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https://www.readbyqxmd.com/read/29781188/a-novel-anti-malarial-drug-derivative-inhibits-cyclic-gmp-amp-synthase-in-trex1-deficient-mice
#1
Jie An, Joshua J Woodward, Weinan Lai, Mark Minie, Xizhang Sun, Lena Tanaka, Jessica M Snyder, Tomikazu Sasaki, Keith B Elkon
OBJECTIVE: Type I interferon (IFN-I) is strongly implicated in the pathogenesis of Systemic Lupus Erythematosus (SLE) as well as rare monogenic 'interferonopathies' such as Aicardi-Goutieres Syndrome (AGS) caused by mutations in the DNA exonuclease, TREX1. The DNA-activated IFN-I pathway, cyclic GMP-AMP (cGAMP) synthase (cGAS), is linked to subsets of AGS and lupus. We identified inhibitors of DNA-cGAS interaction and tested lead candidate, X6, in a mouse model of AGS. METHODS: Trex1-/- mice were treated orally from birth with either X6 or HCQ for 8 weeks...
May 21, 2018: Arthritis & Rheumatology
https://www.readbyqxmd.com/read/29769349/hiv-1-activation-of-innate-immunity-depends-strongly-on-the-intracellular-level-of-trex1-and-sensing-of-incomplete-reverse-transcription-products
#2
Swati Kumar, James H Morrison, David Dingli, Eric Poeschla
TREX1 has been reported to degrade cytosolic immune-stimulatory DNA, including viral DNA generated during HIV-1 infection, but the dynamic range of its capacity to suppress innate immune stimulation is unknown and its full role in the viral life cycle remains unclear. A main purpose of our study was to determine how the intracellular level of TREX1 affects HIV-1 activation and avoidance of innate immunity. Using stable over-expression and CRISPR-mediated gene disruption, we engineered a range of TREX1 levels in human THP-1 monocytes...
May 16, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29740948/astrocytes-an-active-player-in-aicardi-gouti%C3%A3-res-syndrome
#3
Sunetra Sase, Asako Takanohashi, Adeline Vanderver, Akshata Almad
Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy...
May 2018: Brain Pathology
https://www.readbyqxmd.com/read/29734329/structural-basis-for-overhang-excision-and-terminal-unwinding-of-dna-duplexes-by-trex1
#4
Kuan-Wei Huang, Tung-Chang Liu, Ruei-Yue Liang, Lee-Ya Chu, Hiu-Lo Cheng, Jhih-Wei Chu, Yu-Yuan Hsiao
Three prime repair exonuclease 1 (TREX1) is an essential exonuclease in mammalian cells, and numerous in vivo and in vitro data evidenced its participation in immunity regulation and in genotoxicity remediation. In these very complicated cellular functions, the molecular mechanisms by which duplex DNA substrates are processed are mostly elusive because of the lack of structure information. Here, we report multiple crystal structures of TREX1 complexed with various substrates to provide the structure basis for overhang excision and terminal unwinding of DNA duplexes...
May 7, 2018: PLoS Biology
https://www.readbyqxmd.com/read/29718010/phenotypic-variability-in-a-mexican-mestizo-family-with-retinal-vasculopathy-with-cerebral-leukodystrophy-and-trex1-mutation-p-v235gfs-6
#5
Nancy Monroy-Jaramillo, Aurelio Cerón, Elizabeth León, Verónica Rivas, Adriana Ochoa-Morales, María Georgina Arteaga-Alcaraz, Fausto Carlos Nocedal-Rustrian, Cecilia Gallegos, María Elisa Alonso-Vilatela, Teresa Corona, José Flores
Background: Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset, autosomal dominant disease involving microvessels of the brain and eye resulting in central nervous system degeneration with visual disturbances, stroke, motor impairment, and cognitive decline. Frameshift mutations at the C-terminus of TREX1 gene are the molecular cause of this disorder. Objectives: The objective of this study is to present the different clinical manifestations of RVCL in three-related patients and to investigate the presence of TREX1 mutation in the extended genealogy...
