T. Acton
- USA and Southern Iron Disorders Center, Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States of America
| | - Paul C. Adams
- Department of Medicine, London Health Sciences Centre, London, ONT, Canada
| | - John H. Eckfeldt
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States of America
| | - Victor R. Gordeuk
- Division of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States of America
| | - Emily L. Harris
- Division of Cancer Control and Population Sciences, Epidemiology and Genomics Research Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America
| | - Christine E. McLaren
- Department of Epidemiology, University of California, Irvine, CA, United States of America
| | - Helen Harrison
- The Western-Fanshawe Collaborative BScN Program, Fanshawe College, London, ONT, Canada
| | - Gordon D. McLaren
- Division of Hematology/Oncology, Department of Medicine, University of California, Irvine, CA, USA and Department of Veterans Affairs Long Beach Healthcare System, Long Beach, CA, United States of America
| | - David M. Reboussin
- Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, United States of America
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12
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Kawabata H. Transferrin and transferrin receptors update. Free Radic Biol Med 2019; 133:46-54. [PMID: 29969719 DOI: 10.1016/j.freeradbiomed.2018.06.037] [Citation(s) in RCA: 414] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 06/29/2018] [Accepted: 06/29/2018] [Indexed: 12/20/2022]
Abstract
In vertebrates, transferrin (Tf) safely delivers iron through circulation to cells. Tf-bound iron is incorporated through Tf receptor (TfR) 1-mediated endocytosis. TfR1 can mediate cellular uptake of both Tf and H-ferritin, an iron storage protein. New World arenaviruses, which cause hemorrhagic fever, and Plasmodium vivax use TfR1 for entry into host cells. Human TfR2, another receptor for Tf, is predominantly expressed in hepatocytes and erythroid precursors, and holo-Tf dramatically upregulates its expression. TfR2 forms a complex with hemochromatosis protein, HFE, and serves as a component of the iron sensing machinery in hepatocytes. Defects in TfR2 cause systemic iron overload, hemochromatosis, through down-regulation of hepcidin. In erythroid cells, TfR2 forms a complex with the erythropoietin receptor and regulates erythropoiesis. TfR2 facilitates iron transport from lysosomes to mitochondria in erythroblasts and dopaminergic neurons. Administration of apo-Tf, which scavenges free iron, has been explored for various clinical conditions including atransferrinemia, iron overload, and tissue ischemia. Apo-Tf has also been shown to ameliorate anemia in animal models of β-thalassemia. In this review, I provide an update and summary on our knowledge of mammalian Tf and its receptors.
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Affiliation(s)
- Hiroshi Kawabata
- Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku, Uchinada-machi, Ishikawa-ken 920-0293, Japan.
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13
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Abstract
Hepcidin is central to regulation of iron metabolism. Its effect on a cellular level involves binding ferroportin, the main iron export protein, resulting in its internalization and degradation and leading to iron sequestration within ferroportin-expressing cells. Aberrantly increased hepcidin leads to systemic iron deficiency and/or iron restricted erythropoiesis. Furthermore, insufficiently elevated hepcidin occurs in multiple diseases associated with iron overload. Abnormal iron metabolism as a consequence of hepcidin dysregulation is an underlying factor resulting in pathophysiology of multiple diseases and several agents aimed at manipulating this pathway have been designed, with some already in clinical trials. In this chapter, we present an overview of and rationale for exploring the development of hepcidin agonists and antagonists in various clinical scenarios.
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Affiliation(s)
- Yelena Z Ginzburg
- Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
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14
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Guo Y, Busch MP, Seielstad M, Endres-Dighe S, Westhoff CM, Keating B, Hoppe C, Bordbar A, Custer B, Butterworth AS, Kanias T, Mast AE, Kleinman S, Lu Y, Page GP. Development and evaluation of a transfusion medicine genome wide genotyping array. Transfusion 2019; 59:101-111. [PMID: 30456907 PMCID: PMC7032526 DOI: 10.1111/trf.15012] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 07/11/2018] [Accepted: 07/11/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Many aspects of transfusion medicine are affected by genetics. Current single-nucleotide polymorphism (SNP) arrays are limited in the number of targets that can be interrogated and cannot detect all variation of interest. We designed a transfusion medicine array (TM-Array) for study of both common and rare transfusion-relevant variations in genetically diverse donor and recipient populations. STUDY DESIGN AND METHODS The array was designed by conducting extensive bioinformatics mining and consulting experts to identify genes and genetic variation related to a wide range of transfusion medicine clinical relevant and research-related topics. Copy number polymorphisms were added in the alpha globin, beta globin, and Rh gene clusters. RESULTS The final array contains approximately 879,000 SNP and copy number polymorphism markers. Over 99% of SNPs were called reliably. Technical replication showed the array to be robust and reproducible, with an error rate less than 0.03%. The array also had a very low Mendelian error rate (average parent-child trio accuracy of 0.9997). Blood group results were in concordance with serology testing results, and the array accurately identifies rare variants (minor allele frequency of 0.5%). The array achieved high genome-wide imputation coverage for African-American (97.5%), Hispanic (96.1%), East Asian (94.6%), and white (96.1%) genomes at a minor allele frequency of 5%. CONCLUSIONS A custom array for transfusion medicine research has been designed and evaluated. It gives wide coverage and accurate identification of rare SNPs in diverse populations. The TM-Array will be useful for future genetic studies in the diverse fields of transfusion medicine research.
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Affiliation(s)
- Yuelong Guo
- RTI International, Research Triangle Park, North Carolina
| | - Michael P Busch
- Vitalant Research Institute (formerly Blood Systems Research Institute), San Francisco, California
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California
| | - Mark Seielstad
- Vitalant Research Institute (formerly Blood Systems Research Institute), San Francisco, California
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California
| | | | | | - Brendan Keating
- Penn Transplant Institute, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Carolyn Hoppe
- UCSF Benioff Children's Hospital Oakland, Oakland, California
| | | | - Brian Custer
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California
| | - Adam S Butterworth
- MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- NIHR Blood and Transplant Unit in Donor Health and Genomics, University of Cambridge, Cambridge, UK
| | - Tamir Kanias
- Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Alan E Mast
- Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Steve Kleinman
- University of British Columbia, Victoria, British Columbia, Canada
| | - Yontao Lu
- Affymetrix Incorporated, Santa Clara, California
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15
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Loréal O, Cavey T, Robin F, Kenawi M, Guggenbuhl P, Brissot P. Iron as a Therapeutic Target in HFE-Related Hemochromatosis: Usual and Novel Aspects. Pharmaceuticals (Basel) 2018; 11:ph11040131. [PMID: 30486249 PMCID: PMC6315470 DOI: 10.3390/ph11040131] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 11/16/2018] [Accepted: 11/19/2018] [Indexed: 12/13/2022] Open
Abstract
Genetic hemochromatosis is an iron overload disease that is mainly related to the C282Y mutation in the HFE gene. This gene controls the expression of hepcidin, a peptide secreted in plasma by the liver and regulates systemic iron distribution. Homozygous C282Y mutation induces hepcidin deficiency, leading to increased circulating transferrin saturation, and ultimately, iron accumulation in organs such as the liver, pancreas, heart, and bone. Iron in excess may induce or favor the development of complications such as cirrhosis, liver cancer, diabetes, heart failure, hypogonadism, but also complaints such as asthenia and disabling arthritis. Iron depletive treatment mainly consists of venesections that permit the removal of iron contained in red blood cells and the subsequent mobilization of stored iron in order to synthesize hemoglobin for new erythrocytes. It is highly efficient in removing excess iron and preventing most of the complications associated with excess iron in the body. However, this treatment does not target the biological mechanisms involved in the iron metabolism disturbance. New treatments based on the increase of hepcidin levels, by using hepcidin mimetics or inducers, or inhibitors of the iron export activity of ferroportin protein that is the target of hepcidin, if devoid of significant secondary effects, should be useful to better control iron parameters and symptoms, such as arthritis.
