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John H Livingston, Yanick J Crow
The Aicardi-Goutières syndrome (AGS) was first described in 1984, and over the following years was defined by the clinical and radiological features of an early onset, severe, neurologic disorder with intracranial calcification, leukoencephalopathy, and cerebral atrophy, usually associated with a cerebrospinal fluid (CSF) pleocytosis and elevated CSF interferon α activity. It is now recognized that mutations in any of the following seven genes may result in the classical AGS phenotype: TREX1 (AGS1), RNASEH2A (AGS2), RNASEH2B (AGS3), RNASEH2C (AGS4), SAMHD1 (AGS5), ADAR1 (AGS6), and IFIH1 (AGS7)...
September 19, 2016: Neuropediatrics
Anine H Stam, Parul H Kothari, Aisha Shaikh, Andreas Gschwendter, Joanna C Jen, Suzanne Hodgkinson, Todd A Hardy, Michael Hayes, Peter A Kempster, Katya E Kotschet, Ingeborg M Bajema, Sjoerd G van Duinen, Marion L C Maat-Schieman, Paulus T V M de Jong, Marc D de Smet, Didi de Wolff-Rouendaal, Greet Dijkman, Nadine Pelzer, Grant R Kolar, Robert E Schmidt, JoAnne Lacey, Daniel Joseph, David R Fintak, M Gilbert Grand, Elizabeth M Brunt, Helen Liapis, Rula A Hajj-Ali, Mark C Kruit, Mark A van Buchem, Martin Dichgans, Rune R Frants, Arn M J M van den Maagdenberg, Joost Haan, Robert W Baloh, John P Atkinson, Gisela M Terwindt, Michel D Ferrari
Cerebroretinal vasculopathy, hereditary vascular retinopathy, and hereditary endotheliopathy, retinopathy, nephropathy and stroke are neurovascular syndromes initially described as distinct entities. Recently they were shown to be one disease caused by C-terminal frame-shift mutations in TREX1, which was termed 'retinal vasculopathy with cerebral leukodystrophy'. Here we defined the genetic and clinicopathologic spectrum of this clinically and pathophysiologically poorly characterized and frequently misdiagnosed fatal neurovascular disorder...
September 6, 2016: Brain: a Journal of Neurology
M Hughes, J Little, A L Herrick, S Pushpakom, H Byers, J Worthington, W G Newman
No abstract text is available yet for this article.
August 30, 2016: Scandinavian Journal of Rheumatology
Nadja König, Christoph Fiehn, Christine Wolf, Max Schuster, Emanuel Cura Costa, Victoria Tüngler, Hugo Ariel Alvarez, Osvaldo Chara, Kerstin Engel, Raphaela Goldbach-Mansky, Claudia Günther, Min Ae Lee-Kirsch
OBJECTIVES: Familial chilblain lupus is a monogenic form of cutaneous lupus erythematosus caused by loss-of-function mutations in the nucleases TREX1 or SAMHD1. In a family without TREX1 or SAMHD1 mutation, we sought to determine the causative gene and the underlying disease pathology. METHODS: Exome sequencing was used for disease gene identification. Structural analysis was performed by homology modelling and docking simulations. Type I interferon (IFN) activation was assessed in cells transfected with STING cDNA using an IFN-β reporter and Western blotting...
August 26, 2016: Annals of the Rheumatic Diseases
John L Goodier
Retrotransposons have generated about 40 % of the human genome. This review examines the strategies the cell has evolved to coexist with these genomic "parasites", focussing on the non-long terminal repeat retrotransposons of humans and mice. Some of the restriction factors for retrotransposition, including the APOBECs, MOV10, RNASEL, SAMHD1, TREX1, and ZAP, also limit replication of retroviruses, including HIV, and are part of the intrinsic immune system of the cell. Many of these proteins act in the cytoplasm to degrade retroelement RNA or inhibit its translation...
