22 results on '"Szynkiewicz M"'
Search Results
2. Have rapid socioeconomic changes influenced awareness of blood pressure in Poland?
- Author
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Zdrojewski, T, Pienkowski, R, Szynkiewicz, M, and Krupa-Wojciechowska, B
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- 2001
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3. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis
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Ramesh, V, Bernardi, B, Stafa, A, Garone, Caterina, Franzoni, E, Abinun, M, Mitchell, P, Mitra, D, Friswell, M, Nelson, J, Shalev, Sa, Rice, Gi, Gornall, H, Szynkiewicz, M, Aymard, F, Ganesan, V, Prendiville, J, Livingston, Jh, Crow, Yj, Ramesh V, Bernardi B, Stafa A, Garone C, Franzoni E, Abinun M, Mitchell P, Mitra D, Friswell M, Nelson J, Shalev SA, Rice GI, Gornall H, Szynkiewicz M, Aymard F, Ganesan V, Prendiville J, Livingston JH, and Crow YJ
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Male ,DNA Mutational Analysis ,Infant ,Proteins ,Phosphoproteins ,SAM Domain and HD Domain-Containing Protein 1 ,Exodeoxyribonucleases ,Child, Preschool ,Homeostasis ,Humans ,Point Mutation ,Carotid Stenosis ,Female ,Cerebral Arterial Diseases ,Child ,Monomeric GTP-Binding Proteins - Abstract
AIM: To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. METHOD: We used clinical and radiological description and molecular analysis. RESULTS: Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. INTERPRETATION: Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1
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- 2010
4. Algorithmicity of Evolutionary Algorithms
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Leciejewski Sławomir and Szynkiewicz Mariusz
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algorithm ,algorithmicity ,evolutionary algorithms ,scientific term ,philosophy of informatics ,History of scholarship and learning. The humanities ,AZ20-999 - Abstract
In the first part of our article we will refer the penetration of scientific terms into colloquial language, focusing on the sense in which the concept of an algorithm currently functions outside its original scope. The given examples will refer mostly to disciplines not directly related to computer science and to the colloquial language. In the next part we will also discuss the modifications made to the meaning of the term algorithm and how this concept is now understood in computer science. Finally, we will discuss the problem of algorithmicity of evolutionary algorithms, i.e. we will try to answer the question whether – and to what extent – they are still algorithms in the classical sense.
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- 2020
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5. Chilblains as a Diagnostic Sign of Aicardi-Goutières Syndrome
- Author
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Abdel-Salam, G. M. H., primary, El-Kamah, G. Y., additional, Rice, G. I., additional, EL-Darouti, M., additional, Gornall, H., additional, Szynkiewicz, M., additional, Aymard, F., additional, Zaki, M. S., additional, Abdel-Aleem, A. K., additional, Lebon, P., additional, and Crow, Y. J., additional
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- 2010
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6. SOPKARD – THE NEW PREVENTIVE PROGRAM OF THE POLISH SOCIETY OF HYPERTENSION IN GDANSK
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Zdrojewski, T., primary, Januszko, W., additional, Kowalisko, A., additional, Leppert, J., additional, Szynkiewicz, M., additional, Wasilewska, M., additional, Wyrzykowski, B., additional, and Krupa-Wojciechowska, B., additional
- Published
- 2000
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7. Intracerebral large artery disease in Aicardi-Goutières syndrome implicates SAMHD1 in vascular homeostasis.