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Affiliation(s)
- Olivier Loréal
- INSERM, Univ Rennes, INRA, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35033 Rennes, France.
| | - Thibault Cavey
- INSERM, Univ Rennes, INRA, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35033 Rennes, France.
| | - François Robin
- INSERM, Univ Rennes, INRA, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35033 Rennes, France.
| | - Moussa Kenawi
- INSERM, Univ Rennes, INRA, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35033 Rennes, France.
| | - Pascal Guggenbuhl
- INSERM, Univ Rennes, INRA, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35033 Rennes, France.
| | - Pierre Brissot
- INSERM, Univ Rennes, INRA, CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35033 Rennes, France.
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16
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Kordopati V, Salhi A, Razali R, Radovanovic A, Tifratene F, Uludag M, Li Y, Bokhari A, AlSaieedi A, Bin Raies A, Van Neste C, Essack M, Bajic VB. DES-Mutation: System for Exploring Links of Mutations and Diseases. Sci Rep 2018; 8:13359. [PMID: 30190574 PMCID: PMC6127254 DOI: 10.1038/s41598-018-31439-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 08/17/2018] [Indexed: 12/17/2022] Open
Abstract
During cellular division DNA replicates and this process is the basis for passing genetic information to the next generation. However, the DNA copy process sometimes produces a copy that is not perfect, that is, one with mutations. The collection of all such mutations in the DNA copy of an organism makes it unique and determines the organism’s phenotype. However, mutations are often the cause of diseases. Thus, it is useful to have the capability to explore links between mutations and disease. We approached this problem by analyzing a vast amount of published information linking mutations to disease states. Based on such information, we developed the DES-Mutation knowledgebase which allows for exploration of not only mutation-disease links, but also links between mutations and concepts from 27 topic-specific dictionaries such as human genes/proteins, toxins, pathogens, etc. This allows for a more detailed insight into mutation-disease links and context. On a sample of 600 mutation-disease associations predicted and curated, our system achieves precision of 72.83%. To demonstrate the utility of DES-Mutation, we provide case studies related to known or potentially novel information involving disease mutations. To our knowledge, this is the first mutation-disease knowledgebase dedicated to the exploration of this topic through text-mining and data-mining of different mutation types and their associations with terms from multiple thematic dictionaries.
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Affiliation(s)
- Vasiliki Kordopati
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia
| | - Adil Salhi
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia
| | - Rozaimi Razali
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia
| | - Aleksandar Radovanovic
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia
| | - Faroug Tifratene
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia
| | - Mahmut Uludag
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia
| | - Yu Li
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia
| | - Ameerah Bokhari
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia
| | - Ahdab AlSaieedi
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia.,King Abdulaziz University (KAU), Faculty of Applied Medical Sciences (FAMS), Department of Medical Laboratory Technology (MLT), Jeddah, 21589-80324, Saudi Arabia
| | - Arwa Bin Raies
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia
| | - Christophe Van Neste
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia.,Ghent University, Center for Medical Genetics Ghent (CMGG), B-9000, Ghent, Belgium
| | - Magbubah Essack
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia
| | - Vladimir B Bajic
- King Abdullah University of Science and Technology (KAUST), Computational Bioscience Research Center (CBRC), Thuwal, 23955-6900, Saudi Arabia.
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17
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Mladěnka P, Hrdina R, Hübl M, Šimůnek T. The Fate of Iron in The Organism and Its Regulatory Pathways. ACTA MEDICA (HRADEC KRÁLOVÉ) 2018. [DOI: 10.14712/18059694.2018.40] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Iron is an essential element involved in many life-necessary processes. Interestingly, in mammals there is no active excretion mechanism for iron. Therefore iron kinetics has to be meticulously regulated. The most important step for regulation of iron kinetics is absorption. The absorption takes place in small intestine and it is implicated that it requires several proteins. Iron is then released from enterocytes into the circulation and delivered to the cells. Iron movement inside the cell is only partially elucidated and its traffic to mitochondia is not known. Surprisingly, the regulation of various proteins related to iron kinetics and energy metabolism at the molecular level is better described. On contrary, the complex control of iron absorption cannot be fully explicated with present knowledge.
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18
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Del Greco M F, Foco L, Pichler I, Eller P, Eller K, Benyamin B, Whitfield JB, Pramstaller PP, Thompson JR, Pattaro C, Minelli C. Serum iron level and kidney function: a Mendelian randomization study. Nephrol Dial Transplant 2018; 32:273-278. [PMID: 28186534 DOI: 10.1093/ndt/gfw215] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 04/25/2016] [Indexed: 01/01/2023] Open
Abstract
Background Iron depletion is a known consequence of chronic kidney disease (CKD), but there is contradicting epidemiological evidence on whether iron itself affects kidney function and whether its effect is protective or detrimental in the general population. While epidemiological studies tend to be affected by confounding and reverse causation, Mendelian randomization (MR) can provide unconfounded estimates of causal effects by using genes as instruments. Methods We performed an MR study of the effect of serum iron levels on estimated glomerular filtration rate (eGFR), using genetic variants known to be associated with iron. MR estimates of the effect of iron on eGFR were derived based on the association of each variant with iron and eGFR from two large genome-wide meta-analyses on 48 978 and 74 354 individuals. We performed a similar MR analysis for ferritin, which measures iron stored in the body, using variants associated with ferritin. Results A combined MR estimate across all variants showed a 1.3% increase in eGFR per standard deviation increase in iron (95% confidence interval 0.4–2.1%; P = 0.004). The results for ferritin were consistent with those for iron. Secondary MR analyses of the effects of iron and ferritin on CKD did not show significant associations but had very low statistical power. Conclusions Our study suggests a protective effect of iron on kidney function in the general population. Further research is required to confirm this causal association, investigate it in study populations at higher risk of CKD and explore its underlying mechanism of action.
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Affiliation(s)
- Fabiola Del Greco M
- Center for Biomedicine, European Academy of Bolzano/Bozen (EURAC), affiliated with the University of Lübeck, Via Galvani 31, Bolzano, Italy
| | - Luisa Foco
- Center for Biomedicine, European Academy of Bolzano/Bozen (EURAC), affiliated with the University of Lübeck, Via Galvani 31, Bolzano, Italy
| | - Irene Pichler
- Center for Biomedicine, European Academy of Bolzano/Bozen (EURAC), affiliated with the University of Lübeck, Via Galvani 31, Bolzano, Italy
| | | | | | - Beben Benyamin
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia
| | - John B Whitfield
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | | | | | - Peter P Pramstaller
- Center for Biomedicine, European Academy of Bolzano/Bozen (EURAC), affiliated with the University of Lübeck, Via Galvani 31, Bolzano, Italy
| | - John R Thompson
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Cristian Pattaro
- Center for Biomedicine, European Academy of Bolzano/Bozen (EURAC), affiliated with the University of Lübeck, Via Galvani 31, Bolzano, Italy
| | - Cosetta Minelli
- Population Health and Occupational Disease, National Heart and Lung Institute, Imperial College, Emmanuel Kaye Building, 1 Manresa Road, London, UK
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19
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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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20
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Duck KA, Neely EB, Simpson IA, Connor JR. A role for sex and a common HFE gene variant in brain iron uptake. J Cereb Blood Flow Metab 2018; 38:540-548. [PMID: 28350201 PMCID: PMC5851144 DOI: 10.1177/0271678x17701949] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 02/23/2017] [Accepted: 03/07/2017] [Indexed: 11/16/2022]
Abstract
HFE (high iron) is an essential protein for regulating iron transport into cells. Mutations of the HFE gene result in loss of this regulation causing accumulation of iron within the cell. The mutated protein has been found increasingly in numerous neurodegenerative disorders in which increased levels of iron in the brain are reported. Additionally, evidence that these mutations are associated with elevated brain iron challenges the paradigm that the brain is protected by the blood-brain barrier. While much has been studied regarding the role of HFE in cellular iron uptake, it has remained unclear what role the protein plays in the transport of iron into the brain. We investigated regulation of iron transport into the brain using a mouse model with a mutation in the HFE gene. We demonstrated that the rate of radiolabeled iron (59Fe) uptake was similar between the two genotypes despite higher brain iron concentrations in the mutant. However, there were significant differences in iron uptake between males and females regardless of genotype. These data indicate that brain iron status is consistently maintained and tightly regulated at the level of the blood-brain barrier.