2018: Revista de Investigación Clínica; Organo del Hospital de Enfermedades de la Nutrición
https://www.readbyqxmd.com/read/29593264/downregulation-of-cytoplasmic-dnases-is-implicated-in-cytoplasmic-dna-accumulation-and-sasp-in-senescent-cells
#6
Akiko Takahashi, Tze Mun Loo, Ryo Okada, Fumitaka Kamachi, Yoshihiro Watanabe, Masahiro Wakita, Sugiko Watanabe, Shimpei Kawamoto, Kenichi Miyata, Glen N Barber, Naoko Ohtani, Eiji Hara
Accumulating evidence indicates that the senescence-associated secretory phenotype (SASP) contributes to many aspects of physiology and disease. Thus, controlling the SASP will have tremendous impacts on our health. However, our understanding of SASP regulation is far from complete. Here, we show that cytoplasmic accumulation of nuclear DNA plays key roles in the onset of SASP. Although both DNase2 and TREX1 rapidly remove the cytoplasmic DNA fragments emanating from the nucleus in pre-senescent cells, the expression of these DNases is downregulated in senescent cells, resulting in the cytoplasmic accumulation of nuclear DNA...
March 28, 2018: Nature Communications
https://www.readbyqxmd.com/read/29564828/genes-proteins-and-biological-pathways-preventing-chromothripsis
#7
Martin Poot
The highly complex structural genome variations chromothripsis, chromoanasynthesis, and chromoplexy are subsumed under the term chromoanagenesis, which means chromosome rebirth. Precipitated by numerous DNA double-strand breaks, they differ in number of and distances between breakpoints, associated copy number variations, order and orientation of segments, and flanking sequences at joining points. Results from patients with the autosomal dominant cancer susceptibility disorder Li-Fraumeni syndrome implicated somatic TP53 mutations in chromothripsis...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29544907/mendelian-adult-onset-leukodystrophy-genes-in-alzheimer-s-disease-critical-influence-of-csf1r-and-notch3
#8
Celeste Sassi, Michael A Nalls, Perry G Ridge, Jesse R Gibbs, Michelle K Lupton, Claire Troakes, Katie Lunnon, Safa Al-Sarraj, Kristelle S Brown, Christopher Medway, Jenny Lord, James Turton, Jose Bras, Sonja Blumenau, Mareike Thielke, Christa Josties, Dorette Freyer, Annette Dietrich, Monia Hammer, Michael Baier, Ulrich Dirnagl, Kevin Morgan, John F Powell, John S Kauwe, Carlos Cruchaga, Alison M Goate, Andrew B Singleton, Rita Guerreiro, Angela Hodges, John Hardy
Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively...
June 2018: Neurobiology of Aging
https://www.readbyqxmd.com/read/29525183/line1-contributes-to-autoimmunity-through-both-rig-i-and-mda5-mediated-rna-sensing-pathways
#9
Ke Zhao, Juan Du, Yanfeng Peng, Peng Li, Shaohua Wang, Yu Wang, Jingwei Hou, Jian Kang, Wenwen Zheng, Shucheng Hua, Xiao-Fang Yu
Improper host immune activation leads to the development of the autoimmune disease Aicardi-Goutières syndrome (AGS), which is attributed to defined genetic mutations in such proteins as TREX1 and ADAR1. The mechanism of immune activation in AGS patients has not been thoroughly elucidated to date. In this study, we report that endogenous LINE1 components trigger IFNβ production in multiple human cell types, including those defective for cGAS/STING-mediated DNA sensing. In these cells, LINE1 DNA synthesis and retrotransposition were not required for LINE1-triggered immune activation, but RNA sensing pathways were essential...
June 2018: Journal of Autoimmunity
https://www.readbyqxmd.com/read/29386495/-retinal-vasculopathy-with-cerebral-leukoencephalopathy-carrying-trex1-mutation-diagnosed-by-the-intracranial-calcification-a-case-report
#10
Ryouhei Komaki, Takehiro Ueda, Yukio Tsuji, Toko Miyawaki, Sentaro Kusuhara, Shigeo Hara, Tatsushi Toda
A 40-year-old woman with renal dysfunction for 2 years was admitted to our hospital suffering from a headache. Family history revealed that her mother had a headache, renal dysfunction, and brain infarction in younger age. She had a retinal hemorrhage, a retinal atrophy, pitting edema in her lower extremities. Her neurological findings were unremarkable. Brain imaging showed multiple white matter lesions accompanied with calcifications and slightly enhancement. Kidney biopsy showed the thrombotic microangiopathy, Gene analysis demonstrated a causative mutation in three-prime repair exonuclease-1 (TREX1) gene, c...