- Author
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Ramesh V, Bernardi B, Stafa A, Garone C, Franzoni E, Abinun M, Mitchell P, Mitra D, Friswell M, Nelson J, Shalev SA, Rice GI, Gornall H, Szynkiewicz M, Aymard F, Ganesan V, Prendiville J, Livingston JH, and Crow YJ
- Abstract
Aim To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. Method We used clinical and radiological description and molecular analysis. Results Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. Interpretation Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1. [ABSTRACT FROM AUTHOR]
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- 2010
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8. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus
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Ram L. Kumar, Marjo S. van der Knaap, Sanjeev S. Bhaskar, Pierre-Yves Jeannet, John B.P. Stephenson, Gillian I. Rice, Joel Victor Fluss, James O'Sullivan, Raphael Schiffmann, Johannes A. Buckard, Andrea Whitney, Riyana Babul-Hirji, Catheline Vilain, Beverley Anderson, Yanick J. Crow, Emma M. Jenkinson, Gunnar Houge, Ewan Forrest, Vanessa Wermenbol, Peter Baxter, Sarah B. Daly, Marcin Szynkiewicz, Joanne Muter, Rosalind J. Jefferson, Wui K. Chong, Elisabeth Oppliger Leibundgut, Gabriela M. Baerlocher, Stefan Meyer, Jonathan E. Dickerson, Ramesh Mehta, Emma Wakeling, Sarah Risen, José Pedro Vieira, Sakkubai Naidu, Andrea Berger, Calvin Soh, John H. Livingston, David Chitayat, Staffan Lundberg, Simon C. Lovell, Luís Catela Nunes, Helen Stewart, Graeme C.M. Black, John Tolmie, Janice E Brunstom-Hernandez, Jill E. Urquhart, Josephine Mayer, Ghada M H Abdel-Salem, Paul R. Kasher, Charles Marques Lourenço, Simon Hammans, Emilio Franzoni, Caterina Garone, Katrin Õunap, Duccio Maria Cordelli, Prab Prabhakar, Ken K. Nischal, Luisa Bonafé, Michel Philippart, Sébastien Jacquemont, Patrick Ferreira, Imelda Hughes, Jon Stone, Georg Kutschke, Fluss, Joel Victor, Jeannet, Pierre-Yves, Pediatric surgery, NCA - Childhood White Matter Diseases, Anderson BH, Kasher PR, Mayer J, Szynkiewicz M, Jenkinson EM, Bhaskar SS, Urquhart JE, Daly SB, Dickerson JE, O'Sullivan J, Leibundgut EO, Muter J, Abdel-Salem GM, Babul-Hirji R, Baxter P, Berger A, Bonafé L, Brunstom-Hernandez JE, Buckard JA, Chitayat D, Chong WK, Cordelli DM, Ferreira P, Fluss J, Forrest EH, Franzoni E, Garone C, Hammans SR, Houge G, Hughes I, Jacquemont S, Jeannet PY, Jefferson RJ, Kumar R, Kutschke G, Lundberg S, Lourenço CM, Mehta R, Naidu S, Nischal KK, Nunes L, Ounap K, Philippart M, Prabhakar P, Risen SR, Schiffmann R, Soh C, Stephenson JB, Stewart H, Stone J, Tolmie JL, van der Knaap MS, Vieira JP, Vilain CN, Wakeling EL, Wermenbol V, Whitney A, Lovell SC, Meyer S, Livingston JH, Baerlocher GM, Black GC, Rice GI, Crow YJ, Other departments, and Neuroscience Campus Amsterdam - Childhood White Matter Diseases
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DNA polymerase ,Molecular Sequence Data ,Telomere-Binding Proteins ,Histones/metabolism ,HDE GEN ,HDE NEU PED ,CST complex ,CEREBRORETINAL MICROANGIOPATHY, FAMILIAL SYNDROME, CALCIFICATIONS, CYSTS, PROTEIN, DNA, LEUKOENCEPHALOPATHY, EVOLUTION, DEFECTS ,Histones ,chemistry.chemical_compound ,Abnormalities, Multiple/genetics ,Genetics ,medicine ,Abnormalities, Multiple ,Genetic Predisposition to Disease ,Telomere-binding protein ,Telomere/pathology ,ddc:618 ,biology ,Base Sequence ,Genetic Predisposition to Disease/genetics ,DNA replication ,Sequence Analysis, DNA ,Telomere ,medicine.disease ,Flow Cytometry ,Cell biology ,Retinal Telangiectasis/genetics/pathology ,chemistry ,Sequence Analysis, DNA/methods ,biology.protein ,Retinal Telangiectasis ,Primase ,Telomere-Binding Proteins/genetics ,DNA ,Dyskeratosis congenita - Abstract
Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γ 3H2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the I ±-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity. © 2012 Nature America, Inc. All rights reserved.
- Published
- 2012
9. Super-Resolution Microscopy Using a Bioorthogonal-Based Cholesterol Probe Provides Unprecedented Capabilities for Imaging Nanoscale Lipid Heterogeneity in Living Cells.