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Affiliation(s)
- Kari A Duck
- Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA, USA
| | - Elizabeth B Neely
- Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA, USA
| | - Ian A Simpson
- Department of Neural and Behavioral Sciences, Penn State Hershey Medical Center, Hershey, PA, USA
| | - James R Connor
- Department of Neurosurgery, Penn State Hershey Medical Center, Hershey, PA, USA
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21
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Asimakopoulou A, Weiskirchen S, Weiskirchen R. Pathogenesis, Diagnostics, and Treatment of Hereditary Haemochromatosis: A 150 Year-Long Understanding of an Iron Overload Disorder. EUROPEAN MEDICAL JOURNAL 2017. [DOI: 10.33590/emj/10310080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Haemochromatosis is an iron overload disorder that can be inherited or acquired and when diagnosis is delayed, disease progression and death can occur. Iron overload was first described by the French internist Armand Trousseau in 1865 in an article on diabetes in which alterations in skin pigmentations were reported. Some years later, the German pathologist Friedrich Daniel von Recklinghausen coined the term ‘haemochromatosis’ for a metabolic disorder characterised by excess deposition of iron in the tissue. This disorder affects 1 in 200 subjects of Caucasians of Northern European descent. The systemic excess iron build-up condition quickly gained an intense clinical interest. Haemochromatosis can lead to severe pathological symptoms in multiple organs, including the liver, bones, spleen, heart, pancreas, joints, and reproductive organs. With the progress of the disease, hepatic damage predominates. Polymorphisms in several independent genes can lead to haemochromatosis. However, the most widely known haemochromatosis-associated and studied ones are genetic variants in the HFE gene, located on the short arm of human chromosome 6. Early detection and phlebotomy prior to the onset of fibrosis/cirrhosis can reduce morbidity and normalise life expectancy. Consequently, phlebotomy has been accepted for decades as a standard treatment for the reduction of iron load. Nowadays, other methods, such as erythrocytapheresis, therapeutic application of iron chelators and proton pump inhibitors, or hepcidin-targeted therapy, are discussed as alternative personalised treatments of hereditary haemochromatosis. This review focusses on the pathogenesis, diagnosis, and therapy of haemochromatosis.
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Affiliation(s)
- Anastasia Asimakopoulou
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Sabine Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
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22
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Rishi G, Subramaniam VN. The liver in regulation of iron homeostasis. Am J Physiol Gastrointest Liver Physiol 2017; 313:G157-G165. [PMID: 28596277 DOI: 10.1152/ajpgi.00004.2017] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 05/31/2017] [Accepted: 05/31/2017] [Indexed: 01/31/2023]
Abstract
The liver is one of the largest and most functionally diverse organs in the human body. In addition to roles in detoxification of xenobiotics, digestion, synthesis of important plasma proteins, gluconeogenesis, lipid metabolism, and storage, the liver also plays a significant role in iron homeostasis. Apart from being the storage site for excess body iron, it also plays a vital role in regulating the amount of iron released into the blood by enterocytes and macrophages. Since iron is essential for many important physiological and molecular processes, it increases the importance of liver in the proper functioning of the body's metabolism. This hepatic iron-regulatory function can be attributed to the expression of many liver-specific or liver-enriched proteins, all of which play an important role in the regulation of iron homeostasis. This review focuses on these proteins and their known roles in the regulation of body iron metabolism.
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Affiliation(s)
- Gautam Rishi
- Liver Disease and Iron Disorders Research Group, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
| | - V Nathan Subramaniam
- Liver Disease and Iron Disorders Research Group, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
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23
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Hollerer I, Bachmann A, Muckenthaler MU. Pathophysiological consequences and benefits of HFE mutations: 20 years of research. Haematologica 2017; 102:809-817. [PMID: 28280078 PMCID: PMC5477599 DOI: 10.3324/haematol.2016.160432] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 03/01/2017] [Indexed: 12/15/2022] Open
Abstract
Mutations in the HFE (hemochromatosis) gene cause hereditary hemochromatosis, an iron overload disorder that is hallmarked by excessive accumulation of iron in parenchymal organs. The HFE mutation p.Cys282Tyr is pathologically most relevant and occurs in the Caucasian population with a carrier frequency of up to 1 in 8 in specific European regions. Despite this high prevalence, the mutation causes a clinically relevant phenotype only in a minority of cases. In this review, we summarize historical facts and recent research findings about hereditary hemochromatosis, and outline the pathological consequences of the associated gene defects. In addition, we discuss potential advantages of HFE mutations in asymptomatic carriers.
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Affiliation(s)
- Ina Hollerer
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
- European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany
| | | | - Martina U Muckenthaler
- Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Germany
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24
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Reuben A, Chung JW, Lapointe R, Santos MM. The hemochromatosis protein HFE 20 years later: An emerging role in antigen presentation and in the immune system. IMMUNITY INFLAMMATION AND DISEASE 2017; 5:218-232. [PMID: 28474781 PMCID: PMC5569368 DOI: 10.1002/iid3.158] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 01/30/2017] [Accepted: 02/10/2017] [Indexed: 12/13/2022]
Abstract
Introduction Since its discovery, the hemochromatosis protein HFE has been primarily defined by its role in iron metabolism and homeostasis, and its involvement in the genetic disease termed hereditary hemochromatosis (HH). While HH patients are typically afflicted by dysregulated iron levels, many are also affected by several immune defects and increased incidence of autoimmune diseases that have thereby implicated HFE in the immune response. Growing evidence has supported an immunological role for HFE with recent studies describing HFE specifically as it relates to MHC I antigen presentation. Methods/Results Here, we present a comprehensive overview of the relationship between iron metabolism, HFE, and the immune system to better understand the origin and cause of immune defects in HH patients. We further describe the role of HFE in MHC I antigen presentation and its potential to impair autoimmune responses in homeostatic conditions, a mechanism which may be exploited by tumors to evade immune surveillance. Conclusion Overall, this increased understanding of the role of HFE in the immune response sets the stage for better treatment and management of HH and other iron‐related diseases, as well as of the immune defects related to this condition.
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Affiliation(s)
- Alexandre Reuben
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.,Département de Médicine, Université de Montréal, Montréal, Québec, Canada.,Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Jacqueline W Chung
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada
| | - Réjean Lapointe
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.,Département de Médicine, Université de Montréal, Montréal, Québec, Canada.,Institut du Cancer de Montréal, Montréal, Québec, Canada
| | - Manuela M Santos
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.,Département de Médicine, Université de Montréal, Montréal, Québec, Canada.,Institut du Cancer de Montréal, Montréal, Québec, Canada
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25
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Lee SY, Zhu J, Salzberg AC, Zhang B, Liu DJ, Muscat JE, Langan ST, Connor JR. Analysis of single nucleotide variants of HFE gene and association to survival in The Cancer Genome Atlas GBM data. PLoS One 2017; 12:e0174778. [PMID: 28358914 PMCID: PMC5373638 DOI: 10.1371/journal.pone.0174778] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 03/15/2017] [Indexed: 11/18/2022] Open
Abstract
Human hemochromatosis protein (HFE) is involved in iron metabolism. Two major HFE polymorphisms, H63D and C282Y, have been associated with an increased risk of cancers. Previously, we reported decreased gender effects in overall survival based on H63D or C282Y HFE polymorphisms patients with glioblastoma multiforme (GBM). However, the effect of other single nucleotide variation (SNV) in the HFE gene on the cancer development and progression has not been systematically studied. To expand our finding in a larger sample, and to identify other HFE SNV, we analyzed the frequency of somatic SNV in HFE gene and its relationship to survival in GBM patients using The Cancer Genome Atlas (TCGA) GBM (Caucasian only) database. We found 9 SNVs with increased frequency in blood normal of TCGA GBM patients compared to the 1000Genome. Among 9 SNVs, 7 SNVs were located in the intron and 2 SNVs (i.e., H63D, C282Y) in the exon of HFE gene. The statistical analysis demonstrated that blood normal samples of TCGA GBM have more H63D (p = 0.0002, 95% Confidence interval (CI): 0.2119–0.3223) or C282Y (p = 0.0129, 95% CI: 0.0474–0.1159) HFE polymorphisms than 1000Genome. The Kaplan-Meier survival curve for the 264 GBM samples revealed no difference between wild type (WT) HFE and H63D, and WT HFE and C282Y GBM patients. In addition, there was no difference in the survival of male/female GBM patients based on HFE genotype. There was no correlation between HFE expression and survival. In conclusion, the current results suggest that somatic HFE polymorphisms do not impact GBM patients’ survival in the TCGA data set of GBM.