February 28, 2018: Rinshō Shinkeigaku, Clinical Neurology
https://www.readbyqxmd.com/read/29380913/review-vascular-dementia-clinicopathologic-and-genetic-considerations
#11
REVIEW
H V Vinters, C Zarow, E Borys, J D Whitman, S Tung, W G Ellis, L Zheng, H C Chui
The incidence and severity of cerebrovascular disease (CVD) increase with advancing age, as does the risk of developing Alzheimer's disease (AD). Not surprisingly, heterogeneous forms of CVD may coexist with AD changes in the 'ageing brain'. These include angiopathies (affecting both large and small arteries) that result from 'classical' risk factors (hypertension, smoking and diabetes) and others (cerebral amyloid angiopathy) that are biochemically closely linked to AD. The morphologic consequences of these various vascular diseases are infarcts and/or haemorrhages of varying sizes within the brain, which lead to neurocognitive decline that may mimic AD - though the vascular abnormalities are usually detectable by neuroimaging...
April 2018: Neuropathology and Applied Neurobiology
https://www.readbyqxmd.com/read/29322432/renal-histopathological-findings-of-retinal-vasculopathy-with-cerebral-leukodystrophy
#12
Yutaka Tsubata, Takashi Morita, Tetsuo Morioka, Taiji Sasagawa, Kouzo Ikarashi, Noriko Saito, Hisaki Shimada, Shigeru Miyazaki, Shinji Sakai, Hajime Tanaka, Rie Saito, Yasuko Toyoshima, Hiroaki Nozaki, Ichiei Narita
Retinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare autosomal dominant systemic microvascular disease. Neurological disorders and visual disturbance are highlighted as manifestations of RVCL; however, there are few reports focused on nephropathy. Herein, we describe detailed renal histopathological findings in a daughter and father with RVCL, proven by TREX1 genetic analysis. A kidney biopsy of the daughter, 35-year-old with asymptomatic proteinuria, revealed unique and various glomerular changes...
May 2018: CEN Case Reports
https://www.readbyqxmd.com/read/29239743/phenotypic-and-molecular-spectrum-of-aicardi-gouti%C3%A3-res-syndrome-a-study-of-24-patients
#13
Fuad Al Mutairi, Majid Alfadhel, Marwan Nashabat, Ayman W El-Hattab, Tawfeg Ben-Omran, Jozef Hertecant, Wafaa Eyaid, Rehab Ali, Ali Alasmari, Majdi Kara, Waleed Al-Twaijri, Rana Filimban, Abduljabbar Alshenqiti, Mohammed Al-Owain, Eissa Faqeih, Fowzan S Alkuraya
BACKGROUND: Aicardi-Goutières syndrome is a rare genetic neurological disorder with variable clinical manifestations. Molecular detection of specific mutations is required to confirm the diagnosis. The aim of this study was to review the clinical and molecular diagnostic findings in 24 individuals with Aicardi-Goutières syndrome who presented during childhood in an Arab population. MATERIALS AND METHODS: We reviewed the records of 24 patients from six tertiary hospitals in different Arab countries...
January 2018: Pediatric Neurology
https://www.readbyqxmd.com/read/29215161/suppressive-oligodeoxynucleotides-containing-ttaggg-motifs-inhibit-cgas-activation-in-human-monocytes
#14
Folkert Steinhagen, Thomas Zillinger, Konrad Peukert, Mario Fox, Marcus Thudium, Winfried Barchet, Christian Putensen, Dennis Klinman, Eicke Latz, Christian Bode
Type I interferon (IFN) is a critical mediator of autoimmune diseases such as systemic lupus erythematosus (SLE) and Aicardi-Goutières Syndrome (AGS). The recently discovered cyclic-GMP-AMP (cGAMP) synthase (cGAS) induces the production of type I IFN in response to cytosolic DNA and is potentially linked to SLE and AGS. Suppressive oligodeoxynucleotides (ODN) containing repetitive TTAGGG motifs present in mammalian telomeres have proven useful in the treatment of autoimmune diseases including SLE. In this study, we demonstrate that the suppressive ODN A151 effectively inhibits activation of cGAS in response to cytosolic DNA, thereby inhibiting type I IFN production by human monocytes...
December 7, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/29114091/circulating-endothelial-markers-in-retinal-vasculopathy-with-cerebral-leukoencephalopathy-and-systemic-manifestations
#15
Nadine Pelzer, Roel Bijkerk, Marlies E J Reinders, Anton Jan van Zonneveld, Michel D Ferrari, Arn M J M van den Maagdenberg, Jeroen Eikenboom, Gisela M Terwindt
BACKGROUND AND PURPOSE: Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a monogenic small vessel disease, caused by C-terminal truncating TREX1 mutations, that can be considered a model for stroke and vascular dementia. The pathophysiology of RVCL-S is largely unknown, but systemic endothelial involvement has been suggested, leading to pathology in the brain and other highly vascularized organs. Here, we investigated circulating endothelial markers to confirm endothelial involvement and identify biomarkers for disease activity...