- Author
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Lorizate M, Terrones O, Nieto-Garai JA, Rojo-Bartolomé I, Ciceri D, Morana O, Olazar-Intxausti J, Arboleya A, Martin A, Szynkiewicz M, Calleja-Felipe M, Bernardino de la Serna J, and Contreras FX
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- Animals, Cells, Cultured, Cholesterol chemistry, HeLa Cells, Humans, Microscopy, Fluorescence, Models, Molecular, Molecular Conformation, Neurons chemistry, Rats, Spatio-Temporal Analysis, Cholesterol analysis, Membrane Microdomains chemistry, Molecular Imaging methods, Molecular Probes chemistry, Neurons cytology
- Abstract
Despite more than 20 years of work since the lipid raft concept was proposed, the existence of these nanostructures remains highly controversial due to the lack of noninvasive methods to investigate their native nanorganization in living unperturbed cells. There is an unmet need for probes for direct imaging of nanoscale membrane dynamics with high spatial and temporal resolution in living cells. In this paper, a bioorthogonal-based cholesterol probe (chol-N
3 ) is developed that, combined with nanoscopy, becomes a new powerful method for direct visualization and characterization of lipid raft at unprecedented resolution in living cells. The chol-N3 probe mimics cholesterol in synthetic and cellular membranes without perturbation. When combined with live-cell super-resolution microscopy, chol-N3 demonstrates the existence of cholesterol-rich nanodomains of <50 nm at the plasma membrane of resting living cells. Using this tool, the lipid membrane structure of such subdiffraction limit domains is identified, and the nanoscale spatiotemporal organization of cholesterol in the plasma membrane of living cells reveals multiple cholesterol diffusion modes at different spatial localizations. Finally, imaging across thick organ samples outlines the potential of this new method to address essential biological questions that were previously beyond reach., (© 2021 The Authors. Small Methods published by Wiley-VCH GmbH.)- Published
- 2021
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10. Correlative multi-scale cryo-imaging unveils SARS-CoV-2 assembly and egress.
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Mendonça L, Howe A, Gilchrist JB, Sheng Y, Sun D, Knight ML, Zanetti-Domingues LC, Bateman B, Krebs AS, Chen L, Radecke J, Li VD, Ni T, Kounatidis I, Koronfel MA, Szynkiewicz M, Harkiolaki M, Martin-Fernandez ML, James W, and Zhang P
- Subjects
- Animals, COVID-19 epidemiology, COVID-19 virology, Chlorocebus aethiops, Cryoelectron Microscopy, Electron Microscope Tomography, Humans, Pandemics prevention & control, SARS-CoV-2 physiology, SARS-CoV-2 ultrastructure, Vero Cells, Virus Assembly physiology, Virus Release physiology, Virus Replication physiology, COVID-19 immunology, SARS-CoV-2 immunology, Virus Assembly immunology, Virus Release immunology, Virus Replication immunology
- Abstract
Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified viral components and inactivated viruses. However, structural and ultrastructural evidence on how the SARS-CoV-2 infection progresses in the native cellular context is scarce, and there is a lack of comprehensive knowledge on the SARS-CoV-2 replicative cycle. To correlate cytopathic events induced by SARS-CoV-2 with virus replication processes in frozen-hydrated cells, we established a unique multi-modal, multi-scale cryo-correlative platform to image SARS-CoV-2 infection in Vero cells. This platform combines serial cryoFIB/SEM volume imaging and soft X-ray cryo-tomography with cell lamellae-based cryo-electron tomography (cryoET) and subtomogram averaging. Here we report critical SARS-CoV-2 structural events - e.g. viral RNA transport portals, virus assembly intermediates, virus egress pathway, and native virus spike structures, in the context of whole-cell volumes revealing drastic cytppathic changes. This integrated approach allows a holistic view of SARS-CoV-2 infection, from the whole cell to individual molecules., (© 2021. The Author(s).)
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- 2021
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11. Correlative Multi-scale Cryo-imaging Unveils SARS-CoV-2 Assembly and Egress.
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Zhang P, Mendonca L, Howe A, Gilchrist J, Sun D, Knight M, Zanetti-Domingues L, Bateman B, Krebs AS, Chen L, Radecke J, Sheng Y, Li V, Ni T, Kounatidis I, Koronfel M, Szynkiewicz M, Harkiolaki M, Martin-Fernandez M, and James W
- Abstract
Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified recombinant viral components and inactivated viruses. However, structural and ultrastructural evidence on how the SARS-CoV-2 infection progresses in the frozen-hydrated native cellular context is scarce, and there is a lack of comprehensive knowledge on the SARS-CoV-2 replicative cycle. To correlate the cytopathic events induced by SARS-CoV-2 with virus replication process under the frozen-hydrated condition, here we established a unique multi-modal, multi-scale cryo-correlative platform to image SARS-CoV-2 infection in Vero cells. This platform combines serial cryoFIB/SEM volume imaging and soft X-ray cryo-tomography with cell lamellae-based cryo-electron tomography (cryoET) and subtomogram averaging. The results place critical SARS-CoV-2 structural events â€" e.g. viral RNA transport portals on double membrane vesicles, virus assembly and budding intermediates, virus egress pathways, and native virus spike structures from intracellular assembled and extracellular released virus - in the context of whole-cell images. The latter revealed numerous heterogeneous cytoplasmic vesicles, the formation of membrane tunnels through which viruses exit, and the drastic cytoplasm invasion into the nucleus. This integrated approach allows a holistic view of SARS-CoV-2 infection, from the whole cell to individual molecules.
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- 2021
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12. SARS-CoV-2 Assembly and Egress Pathway Revealed by Correlative Multi-modal Multi-scale Cryo-imaging.