2016: Mobile DNA
Katrin Peschke, Martin Achleitner, Kathrin Frenzel, Alexander Gerbaulet, Servi Remzi Ada, Nicolas Zeller, Stefan Lienenklaus, Mathias Lesche, Claire Poulet, Ronald Naumann, Andreas Dahl, Ursula Ravens, Claudia Günther, Werner Müller, Klaus-Peter Knobeloch, Marco Prinz, Axel Roers, Rayk Behrendt
Defects of the intracellular enzyme 3' repair exonuclease 1 (Trex1) cause the rare autoimmune condition Aicardi-Goutières syndrome and are associated with systemic lupus erythematosus. Trex1(-/-) mice develop type I IFN-driven autoimmunity, resulting from activation of the cytoplasmic DNA sensor cyclic GMP-AMP synthase by a nucleic acid substrate of Trex1 that remains unknown. To identify cell types responsible for initiation of autoimmunity, we generated conditional Trex1 knockout mice. Loss of Trex1 in dendritic cells was sufficient to cause IFN release and autoimmunity, whereas Trex1-deficient keratinocytes and microglia produced IFN but did not induce inflammation...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Elizabeth E Gray, Damion Winship, Jessica M Snyder, Stephanie J Child, Adam P Geballe, Daniel B Stetson
Detection of intracellular DNA triggers activation of the STING-dependent interferon-stimulatory DNA (ISD) pathway, which is essential for antiviral responses. Multiple DNA sensors have been proposed to activate this pathway, including AIM2-like receptors (ALRs). Whether the ALRs are essential for activation of this pathway remains unknown. To rigorously explore the function of ALRs, we generated mice lacking all 13 ALR genes. We found that ALRs are dispensable for the type I interferon (IFN) response to transfected DNA ligands, DNA virus infection, and lentivirus infection...
August 16, 2016: Immunity
Emek Uyur Yalçın, Hülya Maraş Genç, Bülent Kara
Aicardi-Goutières syndrome (AGS) is a rare, autosomal recessively inherited, immune-mediated neurodevelopmental disorder. The syndrome causes infantile-onset progressive encephalopathy characterized by the neuroradiologic features of basal ganglia and periventricular white matter calcification, leucodystrophy and cerebral atrophy. Lymphocytosis and elevated levels of interferon alpha (IFN-alpha) in the cerebrospinal fluid are supplementary findings of AGS. It is frequently misdiagnosed as sequelae of congenital infection (pseudo-TORCH) and mostly recognized later...
September 2015: Turkish Journal of Pediatrics
Panapat Phairoh, Thana Suthibatpong, Triwit Rattanarojpong, Nujarin Jongruja, Saengchan Senapin, Kiattawee Choowongkomon, Pongsak Khunrae
ICP35 is a non-structural protein from White spot syndrome virus believed to be important in viral replication. Since ICP35 was found to localize in the host nucleus, it has been speculated that the function of ICP35 might be involved in the interaction of DNA. In this study, we overexpressed, purified and characterized ICP35. The thioredoxin-fused ICP35 (thio-ICP35) was strongly expressed in E. coli and be able to form itself into dimers. Investigation of the interaction between ICP35 and DNA revealed that ICP35 can perform DNase activity...
2016: PloS One
Christine Wolf, Alexander Rapp, Nicole Berndt, Wolfgang Staroske, Max Schuster, Manuela Dobrick-Mattheuer, Stefanie Kretschmer, Nadja König, Thomas Kurth, Dagmar Wieczorek, Karin Kast, M Cristina Cardoso, Claudia Günther, Min Ae Lee-Kirsch
Immune recognition of cytosolic DNA represents a central antiviral defence mechanism. Within the host, short single-stranded DNA (ssDNA) continuously arises during the repair of DNA damage induced by endogenous and environmental genotoxic stress. Here we show that short ssDNA traverses the nuclear membrane, but is drawn into the nucleus by binding to the DNA replication and repair factors RPA and Rad51. Knockdown of RPA and Rad51 enhances cytosolic leakage of ssDNA resulting in cGAS-dependent type I IFN activation...