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Affiliation(s)
- Sang Y. Lee
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania, United States of America
- * E-mail:
| | - Junjia Zhu
- Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Anna C. Salzberg
- Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Bo Zhang
- Department of Biochemistry & Molecular Biology, The Pennsylvania State University College of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Dajiang J. Liu
- Department of Public Health Sciences and Biochemistry & Molecular Biology, Institute for Personalized Medicine, The Pennsylvania State University College of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Joshua E. Muscat
- Department of Public Health Sciences, The Pennsylvania State University College of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Sara T. Langan
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - James R. Connor
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Penn State Hershey Medical Center, Hershey, Pennsylvania, United States of America
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AlFadhli S, Salem M, Shome DK, Mahdi N, Nizam R. The Effects of HFE Polymorphisms on Biochemical Parameters of Iron Status in Arab Beta-Thalassemia Patients. Indian J Hematol Blood Transfus 2017; 33:545-551. [PMID: 29075067 DOI: 10.1007/s12288-016-0775-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2015] [Accepted: 12/28/2016] [Indexed: 12/20/2022] Open
Abstract
In this study, the potential effect of three HFE gene polymorphisms (C282Y, H63D and S65C) and the SLC40A1 A77D polymorphism on iron balance was investigated in 234 subjects (91 Arab beta-thalassemia major (BTM) patients, 34 beta-thalassemia trait (BTT) individuals and 109 health controls). Genotyping was done using restriction-fragment-length polymorphism and direct-sequencing. Serum-iron, total iron binding capacity, transferrin and ferritin were estimated in all BTT and BTM, and in 65 healthy controls. H63D was the only polymorphism detected in our cohort. Allele frequency was 13% in both BTM and BTT and 10% in controls with no significant difference. Serum iron, ferritin and transferrin saturation were significantly higher in normal males heterozygous for H63D as compared to homozygous wild-type males. Ferritin was significantly higher in BTT males with or without H63D polymorphism when compared to the healthy males with H/H genotype. No such difference was observed between H/H versus H/D BTT subgroups. We conclude that H63D is the only significant hemochromatosis-associated polymorphism in the Arabian Gulf region. The heterozygous state of H63D may significantly alter iron parameters in normal males. In BTT, it appears that the beta-thalassemia allele has an overriding influence on ferritin values, and this generally manifest in males.
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Affiliation(s)
- Suad AlFadhli
- Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait University, PO Box 31470, Sulaibekhat, Kuwait
| | - Matra Salem
- Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait University, PO Box 31470, Sulaibekhat, Kuwait
| | - D K Shome
- Department of Pathology, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Najat Mahdi
- Ministry of Health, Alsalmaniya Medical Complex, Manama, Bahrain
| | - Rasheeba Nizam
- Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait University, PO Box 31470, Sulaibekhat, Kuwait
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Sut C, Hamzeh-Cognasse H, Laradi S, Bost V, Aubrège C, Acquart S, Vignal M, Boutahar N, Arthaud CA, Ange Eyraud M, Pozzetto B, Tiberghien P, Garraud O, Cognasse F. Properties of donated red blood cell components from patients with hereditary hemochromatosis. Transfusion 2017; 57:166-177. [PMID: 27807848 DOI: 10.1111/trf.13890] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/25/2016] [Accepted: 08/25/2016] [Indexed: 01/28/2023]
Abstract
BACKGROUND Red blood cells (RBCs) contain large amounts of iron, and periodic therapeutic phlebotomy is thus the main treatment for hereditary hemochromatosis (HH). However, the donation of therapeutic phlebotomy products from asymptomatic patients for transfusion purposes remains controversial. In this study, we compared the quality of RBCs obtained from HH patients with those of non-HH RBCs, within the allowed 42-day storage period. STUDY DESIGN AND METHODS RBCs were obtained from HH patient donors and random regular blood donors by whole blood collection. RBCs were stored for up to 42 days, according to national regulations and standard blood bank conditions in France. The following variables were assessed: hematologic and biochemical results, RBC membrane and soluble inflammatory markers, and the proinflammatory potential of HH RBC supernatant toward endothelial cells in an in vitro model. RESULTS There were no major differences between the two groups in terms of biophysical, biochemical, or soluble immunomodulatory factors. However, we observed small but significant differences in changes in RBC membrane proteins during storage, including increased phosphatidylserine expression and decreased hemolysis in HH compared with normal RBCs. However, there were no differences in terms of bioactivity of soluble immunomodulatory factors in the RBC supernatant during storage between HH and control donors, as determined by their effects on endothelial cells in vitro. CONCLUSIONS These in vitro studies suggest that RBCs from HH patients appear, while exhibiting subtle differences, to be suitable for transfusion purposes according to currently accepted criteria.
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Affiliation(s)
- Caroline Sut
- Etablissement Français du Sang Rhône-Alpes-Auvergne
- Université de Lyon, GIMAP-EA3064
| | | | - Sandrine Laradi
- Etablissement Français du Sang Rhône-Alpes-Auvergne
- Université de Lyon, GIMAP-EA3064
| | - Vincent Bost
- Etablissement Français du Sang Rhône-Alpes-Auvergne
| | | | | | | | - Nadia Boutahar
- Département de Biochimie Hôpital Nord, CHU de Saint-Etienne, Saint Etienne
| | | | | | - Bruno Pozzetto
- Université de Lyon, GIMAP-EA3064
- Département de Microbiologie Hôpital Nord, CHU de Saint-Etienne, Saint Etienne, France
| | - Pierre Tiberghien
- UMR1098, INSERM, Etablissement Français du Sang, Université de Franche-Comté, Besançon, France
- Etablissement Français du Sang, Saint-Denis, France
| | - Olivier Garraud
- Université de Lyon, GIMAP-EA3064
- Institut National de Transfusion Sanguine (INTS), Paris, France
| | - Fabrice Cognasse
- Etablissement Français du Sang Rhône-Alpes-Auvergne
- Université de Lyon, GIMAP-EA3064
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HFE Variants and the Expression of Iron-Related Proteins in Breast Cancer-Associated Lymphocytes and Macrophages. CANCER MICROENVIRONMENT 2016; 9:85-91. [PMID: 28028679 DOI: 10.1007/s12307-016-0191-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 12/20/2016] [Indexed: 02/06/2023]
Abstract
The association of HFE (High Iron FE) major variants with breast cancer risk and behavior has been a matter of discussion for a long time. However, their impact on the expression of iron-related proteins in the breast cancer tissue has never been addressed. In the present study, hepcidin, ferroportin 1, transferrin receptor 1 (TfR1), and ferritin expressions, as well as tissue iron deposition were evaluated in a collection of samples from breast cancers patients and analyzed according to the patients' HFE genotype. Within the group of patients with invasive carcinoma, those carrying the p.Cys282Tyr variant in heterozygosity presented a higher expression of hepcidin in lymphocytes and macrophages than wild-type or p.His63Asp carriers. An increased expression of TfR1 was also observed in all the cell types analyzed but only in p.Cys282Tyr/p.His63Asp compound heterozygous patients. A differential impact of the two HFE variants was further noticed with the observation of a significantly higher percentage of p.Cys282Tyr heterozygous patients presenting tissue iron deposition in comparison to p.His63Asp heterozygous. In the present cohort, no significant associations were found between HFE variants and classical clinicopathological markers of breast cancer behavior and prognosis. Although limited by a low sampling size, our results provide a new possible explanation for the previously reported impact of HFE major variants on breast cancer progression, i.e., not by influencing systemic iron homeostasis but rather by differentially modulating the local cellular expression of iron-related proteins and tissue iron deposition.