December 2017: Stroke; a Journal of Cerebral Circulation
https://www.readbyqxmd.com/read/29100097/monogenic-lupus-it-s-all-new
#16
REVIEW
Patricia Costa-Reis, Kathleen E Sullivan
Monogenic lupus is rare, but its study has contributed immensely to a better understanding of the pathogenesis of systemic lupus erythematosus. The first forms identified were inherited complement deficiencies, which predisposed to lupus due to impaired tolerance, and aberrant clearance of apoptotic bodies and immune complexes. In recent years, several new monogenic disorders with a lupus-like phenotype have been described. These include forms that affect nucleic acid repair, degradation and sensing (TREX1, DNASE1L3), the type I interferon (IFN) pathway (SAMHD1, RNASEH2ABC, ADAR1, IFIH1, ISG15, ACP5, TMEM173) and B cell development checkpoints (PRKCD; RAG2)...
December 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/29028736/superficial-and-deep-capillary-ischemia-as-a-presenting-sign-of-retinal-vasculopathy-with-cerebral-leukoencephalopathy-and-systemic-manifestations
#17
Aaron Nagiel, Robert A Lalane, Joanna C Jen, Allan E Kreiger
PURPOSE: The aim of this study was to investigate the presenting sign of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, a rare autosomal dominant condition caused by mutations in the TREX1 gene, and to explore the potential efficacy of bevacizumab in preventing capillary occlusions. METHODS: Observational case report with the use of ultra-widefield fluorescein angiography, optical coherence tomography, and optical coherence tomography angiography...
October 12, 2017: Retinal Cases & Brief Reports
https://www.readbyqxmd.com/read/28954878/-col4a2-is-associated-with-lacunar-ischemic-stroke-and-deep-ich-meta-analyses-among-21-500-cases-and-40-600-controls
#18
Kristiina Rannikmäe, Vhinoth Sivakumaran, Henry Millar, Rainer Malik, Christopher D Anderson, Mike Chong, Tushar Dave, Guido J Falcone, Israel Fernandez-Cadenas, Jordi Jimenez-Conde, Arne Lindgren, Joan Montaner, Martin O'Donnell, Guillaume Paré, Farid Radmanesh, Natalia S Rost, Agnieszka Slowik, Martin Söderholm, Matthew Traylor, Sara L Pulit, Sudha Seshadri, Brad B Worrall, Daniel Woo, Hugh S Markus, Braxton D Mitchell, Martin Dichgans, Jonathan Rosand, Cathie L M Sudlow
OBJECTIVE: To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD. METHODS: We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes ( COL4A1 , COL4A2 , NOTCH3 , HTRA1 , TREX1 , and CECR1 ) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls)...
October 24, 2017: Neurology
https://www.readbyqxmd.com/read/28932642/trex1-dictates-the-immune-fate-of-irradiated-cancer-cells
#19
Claire Vanpouille-Box, Silvia C Formenti, Sandra Demaria
The optimal radiation dose and fractionation to induce anti-tumor immunity remain elusive. We recently found that the exonuclease TREX1 abrogates the immunogenicity of irradiated cancer cells by degrading interferon-stimulatory cytosolic dsDNA. TREX1 upregulation by radiation dose per fraction beyond a threshold of 10-12 Gy results in poor synergy with immune checkpoint blockers.
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919362/a-homozygote-trex1-mutation-in-two-siblings-with-different-phenotypes-chilblains-and-cerebral-vasculitis
#20
Rabia Miray Kisla Ekinci, Sibel Balci, Atil Bisgin, Derya Ufuk Altintas, Mustafa Yilmaz
Three prime repair exonuclease 1 degrades single and double stranded DNA with 3'-5' nuclease activity and its mutations are related to type 1 IFN mediated autoinflammation due to accumulated intracellular nucleic acids. To date, several cases of systemic lupus erythematosus, Aicardi-Goutieres syndrome, familial chilblain lupus, retinal vasculopathy-cerebral leukodystrophy have been reported with TREX1 mutations. Chilblain lupus is a skin disease characterized by blue-reddish coloring, swelling or ulcers on acral regions of body such as fingertips, heels, nose and auricles...
December 2017: European Journal of Medical Genetics
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