2016: Nature Communications
Sharon A Chung, Anthony K Shum
PURPOSE OF REVIEW: We review select studies of newly discovered rare variants in autoimmune diseases with a focus on newly described monogenic disorders, rheumatoid arthritis, and systemic lupus erythematosus. RECENT FINDINGS: Two new monogenic syndromes of inflammatory arthritis were discovered using whole exome sequencing: the coatomer subunit alpha syndrome because of rare mutations in coatomer subunit alpha and haploinsufficiency of A20 resulting from rare mutations in TNFAIP3...
July 2016: Current Opinion in Rheumatology
Lee Adam Wheeler, Radiana T Trifonova, Vladimir Vrbanac, Natasha S Barteneva, Xing Liu, Brooke Bollman, Lauren Onofrey, Sachin Mulik, Shahin Ranjbar, Andrew D Luster, Andrew M Tager, Judy Lieberman
Despite their antiviral effect, the in vivo effect of interferons on HIV transmission is difficult to predict, because interferons also activate and recruit HIV-susceptible cells to sites of infection. HIV does not normally induce type I interferons in infected cells, but does if TREX1 is knocked down. Here, we investigated the effect of topical TREX1 knockdown and local interferon production on HIV transmission in human cervicovaginal explants and humanized mice. In explants in which TREX1 was knocked down, HIV induced interferons, which blocked infection...
May 24, 2016: Cell Reports
Ho-Chen Lin, Chin-Lin Huang, Yuh-Jeen Huang, I-Lun Hsiao, Chung-Wei Yang, Chun-Yu Chuang
Silver nanoparticles (AgNPs) are commonly used in daily living products. AgNPs can induce inflammatory response in neuronal cells, and potentially develop neurological disorders. The gene networks in response to AgNPs-induced neurodegenerative progression have not been clarified in various brain neural cells. This study found that 3-5nm AgNPs were detectable to enter the nuclei of mouse neuronal cells after 24-h of exposure. The differentially expressed genes in mouse brain neural cells exposure to AgNPs were further identified using Phalanx Mouse OneArray® chip, and permitted to explore the gene network pathway regulating in neurodegenerative progression according to Cytoscape analysis...
August 2016: Toxicology in Vitro: An International Journal Published in Association with BIBRA
James T Rosenbaum, Cailin H Sibley, Phoebe Lin
PURPOSE OF REVIEW: Ophthalmologists and rheumatologists frequently have a miscommunication among themselves, and as a result differ in their opinion for patients consulting them with retinal vasculitis. This report seeks to establish a common understanding of the term, retinal vasculitis, and to review recent studies on this diagnosis. RECENT FINDINGS: The genetic basis of some rare forms of retinal vascular disease has recently been described. Identified genes include CAPN5, TREX1, and TNFAIP3; Behçet's disease is a systemic illness that is very commonly associated with occlusive retinal vasculitis; retinal imaging, including fluorescein angiography and other newer imaging modalities, has proven crucial to the identification and characterization of retinal vasculitis and its complications; although monoclonal antibodies to interleukin-17A or interleukin-1 beta failed in trials for Behçet's disease, antibodies to TNF-alpha, either infliximab or adalimumab, have demonstrated consistent benefit in managing this disease...
May 2016: Current Opinion in Rheumatology
Saturnino Ortiz-Madinaveitia, David Conejo-Moreno, Javier López-Pisón, José Luis Peña-Segura, M Luisa Serrano-Madrid, Ingrid C Durán-Palacios, Pilar Peláez-Cabo
INTRODUCTION: Aicardi-Goutieres syndrome is a rare immune disorder due to mutations in seven different genes that encode proteins called TREX1, ribonuclease H2 complex, SAMHD1, ADAR and IDIH1 (MDA5), which are involved in acid nucleic metabolism. Two cases are described in detail below caused by RNASEH2B gene mutation, one of which displays a mutation no described to date. CASE REPORTS: Case 1: male consulting because from 5-month-old shows loss of maturity items acquired until then, coming with several fever episodes...