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Khan P, Shandilya A, Jayaram B, Islam A, Ahmad F, Hassan MI. Effect of pH on the stability of hemochromatosis factor E: a combined spectroscopic and molecular dynamics simulation-based study. J Biomol Struct Dyn 2016; 35:1582-1598. [PMID: 27174123 DOI: 10.1080/07391102.2016.1189359] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Hereditary hemochromatosis is an iron overburden condition, which is mainly governed by hereditary hemochromatosis factor E (HFE), a member of major histocompatibility complex class I. To understand the effect of pH on the structure and stability of HFE, we have cloned, expressed, and purified the HFE in the bacterial system and performed circular dichroism, fluorescence, and absorbance measurements at a wide pH range (pH 3.0-11.0). We found that HFE remains stable in the pH range 7.5-11.0 and gets completely acid denatured at low pH values. In this work, we also analyzed the contribution of salt bridges to the stability of HFE. We further performed molecular dynamics simulations for 80 ns at different pH values. An excellent agreement was observed between results from biophysical and MD simulation studies. At lower pH, HFE undergoes denaturation and may be driven toward a degradation pathway, such as ubiquitination. Hence, HFE is not available to bind again with transferrin receptor1 to negatively regulate iron homeostasis. Further we postulated that, might be low pH of cancerous cells helps them to meet their high iron requirement.
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Affiliation(s)
- Parvez Khan
- a Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia , New Delhi 110025 , India
| | - Ashutosh Shandilya
- b Department of Chemistry , Indian Institute of Technology Delhi , New Delhi 110016 , India
| | - B Jayaram
- b Department of Chemistry , Indian Institute of Technology Delhi , New Delhi 110016 , India
| | - Asimul Islam
- a Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia , New Delhi 110025 , India
| | - Faizan Ahmad
- a Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia , New Delhi 110025 , India
| | - Md Imtaiyaz Hassan
- a Centre for Interdisciplinary Research in Basic Sciences , Jamia Millia Islamia , New Delhi 110025 , India
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Abstract
Iron is an essential element for human development. It is a major requirement for cellular processes such as oxygen transport, energy metabolism, neurotransmitter synthesis, and myelin synthesis. Despite its crucial role in these processes, iron in the ferric form can also produce toxic reactive oxygen species. The duality of iron’s function highlights the importance of maintaining a strict balance of iron levels in the body. As a result, organisms have developed elegant mechanisms of iron uptake, transport, and storage. This review will focus on the mechanisms that have evolved at physiological barriers, such as the intestine, the placenta, and the blood–brain barrier (BBB), where iron must be transported. Much has been written about the processes for iron transport across the intestine and the placenta, but less is known about iron transport mechanisms at the BBB. In this review, we compare the established pathways at the intestine and the placenta as well as describe what is currently known about iron transport at the BBB and how brain iron uptake correlates with processes at these other physiological barriers.
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Affiliation(s)
- Kari A Duck
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA
| | - James R Connor
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
- Department of Neurosurgery, Neural and Behavioral Sciences and Pediatrics, Center for Aging and Neurodegenerative Diseases, Penn State Hershey Medical Center, 500 University Drive, MC H110, C3830, Hershey, PA, 17033, USA.
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31
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Anderson CK, Brossay L. The role of MHC class Ib-restricted T cells during infection. Immunogenetics 2016; 68:677-91. [PMID: 27368413 DOI: 10.1007/s00251-016-0932-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 05/22/2016] [Indexed: 01/02/2023]
Abstract
Even though major histocompatibility complex (MHC) class Ia and many Ib molecules have similarities in structure, MHC class Ib molecules tend to have more specialized functions, which include the presentation of non-peptidic antigens to non-classical T cells. Likewise, non-classical T cells also have unique characteristics, including an innate-like phenotype in naïve animals and rapid effector functions. In this review, we discuss the role of MAIT and NKT cells during infection but also the contribution of less studied MHC class Ib-restricted T cells such as Qa-1-, Qa-2-, and M3-restricted T cells. We focus on describing the types of antigens presented to non-classical T cells, their response and cytokine profile following infection, as well as the overall impact of these T cells to the immune system.
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Affiliation(s)
- Courtney K Anderson
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Box G-B618, Providence, RI, 02912, USA
| | - Laurent Brossay
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Box G-B618, Providence, RI, 02912, USA.
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32
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Piñero DJ, Connor JR. Iron in the Brain: An Important Contributor in Normal and Diseased States. Neuroscientist 2016. [DOI: 10.1177/107385840000600607] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Iron is essential for normal neurological function because of its role in oxidative metabolism and because it is a cofactor in the synthesis of neurotransmitters and myelin. In the past several years, there has been increased attention to the importance of oxidative stress in the central nervous system. Iron is the most important inducer of reactive oxygen species, therefore, the relation of iron to neurodegenerative processes is more appreciated today than it was a few years ago. Nevertheless, despite this increased attention and awareness, our knowledge of iron metabolism in the brain at the cellular and molecular levels is still limited. Iron is distributed in a heterogeneous fashion among the different regions and cells of the brain. This regional and cellular heterogeneity is preserved across many species. Brain iron concentrations are not static; they increase with age and in many diseases and decrease when iron is deficient in the diet. In infants and children, insufficient iron in the diet is associated with decreased brain iron and with changes in behavior and cognitive functioning. Abnormal iron accumulation in the diseased brain areas and, in some cases, alterations in iron-related proteins have been reported in many neurodegenerative diseases, including Hallervorden-Spatz syndrome, Alzheimer’s disease, Parkinson’s disease, and Friedreich’s ataxia. There is strong evidence for iron-mediated oxidative damage as a primary contributor to cell death in these disorders. Demyelinating diseases, such as multiple sclerosis, especially warrant study in relation to iron availability. Myelin synthesis and maintenance have a high iron requirement, thus, oligodendrocytes must have a relatively high and constant supply of iron. However, the high oxygen utilization, high density of lipids, and high iron content of white matter all combine to increase the risk of oxidative damage. We review here the current knowledge of the normal metabolism of iron in the brain and the suspected role of iron in neuropathology.
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Affiliation(s)
- Domingo J. Piñero
- George M. Leader Family Laboratory for Alzheimer’s Disease Research, Department of Neuroscience & Anatomy, Penn State University, College of Medicine, Hershey, Pennsylvania
| | - James R. Connor
- George M. Leader Family Laboratory for Alzheimer’s Disease Research, Department of Neuroscience & Anatomy, Penn State University, College of Medicine, Hershey, Pennsylvania,
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Li L, Dong M, Wang XG. The Implication and Significance of Beta 2 Microglobulin: A Conservative Multifunctional Regulator. Chin Med J (Engl) 2016; 129:448-55. [PMID: 26879019 PMCID: PMC4800846 DOI: 10.4103/0366-6999.176084] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE This review focuses on the current knowledge on the implication and significance of beta 2 microglobulin (β2M), a conservative immune molecule in vertebrate. DATA SOURCES The data used in this review were obtained from PubMed up to October 2015. Terms of β2M, immune response, and infection were used in the search. STUDY SELECTIONS Articles related to β2M were retrieved and reviewed. Articles focusing on the characteristic and function of β2M were selected. The exclusion criteria of articles were that the studies on β2M-related molecules. RESULTS β2M is critical for the immune surveillance and modulation in vertebrate animals. The dysregulation of β2M is associated with multiple diseases, including endogenous and infectious diseases. β2M could directly participate in the development of cancer cells, and the level of β2M is deemed as a prognostic marker for several malignancies. It also involves in forming major histocompatibility complex (MHC class I or MHC I) or like heterodimers, covering from antigen presentation to immune homeostasis. CONCLUSIONS Based on the characteristic of β2M, it or its signaling pathway has been targeted as biomedical or therapeutic tools. Moreover, β2M is highly conserved among different species, and overall structures are virtually identical, implying the versatility of β2M on applications.
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Affiliation(s)
- Ling Li
- Department of Food Quality and Safety, College of Food Science and Biotechnology, Tianjin Agricultural University, Tianjin 300384, China
- Tianjin Engineering Research Center of Agricultural Products Processing, Tianjin 300384, China
| | - Mei Dong
- Department of Clinical Laboratory, Wangdu Hospital of Traditional Chinese Medicine, Baoding, Hebei 072450, China
| | - Xiao-Guang Wang
- Department of Immunology and Microbiology, Anschutz Medical Campus, University of Colorado Denver, Aurora 80045, Colorado, USA
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Latour C, Besson-Fournier C, Meynard D, Silvestri L, Gourbeyre O, Aguilar-Martinez P, Schmidt PJ, Fleming MD, Roth MP, Coppin H. Differing impact of the deletion of hemochromatosis-associated molecules HFE and transferrin receptor-2 on the iron phenotype of mice lacking bone morphogenetic protein 6 or hemojuvelin. Hepatology 2016; 63:126-37. [PMID: 26406355 DOI: 10.1002/hep.28254] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 09/22/2015] [Indexed: 12/07/2022]
Abstract
UNLABELLED Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up-regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and β2-microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6-deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6-deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6-deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys. CONCLUSION These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice.