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Mendonça L, Howe A, Gilchrist JB, Sun D, Knight ML, Zanetti-Domingues LC, Bateman B, Krebs AS, Chen L, Radecke J, Sheng Y, Li VD, Ni T, Kounatidis I, Koronfel MA, Szynkiewicz M, Harkiolaki M, Martin-Fernandez ML, James W, and Zhang P
- Abstract
Since the outbreak of the SARS-CoV-2 pandemic, there have been intense structural studies on purified recombinant viral components and inactivated viruses. However, investigation of the SARS-CoV-2 infection in the native cellular context is scarce, and there is a lack of comprehensive knowledge on SARS-CoV-2 replicative cycle. Understanding the genome replication, assembly and egress of SARS-CoV-2, a multistage process that involves different cellular compartments and the activity of many viral and cellular proteins, is critically important as it bears the means of medical intervention to stop infection. Here, we investigated SARS-CoV-2 replication in Vero cells under the near-native frozen-hydrated condition using a unique correlative multi-modal, multi-scale cryo-imaging approach combining soft X-ray cryo-tomography and serial cryoFIB/SEM volume imaging of the entire SARS-CoV-2 infected cell with cryo-electron tomography (cryoET) of cellular lamellae and cell periphery, as well as structure determination of viral components by subtomogram averaging. Our results reveal at the whole cell level profound cytopathic effects of SARS-CoV-2 infection, exemplified by a large amount of heterogeneous vesicles in the cytoplasm for RNA synthesis and virus assembly, formation of membrane tunnels through which viruses exit, and drastic cytoplasm invasion into nucleus. Furthermore, cryoET of cell lamellae reveals how viral RNAs are transported from double-membrane vesicles where they are synthesized to viral assembly sites; how viral spikes and RNPs assist in virus assembly and budding; and how fully assembled virus particles exit the cell, thus stablishing a model of SARS-CoV-2 genome replication, virus assembly and egress pathways.
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- 2020
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13. Characterization of human disease phenotypes associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR, and IFIH1.
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Crow YJ, Chase DS, Lowenstein Schmidt J, Szynkiewicz M, Forte GM, Gornall HL, Oojageer A, Anderson B, Pizzino A, Helman G, Abdel-Hamid MS, Abdel-Salam GM, Ackroyd S, Aeby A, Agosta G, Albin C, Allon-Shalev S, Arellano M, Ariaudo G, Aswani V, Babul-Hirji R, Baildam EM, Bahi-Buisson N, Bailey KM, Barnerias C, Barth M, Battini R, Beresford MW, Bernard G, Bianchi M, Billette de Villemeur T, Blair EM, Bloom M, Burlina AB, Carpanelli ML, Carvalho DR, Castro-Gago M, Cavallini A, Cereda C, Chandler KE, Chitayat DA, Collins AE, Sierra Corcoles C, Cordeiro NJ, Crichiutti G, Dabydeen L, Dale RC, D'Arrigo S, De Goede CG, De Laet C, De Waele LM, Denzler I, Desguerre I, Devriendt K, Di Rocco M, Fahey MC, Fazzi E, Ferrie CD, Figueiredo A, Gener B, Goizet C, Gowrinathan NR, Gowrishankar K, Hanrahan D, Isidor B, Kara B, Khan N, King MD, Kirk EP, Kumar R, Lagae L, Landrieu P, Lauffer H, Laugel V, La Piana R, Lim MJ, Lin JP, Linnankivi T, Mackay MT, Marom DR, Marques Lourenço C, McKee SA, Moroni I, Morton JE, Moutard ML, Murray K, Nabbout R, Nampoothiri S, Nunez-Enamorado N, Oades PJ, Olivieri I, Ostergaard JR, Pérez-Dueñas B, Prendiville JS, Ramesh V, Rasmussen M, Régal L, Ricci F, Rio M, Rodriguez D, Roubertie A, Salvatici E, Segers KA, Sinha GP, Soler D, Spiegel R, Stödberg TI, Straussberg R, Swoboda KJ, Suri M, Tacke U, Tan TY, te Water Naude J, Wee Teik K, Thomas MM, Till M, Tonduti D, Valente EM, Van Coster RN, van der Knaap MS, Vassallo G, Vijzelaar R, Vogt J, Wallace GB, Wassmer E, Webb HJ, Whitehouse WP, Whitney RN, Zaki MS, Zuberi SM, Livingston JH, Rozenberg F, Lebon P, Vanderver A, Orcesi S, and Rice GI
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- Genetic Association Studies, Genotype, Humans, Interferon-Induced Helicase, IFIH1, Interferons blood, Interferons cerebrospinal fluid, Pterins cerebrospinal fluid, SAM Domain and HD Domain-Containing Protein 1, Adenosine Deaminase genetics, Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System genetics, DEAD-box RNA Helicases genetics, Exodeoxyribonucleases genetics, Monomeric GTP-Binding Proteins genetics, Mutation, Nervous System Malformations diagnosis, Nervous System Malformations genetics, Phenotype, Phosphoproteins genetics, Ribonuclease H genetics
- Abstract
Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials., (© 2015 Wiley Periodicals, Inc.)