February 16, 2016: Revista de Neurologia
Ivana Vodopivec, Derek H Oakley, Cory A Perugino, Nagagopal Venna, E Tessa Hedley-Whyte, John H Stone
Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare, autosomal dominant condition caused by mutations of TREX1 (3-prime repair exonuclease-1). The phenotypic expressions range from isolated retinal involvement to varying degrees of retinopathy, cerebral infarction with calcium depositions, nephropathy, and hepatopathy. We report a case of RVCL caused by a novel TREX1 mutation. This patient's multisystem presentation, retinal involvement interpreted as "retinal vasculitis," and improvement of neuroimaging abnormalities with dexamethasone led to the accepted diagnosis of a rheumatologic disorder resembling Behçet disease...
April 2016: Annals of Neurology
John Maciejowski, Yilong Li, Nazario Bosco, Peter J Campbell, Titia de Lange
Telomere crisis occurs during tumorigenesis when depletion of the telomere reserve leads to frequent telomere fusions. The resulting dicentric chromosomes have been proposed to drive genome instability. Here, we examine the fate of dicentric human chromosomes in telomere crisis. We observed that dicentric chromosomes invariably persisted through mitosis and developed into 50-200 μm chromatin bridges connecting the daughter cells. Before their resolution at 3-20 hr after anaphase, the chromatin bridges induced nuclear envelope rupture in interphase, accumulated the cytoplasmic 3' nuclease TREX1, and developed RPA-coated single stranded (ss) DNA...
December 17, 2015: Cell
Anneleen Decock, Maté Ongenaert, Robrecht Cannoodt, Kimberly Verniers, Bram De Wilde, Geneviève Laureys, Nadine Van Roy, Ana P Berbegall, Julie Bienertova-Vasku, Nick Bown, Nathalie Clément, Valérie Combaret, Michelle Haber, Claire Hoyoux, Jayne Murray, Rosa Noguera, Gaelle Pierron, Gudrun Schleiermacher, Johannes H Schulte, Ray L Stallings, Deborah A Tweddle, Katleen De Preter, Frank Speleman, Jo Vandesompele
Accurate assessment of neuroblastoma outcome prediction remains challenging. Therefore, this study aims at establishing novel prognostic tumor DNA methylation biomarkers. In total, 396 low- and high-risk primary tumors were analyzed, of which 87 were profiled using methyl-CpG-binding domain (MBD) sequencing for differential methylation analysis between prognostic patient groups. Subsequently, methylation-specific PCR (MSP) assays were developed for 78 top-ranking differentially methylated regions and tested on two independent cohorts of 132 and 177 samples, respectively...
January 12, 2016: Oncotarget
Roberta La Piana, Carla Uggetti, Federico Roncarolo, Adeline Vanderver, Ivana Olivieri, Davide Tonduti, Guy Helman, Umberto Balottin, Elisa Fazzi, Yanick J Crow, John Livingston, Simona Orcesi
OBJECTIVE: To perform an updated characterization of the neuroradiologic features of Aicardi-Goutières syndrome (AGS). METHODS: The neuroradiologic data of 121 subjects with AGS were collected. The CT and MRI data were analyzed with a systematic approach. Moreover, we evaluated if an association exists between the neuroradiologic findings, clinical features, and genotype. RESULTS: Brain calcifications were present in 110 subjects (90.9%)...
January 5, 2016: Neurology
Radhika Dhamija, David Schiff, M Beatriz S Lopes, Joanna C Jen, Doris D Lin, Bradford B Worrall
No abstract text is available yet for this article.
November 3, 2015: Neurology
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