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Affiliation(s)
- Chloé Latour
- Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France
| | - Céline Besson-Fournier
- Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France
| | - Delphine Meynard
- Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France
| | - Laura Silvestri
- San Raffaele Scientific Institute & Vita-Salute University, Milan, Italy
| | - Ophélie Gourbeyre
- Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France
| | - Patricia Aguilar-Martinez
- Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France.,Laboratory of Haematology, CHRU de Montpellier, Hôpital Saint Eloi, Montpellier, France
| | - Paul J Schmidt
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Mark D Fleming
- Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, MA
| | - Marie-Paule Roth
- Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France
| | - Hélène Coppin
- Centre de Physiopathologie de Toulouse Purpan, Inserm U1043, CNRS U5282, Université de Toulouse III, Toulouse, France
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Barton JC, Edwards CQ, Acton RT. HFE gene: Structure, function, mutations, and associated iron abnormalities. Gene 2015; 574:179-92. [PMID: 26456104 PMCID: PMC6660136 DOI: 10.1016/j.gene.2015.10.009] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 10/04/2015] [Accepted: 10/06/2015] [Indexed: 01/05/2023]
Abstract
The hemochromatosis gene HFE was discovered in 1996, more than a century after clinical and pathologic manifestations of hemochromatosis were reported. Linked to the major histocompatibility complex (MHC) on chromosome 6p, HFE encodes the MHC class I-like protein HFE that binds beta-2 microglobulin. HFE influences iron absorption by modulating the expression of hepcidin, the main controller of iron metabolism. Common HFE mutations account for ~90% of hemochromatosis phenotypes in whites of western European descent. We review HFE mapping and cloning, structure, promoters and controllers, and coding region mutations, HFE protein structure, cell and tissue expression and function, mouse Hfe knockouts and knockins, and HFE mutations in other mammals with iron overload. We describe the pertinence of HFE and HFE to mechanisms of iron homeostasis, the origin and fixation of HFE polymorphisms in European and other populations, and the genetic and biochemical basis of HFE hemochromatosis and iron overload.
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Affiliation(s)
- James C Barton
- Southern Iron Disorders Center, Birmingham, AL, USA and Department of Medicine; University of Alabama at Birmingham, Birmingham, AL, USA.
| | - Corwin Q Edwards
- Department of Medicine, Intermountain Medical Center and University of Utah, Salt Lake City, UT, USA.
| | - Ronald T Acton
- Southern Iron Disorders Center, Birmingham, AL, USA and Department of Medicine; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA.
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Association Studies of HFE C282Y and H63D Variants with Oral Cancer Risk and Iron Homeostasis Among Whites and Blacks. Cancers (Basel) 2015; 7:2386-96. [PMID: 26690219 PMCID: PMC4695898 DOI: 10.3390/cancers7040898] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2015] [Revised: 10/25/2015] [Accepted: 12/02/2015] [Indexed: 01/29/2023] Open
Abstract
Background: Polymorphisms in the hemochromatosis (HFE) gene are associated with excessive iron absorption from the diet, and pro-oxidant effects of iron accumulation are thought to be a risk factor for several types of cancer. Methods: The C282Y (rs1800562) and H63D (rs1799945) polymorphisms were genotyped in 301 oral cancer cases and 437 controls and analyzed in relation to oral cancer risk, and serum iron biomarker levels from a subset of 130 subjects. Results: Individuals with the C282Y allele had lower total iron binding capacity (TIBC) (321.2 ± 37.2 µg/dL vs. 397.7 ± 89.0 µg/dL, p = 0.007) and higher percent transferrin saturation (22.0 ± 8.7 vs. 35.6 ± 22.9, p = 0.023) than wild type individuals. Iron and ferritin levels approached significantly higher levels for the C282Y allele (p = 0.0632 and p = 0.0588, respectively). Conclusions: Iron biomarker levels were elevated by the C282Y allele, but neither (rs1800562) nor (rs1799945) was associated with oral cancer risk in blacks and whites.
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Silva B, Faustino P. An overview of molecular basis of iron metabolism regulation and the associated pathologies. Biochim Biophys Acta Mol Basis Dis 2015; 1852:1347-59. [PMID: 25843914 DOI: 10.1016/j.bbadis.2015.03.011] [Citation(s) in RCA: 201] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 03/05/2015] [Accepted: 03/27/2015] [Indexed: 12/18/2022]
Abstract
Iron is essential for several vital biological processes. Its deficiency or overload drives to the development of several pathologies. To maintain iron homeostasis, the organism controls the dietary iron absorption by enterocytes, its recycling by macrophages and storage in hepatocytes. These processes are mainly controlled by hepcidin, a liver-derived hormone which synthesis is regulated by iron levels, inflammation, infection, anemia and erythropoiesis. Besides the systemic regulation of iron metabolism mediated by hepcidin, cellular regulatory processes also occur. Cells are able to regulate themselves the expression of the iron metabolism-related genes through different post-transcriptional mechanisms, such as the alternative splicing, microRNAs, the IRP/IRE system and the proteolytic cleavage. Whenever those mechanisms are disturbed, due to genetic or environmental factors, iron homeostasis is disrupted and iron related pathologies may arise.
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Affiliation(s)
- Bruno Silva
- Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal
| | - Paula Faustino
- Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal.
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Lee SM, Loguinov A, Fleming RE, Vulpe CD. Effects of strain and age on hepatic gene expression profiles in murine models of HFE-associated hereditary hemochromatosis. GENES AND NUTRITION 2014; 10:443. [PMID: 25427953 DOI: 10.1007/s12263-014-0443-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 11/15/2014] [Indexed: 12/20/2022]
Abstract
Hereditary hemochromatosis is an iron overload disorder most commonly caused by a defect in the HFE gene. While the genetic defect is highly prevalent, the majority of individuals do not develop clinically significant iron overload, suggesting the importance of genetic modifiers. Murine hfe knockout models have demonstrated that strain background has a strong effect on the severity of iron loading. We noted that hepatic iron loading in hfe-/- mice occurs primarily over the first postnatal weeks (loading phase) followed by a timeframe of relatively static iron concentrations (plateau phase). We thus evaluated the effects of background strain and of age on hepatic gene expression in Hfe knockout mice (hfe-/-). Hepatic gene expression profiles were examined using cDNA microarrays in 4- and 8-week-old hfe-/- and wild-type mice on two different genetic backgrounds, C57BL/6J (C57) and AKR/J (AKR). Genes differentially regulated in all hfe-/- mice groups, compared with wild-type mice, including those involved in cell survival, stress and damage responses and lipid metabolism. AKR strain-specific changes in lipid metabolism genes and C57 strain-specific changes in cell adhesion and extracellular matrix protein genes were detected in hfe-/- mice. Mouse strain and age are each significantly associated with hepatic gene expression profiles in hfe-/- mice. These affects may underlie or reflect differences in iron loading in these mice.
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Affiliation(s)
- Seung-Min Lee
- Department of Food and Nutrition, College of Human Ecology, Yonsei University, Seoul, South Korea,
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Silva B, Ferreira J, Santos V, Baldaia C, Serejo F, Faustino P. The soluble form of HFE protein regulates hephaestin mRNA expression in the duodenum through an endocytosis-dependent mechanism. Biochim Biophys Acta Mol Basis Dis 2014; 1842:2298-305. [DOI: 10.1016/j.bbadis.2014.07.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2013] [Revised: 06/25/2014] [Accepted: 07/15/2014] [Indexed: 12/12/2022]
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Ali-Rahmani F, Schengrund CL, Connor JR. HFE gene variants, iron, and lipids: a novel connection in Alzheimer's disease. Front Pharmacol 2014; 5:165. [PMID: 25071582 PMCID: PMC4086322 DOI: 10.3389/fphar.2014.00165] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Accepted: 06/24/2014] [Indexed: 12/14/2022] Open
Abstract
Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiological, genetic, and molecular evidence of disruption of cholesterol homeostasis in several neurodegenerative diseases, in particular Alzheimer's disease (AD). Despite the efforts that have been made to identify factors that can trigger the pathological events associated with neurodegenerative diseases they remain mostly unknown. Because molecular phenotypes such as oxidative stress, synaptic failure, neuronal loss, and cognitive decline, characteristics associated with AD, have been shown to result from disruption of a number of pathways, one can easily argue that the phenotype seen may not arise from a linear sequence of events. Therefore, a multi-targeted approach is needed to understand a complex disorder like AD. This can be achieved only when knowledge about interactions between the different pathways and the potential influence of environmental factors on them becomes available. Toward this end, this review discusses what is known about the roles and interactions of iron and cholesterol in neurodegenerative diseases. It highlights the effects of gene variants of HFE (H63D- and C282Y-HFE) on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases.