- Published
- 2015
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14. A type I interferon signature identifies bilateral striatal necrosis due to mutations in ADAR1.
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Livingston JH, Lin JP, Dale RC, Gill D, Brogan P, Munnich A, Kurian MA, Gonzalez-Martinez V, De Goede CG, Falconer A, Forte G, Jenkinson EM, Kasher PR, Szynkiewicz M, Rice GI, and Crow YJ
- Subjects
- Case-Control Studies, Child, Preschool, DNA Mutational Analysis, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Infant, Male, Molecular Diagnostic Techniques, Mutation, Missense, RNA-Binding Proteins, Striatonigral Degeneration enzymology, Striatonigral Degeneration genetics, Adenosine Deaminase genetics, Interferon Type I physiology, Striatonigral Degeneration congenital
- Abstract
Background: We recently observed mutations in ADAR1 to cause a phenotype of bilateral striatal necrosis (BSN) in a child with the type I interferonopathy Aicardi-Goutières syndrome (AGS). We therefore decided to screen patients with apparently non-syndromic BSN for ADAR1 mutations, and for an upregulation of interferon-stimulated genes (ISGs)., Methods: We performed Sanger sequencing of ADAR1 in a series of patients with BSN presenting to us during our routine clinical practice. We then undertook detailed clinical and neuroradiological phenotyping in nine mutation-positive children. We also measured the expression of ISGs in peripheral blood from these patients, and in children with BSN who did not have ADAR1 mutations., Results: Nine ADAR1 mutation-positive patients from seven families demonstrated an acute (five cases) or subacute (four cases) onset of refractory, four-limb dystonia starting between 8 months and 5 years of age. Eight patients were developmentally normal at initial presentation. In seven cases, the disease was inherited as an autosomal recessive trait, while two related patients were found to have a heterozygous (dominant) ADAR1 mutation. All seven mutation-positive patients assayed showed an upregulation of ISGs (median: 12.50, IQR: 6.43-36.36) compared to controls (median: 0.93, IQR: 0.57-1.30), a so-called interferon signature, present many years after disease onset. No interferon signature was present in four children with BSN negative for mutations in ADAR1 (median: 0.63, IQR: 0.47-1.10)., Conclusions: ADAR1-related disease should be considered in the differential diagnosis of apparently non-syndromic BSN with severe dystonia of varying evolution. The finding of an interferon signature provides a useful screening test for the presence of ADAR1 mutations in this context, and may suggest novel treatment approaches.
- Published
- 2014
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15. Assessment of interferon-related biomarkers in Aicardi-Goutières syndrome associated with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR: a case-control study.
- Author
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Rice GI, Forte GM, Szynkiewicz M, Chase DS, Aeby A, Abdel-Hamid MS, Ackroyd S, Allcock R, Bailey KM, Balottin U, Barnerias C, Bernard G, Bodemer C, Botella MP, Cereda C, Chandler KE, Dabydeen L, Dale RC, De Laet C, De Goede CG, Del Toro M, Effat L, Enamorado NN, Fazzi E, Gener B, Haldre M, Lin JP, Livingston JH, Lourenco CM, Marques W Jr, Oades P, Peterson P, Rasmussen M, Roubertie A, Schmidt JL, Shalev SA, Simon R, Spiegel R, Swoboda KJ, Temtamy SA, Vassallo G, Vilain CN, Vogt J, Wermenbol V, Whitehouse WP, Soler D, Olivieri I, Orcesi S, Aglan MS, Zaki MS, Abdel-Salam GM, Vanderver A, Kisand K, Rozenberg F, Lebon P, and Crow YJ
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- Adolescent, Adult, Autoantibodies blood, Autoimmune Diseases of the Nervous System genetics, Biomarkers, Case-Control Studies, Child, Child, Preschool, Female, Genetic Heterogeneity, Genotype, Humans, Infant, Interferon Type I blood, Interferon Type I cerebrospinal fluid, Interferon Type I immunology, Male, Mutation, Nervous System Malformations genetics, Neutralization Tests, Prospective Studies, RNA, Messenger biosynthesis, RNA-Binding Proteins, SAM Domain and HD Domain-Containing Protein 1, Up-Regulation, Young Adult, Adenosine Deaminase genetics, Autoimmune Diseases of the Nervous System metabolism, Exodeoxyribonucleases genetics, Gene Expression Regulation, Interferon Type I physiology, Monomeric GTP-Binding Proteins genetics, Nervous System Malformations metabolism, Phosphoproteins genetics, Ribonuclease H genetics
- Abstract
Background: Aicardi-Goutières syndrome (AGS) is an inflammatory disorder caused by mutations in any of six genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, and ADAR). The disease is severe and effective treatments are urgently needed. We investigated the status of interferon-related biomarkers in patients with AGS with a view to future use in diagnosis and clinical trials., Methods: In this case-control study, samples were collected prospectively from patients with mutation-proven AGS. The expression of six interferon-stimulated genes (ISGs) was measured by quantitative PCR, and the median fold change, when compared with the median of healthy controls, was used to create an interferon score for each patient. Scores higher than the mean of controls plus two SD (>2·466) were designated as positive. Additionally, we collated historical data for interferon activity, measured with a viral cytopathic assay, in CSF and serum from mutation-positive patients with AGS. We also undertook neutralisation assays of interferon activity in serum, and looked for the presence of autoantibodies against a panel of interferon proteins., Findings: 74 (90%) of 82 patients had a positive interferon score (median 12·90, IQR 6·14-20·41) compared with two (7%) of 29 controls (median 0·93, IQR 0·57-1·30). Of the eight patients with a negative interferon score, seven had mutations in RNASEH2B (seven [27%] of all 26 patients with mutations in this gene). Repeat sampling in 16 patients was consistent for the presence or absence of an interferon signature on 39 of 41 occasions. Interferon activity (tested in 147 patients) was negatively correlated with age (CSF, r=-0·604; serum, r=-0·289), and was higher in CSF than in serum in 104 of 136 paired samples. Neutralisation assays suggested that measurable antiviral activity was related to interferon α production. We did not record significantly increased concentrations of autoantibodies to interferon subtypes in patients with AGS, or an association between the presence of autoantibodies and interferon score or serum interferon activity., Interpretation: AGS is consistently associated with an interferon signature, which is apparently sustained over time and can thus be used to differentiate patients with AGS from controls. If future studies show that interferon status is a reactive biomarker, the measurement of an interferon score might prove useful in the assessment of treatment efficacy in clinical trials., Funding: European Union's Seventh Framework Programme; European Research Council., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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16. Synonymous mutations in RNASEH2A create cryptic splice sites impairing RNase H2 enzyme function in Aicardi-Goutières syndrome.
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Rice GI, Reijns MA, Coffin SR, Forte GM, Anderson BH, Szynkiewicz M, Gornall H, Gent D, Leitch A, Botella MP, Fazzi E, Gener B, Lagae L, Olivieri I, Orcesi S, Swoboda KJ, Perrino FW, Jackson AP, and Crow YJ
- Subjects
- Autoimmune Diseases of the Nervous System diagnosis, Autoimmune Diseases of the Nervous System enzymology, Female, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Mutation, Missense, Nervous System Malformations diagnosis, Nervous System Malformations enzymology, Ribonuclease H metabolism, Autoimmune Diseases of the Nervous System genetics, Nervous System Malformations genetics, Point Mutation, RNA Splice Sites, Ribonuclease H genetics
- Abstract
Aicardi-Goutières syndrome is an inflammatory disorder resulting from mutations in TREX1, RNASEH2A/2B/2C, SAMHD1, or ADAR1. Here, we provide molecular, biochemical, and cellular evidence for the pathogenicity of two synonymous variants in RNASEH2A. Firstly, the c.69G>A (p.Val23Val) mutation causes the formation of a splice donor site within exon 1, resulting in an out of frame deletion at the end of exon 1, leading to reduced RNase H2 protein levels. The second mutation, c.75C>T (p.Arg25Arg), also introduces a splice donor site within exon 1, and the internal deletion of 18 amino acids. The truncated protein still forms a heterotrimeric RNase H2 complex, but lacks catalytic activity. However, as a likely result of leaky splicing, a small amount of full-length active protein is apparently produced in an individual homozygous for this mutation. Recognition of the disease causing status of these variants allows for diagnostic testing in relevant families., (© 2013 WILEY PERIODICALS, INC.)
- Published
- 2013
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17. Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation.