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Affiliation(s)
- Fatima Ali-Rahmani
- Departments of Neurosurgery, Neural and Behavioral Sciences and Pediatrics, Center for Aging and Neurodegenerative Diseases, Penn State Hershey Medical CenterHershey, PA, USA
- Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of MedicineHershey, PA, USA
| | - Cara-Lynne Schengrund
- Departments of Biochemistry and Molecular Biology, The Pennsylvania State University College of MedicineHershey, PA, USA
| | - James R. Connor
- Departments of Neurosurgery, Neural and Behavioral Sciences and Pediatrics, Center for Aging and Neurodegenerative Diseases, Penn State Hershey Medical CenterHershey, PA, USA
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Padula MC, Martelli G, Larocca M, Rossano R, Olivieri A. A novel homozygous stop-codon mutation in human HFE responsible for nonsense-mediated mRNA decay. Blood Cells Mol Dis 2014; 53:138-43. [PMID: 24920245 DOI: 10.1016/j.bcmd.2014.04.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 04/30/2014] [Accepted: 04/30/2014] [Indexed: 12/12/2022]
Abstract
HFE-hemochromatosis (HH) is an autosomal disease characterized by excessive iron absorption. Homozygotes for H63D variant, and still less H63D heterozygotes, generally do not express HH phenotype. The data collected in our previous study in the province of Matera (Basilicata, Italy) underlined that some H63D carriers showed altered iron metabolism, without additional factors. In this study, we selected a cohort of 10/22 H63D carriers with severe biochemical iron overload (BIO). Additional analysis was performed for studying HFE exons, exon-intron boundaries, and untranslated regions (UTRs) by performing DNA extraction, PCR amplification and sequencing. The results showed a novel substitution (NM_000410.3:c.847C>T) in a patient exon 4 (GenBankJQ478433); it introduces a premature stop-codon (PTC). RNA extraction and reverse-transcription were also performed. Quantitative real-time PCR was carried out for verifying if our aberrant mRNA is targeted for nonsense-mediated mRNA decay (NMD); we observed that patient HFE mRNA was expressed much less than calibrator, suggesting that the mutated HFE protein cannot play its role in iron metabolism regulation, resulting in proband BIO. Our finding is the first evidence of a variation responsible for a PTC in iron cycle genes. The genotype-phenotype correlation observed in our cases could be related to the additional mutation.
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Affiliation(s)
- Maria Carmela Padula
- Department of Science, University of Basilicata, Viale dell'Ateneo Lucano, 85100 Potenza, Italy.
| | - Giuseppe Martelli
- Department of Science, University of Basilicata, Viale dell'Ateneo Lucano, 85100 Potenza, Italy
| | - Marilena Larocca
- Department of Science, University of Basilicata, Viale dell'Ateneo Lucano, 85100 Potenza, Italy
| | - Rocco Rossano
- Department of Science, University of Basilicata, Viale dell'Ateneo Lucano, 85100 Potenza, Italy
| | - Attilio Olivieri
- Clinic of Hematology, Hospital-University Company "Ospedali Riuniti di Ancona", Via Conca, 60126 Ancona, Italy
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Abstract
Mutations in HFE are the most common cause of hereditary hemochromatosis (HH). HFE mutations result in reduced expression of hepcidin, a hepatic hormone, which negatively regulates iron absorption from the duodenum and iron release from macrophages. However, the mechanism by which HFE regulates hepcidin expression in hepatocytes is not well understood. It is known that the bone morphogenetic protein (BMP) pathway plays a central role in controlling hepcidin expression in the liver. Here we show that HFE overexpression increased Smad1/5/8 phosphorylation and hepcidin expression, whereas inhibition of BMP signaling abolished HFE-induced hepcidin expression in Hep3B cells. HFE was found to associate with ALK3, inhibiting ALK3 ubiquitination and proteasomal degradation and increasing ALK3 protein expression and accumulation on the cell surface. The 2 HFE mutants associated with HH, HFE C282Y and HFE H63D, regulated ALK3 protein ubiquitination and trafficking differently, but both failed to increase ALK3 cell-surface expression. Deletion of Hfe in mice resulted in a decrease in hepatic ALK3 protein expression. Our results provide evidence that HFE induces hepcidin expression via the BMP pathway: HFE interacts with ALK3 to stabilize ALK3 protein and increase ALK3 expression at the cell surface.
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Reuben A, Phénix M, Santos MM, Lapointe R. The WT hemochromatosis protein HFE inhibits CD8⁺ T-lymphocyte activation. Eur J Immunol 2014; 44:1604-14. [PMID: 24643698 DOI: 10.1002/eji.201343955] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 01/21/2014] [Accepted: 02/11/2014] [Indexed: 11/05/2022]
Abstract
MHC class I (MHC I) antigen presentation is a ubiquitous process by which cells present endogenous proteins to CD8(+) T lymphocytes during immune surveillance and response. Hereditary hemochromatosis protein, HFE, is involved in cellular iron uptake but, while structurally homologous to MHC I, is unable to bind peptides. However, increasing evidence suggests a role for HFE in the immune system. Here, we investigated the impact of HFE on CD8(+) T-lymphocyte activation. Using transient HFE transfection assays in a model of APCs, we show that WT HFE (HFEWT ), but not C282Y-mutated HFE, inhibits secretion of MIP-1β from antigen-specific CD8(+) T lymphocytes. HFEWT expression also resulted in major decreases in CD8(+) T-lymphocyte activation as measured by 4-1BB expression. We further demonstrate that inhibition of CD8(+) T-lymphocyte activation was independent of MHC I surface levels, β2-m competition, HFE interaction with transferrin receptor, antigen origin, or epitope affinity. Finally, we identified the α1-2 domains of HFEWT as being responsible for inhibiting CD8(+) T-lymphocyte activation. Our data imply a new role for HFEWT in altering CD8(+) T-lymphocyte reactivity, which could modulate antigen immunogenicity.
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Affiliation(s)
- Alexandre Reuben
- Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) Institut du cancer de Montréal, Montréal, Québec, Canada; Département de Médecine, Université de Montréal, Montréal, Québec, Canada
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Adams PC. Hepcidin in hemochromatosis: the message or the messenger? Hepatology 2014; 59:749-50. [PMID: 23996780 DOI: 10.1002/hep.26715] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 08/24/2013] [Indexed: 12/29/2022]
Affiliation(s)
- Paul C Adams
- Department of Medicine, University Hospital, London, Ontario, Canada
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Ali-Rahmani F, Huang MA, Schengrund CL, Connor JR, Lee SY. C282Y-HFE gene variant affects cholesterol metabolism in human neuroblastoma cells. PLoS One 2014; 9:e88724. [PMID: 24533143 PMCID: PMC3922969 DOI: 10.1371/journal.pone.0088724] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Accepted: 01/10/2014] [Indexed: 11/26/2022] Open
Abstract
Although disruptions in the maintenance of iron and cholesterol metabolism have been implicated in several cancers, the association between variants in the HFE gene that is associated with cellular iron uptake and cholesterol metabolism has not been studied. The C282Y-HFE variant is a risk factor for different cancers, is known to affect sphingolipid metabolism, and to result in increased cellular iron uptake. The effect of this variant on cholesterol metabolism and its possible relevance to cancer phenotype was investigated using wild type (WT) and C282Y-HFE transfected human neuroblastoma SH-SY5Y cells. Expression of C282Y-HFE in SH-SY5Y cells resulted in a significant increase in total cholesterol as well as increased transcription of a number of genes involved in its metabolism compared to cells expressing WT-HFE. The marked increase in expression of NPC1L1 relative to that of most other genes, was accompanied by a significant increase in expression of NPC1, a protein that functions in cholesterol uptake by cells. Because inhibitors of cholesterol metabolism have been proposed to be beneficial for treating certain cancers, their effect on the viability of C282Y-HFE neuroblastoma cells was ascertained. C282Y-HFE cells were significantly more sensitive than WT-HFE cells to U18666A, an inhibitor of desmosterol Δ24-reductase the enzyme catalyzing the last step in cholesterol biosynthesis. This was not seen for simvastatin, ezetimibe, or a sphingosine kinase inhibitor. These studies indicate that cancers presenting in carriers of the C282Y-HFE allele might be responsive to treatment designed to selectively reduce cholesterol content in their tumor cells.