- Author
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Belot A, Kasher PR, Trotter EW, Foray AP, Debaud AL, Rice GI, Szynkiewicz M, Zabot MT, Rouvet I, Bhaskar SS, Daly SB, Dickerson JE, Mayer J, O'Sullivan J, Juillard L, Urquhart JE, Fawdar S, Marusiak AA, Stephenson N, Waszkowycz B, W Beresford M, Biesecker LG, C M Black G, René C, Eliaou JF, Fabien N, Ranchin B, Cochat P, Gaffney PM, Rozenberg F, Lebon P, Malcus C, Crow YJ, Brognard J, and Bonnefoy N
- Subjects
- Adolescent, Adult, B-Lymphocytes immunology, B-Lymphocytes metabolism, Cell Proliferation, Child, Female, Genetic Variation, Homozygote, Humans, Hyperplasia, Immune Tolerance, Lupus Erythematosus, Systemic pathology, Male, Polymorphism, Single Nucleotide, Protein Kinase C-delta immunology, Young Adult, Apoptosis, B-Lymphocytes pathology, Lupus Erythematosus, Systemic enzymology, Lupus Erythematosus, Systemic genetics, Mutation, Missense, Protein Kinase C-delta deficiency, Protein Kinase C-delta genetics
- Abstract
Objective: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal-recessive form of SLE., Methods: We studied 3 siblings with juvenile-onset SLE from 1 consanguineous kindred and used next-generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology., Results: We identified a homozygous missense mutation in PRKCD, encoding protein kinase δ (PKCδ), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor- and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype., Conclusion: Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE., (Copyright © 2013 by the American College of Rheumatology.)
- Published
- 2013
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18. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature.
- Author
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Rice GI, Kasher PR, Forte GM, Mannion NM, Greenwood SM, Szynkiewicz M, Dickerson JE, Bhaskar SS, Zampini M, Briggs TA, Jenkinson EM, Bacino CA, Battini R, Bertini E, Brogan PA, Brueton LA, Carpanelli M, De Laet C, de Lonlay P, del Toro M, Desguerre I, Fazzi E, Garcia-Cazorla A, Heiberg A, Kawaguchi M, Kumar R, Lin JP, Lourenco CM, Male AM, Marques W Jr, Mignot C, Olivieri I, Orcesi S, Prabhakar P, Rasmussen M, Robinson RA, Rozenberg F, Schmidt JL, Steindl K, Tan TY, van der Merwe WG, Vanderver A, Vassallo G, Wakeling EL, Wassmer E, Whittaker E, Livingston JH, Lebon P, Suzuki T, McLaughlin PJ, Keegan LP, O'Connell MA, Lovell SC, and Crow YJ
- Subjects
- Alu Elements genetics, Animals, Exome, Gene Expression, Humans, Mice, Mutation, Protein Conformation, RNA, Double-Stranded genetics, RNA-Binding Proteins, Sequence Analysis, DNA, Signal Transduction, Structure-Activity Relationship, Adenosine Deaminase genetics, Autoimmune Diseases of the Nervous System genetics, Interferon Type I genetics, Interferon Type I metabolism, Nervous System Malformations genetics, RNA, Double-Stranded metabolism
- Abstract
Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.
- Published
- 2012
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19. Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus.
- Author
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Anderson BH, Kasher PR, Mayer J, Szynkiewicz M, Jenkinson EM, Bhaskar SS, Urquhart JE, Daly SB, Dickerson JE, O'Sullivan J, Leibundgut EO, Muter J, Abdel-Salem GM, Babul-Hirji R, Baxter P, Berger A, Bonafé L, Brunstom-Hernandez JE, Buckard JA, Chitayat D, Chong WK, Cordelli DM, Ferreira P, Fluss J, Forrest EH, Franzoni E, Garone C, Hammans SR, Houge G, Hughes I, Jacquemont S, Jeannet PY, Jefferson RJ, Kumar R, Kutschke G, Lundberg S, Lourenço CM, Mehta R, Naidu S, Nischal KK, Nunes L, Ounap K, Philippart M, Prabhakar P, Risen SR, Schiffmann R, Soh C, Stephenson JB, Stewart H, Stone J, Tolmie JL, van der Knaap MS, Vieira JP, Vilain CN, Wakeling EL, Wermenbol V, Whitney A, Lovell SC, Meyer S, Livingston JH, Baerlocher GM, Black GC, Rice GI, and Crow YJ
- Subjects
- Base Sequence, Flow Cytometry, Histones metabolism, Molecular Sequence Data, Retinal Telangiectasis pathology, Sequence Analysis, DNA methods, Abnormalities, Multiple genetics, Genetic Predisposition to Disease genetics, Retinal Telangiectasis genetics, Telomere pathology, Telomere-Binding Proteins genetics
- Abstract
Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.
- Published
- 2012
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20. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature.
- Author
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Briggs TA, Rice GI, Daly S, Urquhart J, Gornall H, Bader-Meunier B, Baskar K, Baskar S, Baudouin V, Beresford MW, Black GC, Dearman RJ, de Zegher F, Foster ES, Francès C, Hayman AR, Hilton E, Job-Deslandre C, Kulkarni ML, Le Merrer M, Linglart A, Lovell SC, Maurer K, Musset L, Navarro V, Picard C, Puel A, Rieux-Laucat F, Roifman CM, Scholl-Bürgi S, Smith N, Szynkiewicz M, Wiedeman A, Wouters C, Zeef LA, Casanova JL, Elkon KB, Janckila A, Lebon P, and Crow YJ
- Subjects
- Animals, Autoimmunity, Bone Diseases, Developmental enzymology, Cattle, Chromosomes, Human, Pair 19, Female, Humans, Inflammation, Lupus Erythematosus, Systemic metabolism, Male, Models, Molecular, Mutation, Mutation, Missense, Phenotype, Sclerosis pathology, Tartrate-Resistant Acid Phosphatase, Acid Phosphatase deficiency, Acid Phosphatase genetics, Bone Diseases, Developmental genetics, Bone Diseases, Developmental pathology, Gene Expression Regulation, Interferon Type I metabolism, Isoenzymes deficiency, Isoenzymes genetics
- Abstract
We studied ten individuals from eight families showing features consistent with the immuno-osseous dysplasia spondyloenchondrodysplasia. Of particular note was the diverse spectrum of autoimmune phenotypes observed in these individuals (cases), including systemic lupus erythematosus, Sjögren's syndrome, hemolytic anemia, thrombocytopenia, hypothyroidism, inflammatory myositis, Raynaud's disease and vitiligo. Haplotype data indicated the disease gene to be on chromosome 19p13, and linkage analysis yielded a combined multipoint log(10) odds (LOD) score of 3.6. Sequencing of ACP5, encoding tartrate-resistant acid phosphatase, identified biallelic mutations in each of the cases studied, and in vivo testing confirmed a loss of expressed protein. All eight cases assayed showed elevated serum interferon alpha activity, and gene expression profiling in whole blood defined a type I interferon signature. Our findings reveal a previously unrecognized link between tartrate-resistant acid phosphatase activity and interferon metabolism and highlight the importance of type I interferon in the genesis of autoimmunity.
- Published
- 2011
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21. Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus.
- Author
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Ravenscroft JC, Suri M, Rice GI, Szynkiewicz M, and Crow YJ
- Subjects
- Adolescent, Chilblains genetics, Chilblains pathology, Female, Humans, Lupus Erythematosus, Cutaneous genetics, Lupus Erythematosus, Cutaneous pathology, Male, Middle Aged, Mutation genetics, SAM Domain and HD Domain-Containing Protein 1, Genes, Dominant genetics, Monomeric GTP-Binding Proteins genetics, Phenotype
- Published
- 2011
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22. Differential regulation of oestrogen receptor β isoforms by 5' untranslated regions in cancer.
- Author
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Smith L, Brannan RA, Hanby AM, Shaaban AM, Verghese ET, Peter MB, Pollock S, Satheesha S, Szynkiewicz M, Speirs V, and Hughes TA
- Subjects
- Blotting, Western, Breast Neoplasms genetics, Breast Neoplasms metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Estrogen Receptor beta metabolism, Eukaryotic Initiation Factor-4E genetics, Eukaryotic Initiation Factor-4E metabolism, Female, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Neoplasms genetics, Neoplasms metabolism, Neoplasms pathology, Protein Biosynthesis, Protein Isoforms genetics, Protein Isoforms metabolism, Reverse Transcriptase Polymerase Chain Reaction, Tissue Array Analysis, 5' Untranslated Regions genetics, Alternative Splicing, Estrogen Receptor beta genetics, Gene Expression Profiling
- Abstract
Oestrogen receptors (ERs) are critical regulators of the behaviour of many cancers. Despite this, the roles and regulation of one of the two known ERs - ERβ- are poorly understood. This is partly because analyses have been confused by discrepancies between ERβ expression at mRNA and proteins levels, and because ERβ is expressed as several functionally distinct isoforms. We investigated human ERβ 5' untranslated regions (UTRs) and their influences on ERβ expression and function. We demonstrate that two alternative ERβ 5'UTRs have potent and differential influences on expression acting at the level of translation. We show that their influences are modulated by cellular context and in carcinogenesis, and demonstrate the contributions of both upstream open reading frames and RNA secondary structure. These regulatory mechanisms offer explanations for the non-concordance of ERβ mRNA and protein. Importantly, we also demonstrate that 5'UTRs allow the first reported mechanisms for differential regulation of the expression of the ERβ isoforms 1, 2 and 5, and thereby have critical influences on ERβ function., (© 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)
- Published
- 2010
- Full Text
- View/download PDF
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