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Affiliation(s)
- Fatima Ali-Rahmani
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Michael A Huang
- Division of Pediatric Hematology/Oncology, The Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - C-L Schengrund
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - James R Connor
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | - Sang Y Lee
- Department of Neurosurgery, The Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Penn State M.S. Hershey Medical Center, Hershey, Pennsylvania, United States of America
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Ellervik C, Mandrup-Poulsen T, Tybjærg-Hansen A, Nordestgaard BG. Total and cause-specific mortality by elevated transferrin saturation and hemochromatosis genotype in individuals with diabetes: two general population studies. Diabetes Care 2014; 37:444-52. [PMID: 24130348 DOI: 10.2337/dc13-1198] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Mortality is increased in patients with hereditary hemochromatosis, in individuals from the general population with increased transferrin saturation (TS), and also in patients with type 1 diabetes and increased TS from a highly specialized diabetes clinic. Thus, we have recommended targeted screening for TS in specialized diabetes clinics. Whether mortality is also increased in individuals from the general population with diabetes and increased TS is unknown. RESEARCH DESIGN AND METHODS In two Danish population studies (N = 84,865), we examined mortality according to baseline levels of TS and hemochromatosis genotype (HFE) G → A substitution at nucleotide 845 in codon 282 (C282Y/C282Y) in individuals with diabetes (type 1, N = 118; type 2, N = 3,228; total, N = 3,346). RESULTS The cumulative survival rate was reduced in individuals with diabetes with TS ≥50% vs. <50% (log-rank; P < 0.0001), with median survival ages of 66 and 79 years, respectively. The hazard ratio (HR) for TS ≥50% vs. <50% was 2.0 (95% CI 1.3-2.8; P = 0.0004) for total mortality overall (and similar for men and women separately); 2.6 (1.3-5.4; P = 0.008) for neoplasms; and 3.4 (2.0-6.0; P = 0.00002) for endocrinological causes. A stepwise increased risk of total mortality was observed for stepwise increasing TS (log-rank test, P = 0.0001), with an HR for TS ≥70% vs. TS <20% of 4.8 (2.0-12; P = 0.0006). The HR for total mortality in individuals with diabetes for C282Y/C282Y versus wild type/wild type was 3.3 (1.04-10; P = 0.04), and for C282Y/C282Y and TS ≥50% versus wild type/wild type and TS <50% was 6.0 (1.5-24; P = 0.01). Six percent of these premature deaths can possibly be avoided by early screening for TS or HFE genotype. CONCLUSIONS Individuals with diabetes, ascertained in the general population, with increased TS or HFE genotype have a twofold to sixfold increased risk of premature death.
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Evidence for the high importance of co-morbid factors in HFE C282Y/H63D patients cared by phlebotomies: results from an observational prospective study. PLoS One 2013; 8:e81128. [PMID: 24339903 PMCID: PMC3855242 DOI: 10.1371/journal.pone.0081128] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 10/09/2013] [Indexed: 12/17/2022] Open
Abstract
Despite type I haemochromatosis (HC) is mainly associated with the HFE C282Y/C282Y genotype, a second genotype -C282Y/H63D- has mostly been described in other patients. Its association with HC, apart from any associated co-morbid factors, remains unclear and complex to interpret for physicians. This study assesses the weight of this genotype and the role of co-morbid factors in the occurrence of iron overload. This prospective study included the C282Y/C282Y (n = 172) and C282Y/H63D (n = 58) patients enrolled in a phlebotomy program between 2004 and 2007 in a blood centre of western Brittany (Brest, France), where HC is frequent. We compared prevalence of these two genotypes, as well as patients' profile regarding degree of iron overload and prevalence of co-morbid factors. First, we confirmed the obvious deficit of C282Y/H63D compound heterozygotes among patients cared by phlebotomies. This genotype was 3.0 times less frequent than the C282Y/C282Y genotype among those patients (18.9% vs. 56.0%) whereas it was 4.9 times more frequent in the general population (4.3% vs. 0.9%; p<0.0001). Despite a similar level of hyperferritinaemia, the C282Y/H63D patients who came to medical attention had a milder plasma iron overload, reflected by a lower transferrin saturation median (52.0% vs. 84.0%; p<0.0001). They also exhibited more frequently co-morbid factors, as heavy drinking (26.0% vs. 13.9%; p = 0.0454), overweight (66.7% vs. 39.4%; p = 0.0005) or both (21.3% vs. 2.6%; p<0.0001). Ultimately, they required a lower amount of iron removed to reach depletion (2.1 vs. 3.4 g; p<0.0001), clearly reflecting their lower tissue iron. This study confirms that H63D is a discrete genetic susceptibility factor whose expression is most visible in association with other co-factors. It highlights the importance of searching for co-morbidities in these diagnostic situations and of providing lifestyle and dietary advice.
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Lenarduzzi M, Hui ABY, Yue S, Ito E, Shi W, Williams J, Bruce J, Sakemura-Nakatsugawa N, Xu W, Schimmer A, Liu FF. Hemochromatosis enhances tumor progression via upregulation of intracellular iron in head and neck cancer. PLoS One 2013; 8:e74075. [PMID: 23991213 PMCID: PMC3753261 DOI: 10.1371/journal.pone.0074075] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2013] [Accepted: 07/22/2013] [Indexed: 12/13/2022] Open
Abstract
Introduction Despite improvements in treatment strategies for head and neck squamous cell carcinoma (HNSCC), outcomes have not significantly improved; highlighting the importance of identifying novel therapeutic approaches to target this disease. To address this challenge, we proceeded to evaluate the role of iron in HNSCC. Experimental Design Expression levels of iron-related genes were evaluated in HNSCC cell lines using quantitative RT-PCR. Cellular phenotypic effects were assessed using viability (MTS), clonogenic survival, BrdU, and tumor formation assays. The prognostic significance of iron-related proteins was determined using immunohistochemistry. Results In a panel of HNSCC cell lines, hemochromatosis (HFE) was one of the most overexpressed genes involved in iron regulation. In vitro knockdown of HFE in HNSCC cell lines significantly decreased hepcidin (HAMP) expression and intracellular iron level. This in turn, resulted in a significant decrease in HNSCC cell viability, clonogenicity, DNA synthesis, and Wnt signalling. These cellular changes were reversed by re-introducing iron back into HNSCC cells after HFE knockdown, indicating that iron was mediating this phenotype. Concordantly, treating HNSCC cells with an iron chelator, ciclopirox olamine (CPX), significantly reduced viability and clonogenic survival. Finally, patients with high HFE expression experienced a reduced survival compared to patients with low HFE expression. Conclusions Our data identify HFE as potentially novel prognostic marker in HNSCC that promotes tumour progression via HAMP and elevated intracellular iron levels, leading to increased cellular proliferation and tumour formation. Hence, these findings suggest that iron chelators might have a therapeutic role in HNSCC management.
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Affiliation(s)
- Michelle Lenarduzzi
- Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Angela B. Y. Hui
- Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
| | - Shijun Yue
- Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
| | - Emma Ito
- Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
| | - Wei Shi
- Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
| | - Justin Williams
- Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
| | - Jeff Bruce
- Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | | | - Wei Xu
- Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Aaron Schimmer
- Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Fei-Fei Liu
- Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Radiation Medicine Program, University Health Network, Toronto, Ontario, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
- * E-mail:
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