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https://read.qxmd.com/read/30868116/exome-sequencing-identifies-molecular-diagnosis-in-children-with-drug-resistant-epilepsy
#1
Mandy Ho-Yin Tsang, Gordon Ka-Chun Leung, Alvin Chi-Chung Ho, Kit-San Yeung, Christopher Chun-Yu Mak, Steven Lim-Cho Pei, Mullin Ho-Chung Yu, Anita Sik-Yau Kan, Kelvin Yuen-Kwong Chan, Karen Ling Kwong, So-Lun Lee, Ada Wing-Yan Yung, Cheuk-Wing Fung, Brian Hon-Yin Chung
Objective: Early onset drug-resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure-free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug-resistant epilepsy and evaluate whether the findings can provide information on patient management. Methods: We include patients with drug-resistant epilepsy onset before 18 years of age...
March 2019: Epilepsia Open
https://read.qxmd.com/read/30838928/the-space-time-continuum-of-cortical-dysplasia
#2
Laura A Jansen
Somatic Mutations Activating the mTOR Pathway in Dorsal Telencephalic Progenitors Cause a Continuum of Cortical Dysplasias D'Gama AM, Woodworth MB, Hossain AA, Bizzotto S, Hatem NE, LaCoursiere CM, Najm I, Ying Z, Yang E, Barkovich AJ, Kwiatkowski DJ, Vinters HV, Madsen JR, Mathern GW, Blümcke I, Poduri A, Walsh CA. Cell Rep. 2017;21:3754-3766. Focal cortical dysplasia (FCD) and hemimegalencephaly (HME) are epileptogenic neurodevelopmental malformations caused by mutations in mTOR pathway genes. Deep sequencing of these genes in FCD/HME brain tissue identified an etiology in 27 (41%) of 66 cases...
January 2019: Epilepsy Currents
https://read.qxmd.com/read/30782578/a-comprehensive-clinico-pathological-and-genetic-evaluation-of-bottom-of-sulcus-focal-cortical-dysplasia-in-patients-with-difficult-to-localize-focal-epilepsy
#3
Zhong Ying, Irene Wang, Ingmar Blümcke, Juan Bulacio, Andreas Alexopoulos, Lara Jehi, William Bingaman, Jorge Gonzalez-Martinez, Katja Kobow, Lisa Marie Niestroj, Dennis Lal, Konrad Koelble, Imad Najm
We comprehensively studied the clinical presentation, stereo-EEG and MRI findings, histopathological diagnosis, and brain somatic mutations in a retrospective series of drug-resistant patients with difficult-to-localize epilepsy due to focal cortical dysplasia at the bottom of a sulcus (BOS-FCD). We identified 10 patients with BOS-FCD from the Cleveland Clinic epilepsy surgery database submitted for intracranial video-EEG monitoring. Brain MRI, including voxel-based morphometric analysis and surgical tissue submitted for histopathology, was reviewed...
February 18, 2019: Epileptic Disorders: International Epilepsy Journal with Videotape
https://read.qxmd.com/read/30767899/depdc5-mutation-and-familial-focal-epilepsy-with-variable-foci-genotype-and-phenotype-of-a-family
#4
Marina Aberastury, Romina Fernández, Marta Córdoba, Betiana Comas, Martín Peralta, Guillermo Agosta, Marcelo Kauffman, Walter Silva
Familial focal epilepsy with variable foci is a relatively rare autosomal disease with an unclear incidence, which is characterized by focal seizures arising from different cortical regions in different family members. We describe three members of a two-generation Argentine family with familial focal epilepsy with variable foci syndrome and a DEPDC5 gene mutation. The mean onset age was nine years old. The father experienced episodes with occipital semiology and both siblings exhibited frontal lobe seizures...
February 15, 2019: Epileptic Disorders: International Epilepsy Journal with Videotape
https://read.qxmd.com/read/30723271/a-variant-in-the-mica-gene-is-associated-with-liver-fibrosis-progression-in-chronic-hepatitis-c-through-tgf-%C3%AE-1-dependent-mechanisms
#5
Rasha El Sharkawy, Ali Bayoumi, Mayada Metwally, Alessandra Mangia, Thomas Berg, Manuel Romero-Gomez, Maria Lorena Abate, William L Irving, David Sheridan, Gregory J Dore, Ulrich Spengler, Pietro Lampertico, Elisabetta Bugianesi, Martin Weltman, Lindsay Mollison, Wendy Cheng, Stephen Riordan, Rosanna Santoro, Rocío Gallego-Durán, Janett Fischer, Jacob Nattermann, Roberta D'Ambrosio, Duncan McLeod, Elizabeth Powell, Olivier Latchoumanin, Khaled Thabet, Mustafa A M Najim, Mark W Douglas, Christopher Liddle, Liang Qiao, Jacob George, Mohammed Eslam
Hepatocarcinogenesis is tightly linked to liver fibrosis. Recently, two GWAS variants, MICA rs2596542 and DEPDC5 rs1012068 were identified as being associated with the development of HCV-induced hepatocellular carcinoma (HCC) in Japanese patients. The role of these variants on hepatic inflammation and fibrosis that are closely associated with HCC development is not known, nor are the biological mechanisms underlying their impact on the liver. Here, we demonstrate in 1689 patients with chronic hepatitis C (CHC) (1,501 with CHC and 188 with HCV-related HCC), that the MICA (T) allele, despite not being associated with HCC susceptibility, is associated with increased fibrosis stage (OR: 1...
February 5, 2019: Scientific Reports
https://read.qxmd.com/read/30683632/correlation-between-the-depdc5-rs1012068-polymorphism-and-the-risk-of-hbv-related-hepatocellular-carcinoma
#6
Wenxuan Liu, Ning Ma, Dongqiang Zhao, Xia Gao, Xiaolin Zhang, Lei Yang, Liu Dianwu
INTRODUCTION: HBV and/or HCV infection is the main cause of hepatocellular carcinoma (HCC), but the molecular mechanisms by which HBV promotes HCC are not clear. In 2011, the result of a GWAS revealed a common variant of DEPDC5 affected HCC susceptibility in patient with chronic HCV infection in Japan. This study investigated the correlation between DEPDC5 polymorphism and HBV-related HCC. MATERIALS AND METHODS: 1289 samples of Han population were involved in northern China and peripheral blood samples were obtained, including 506 healthy controls, 217 Hepatitis B chronic (CHB) and 258 liver cirrhosis (LC), and 308 HBV-related HCC patients...
January 22, 2019: Clinics and Research in Hepatology and Gastroenterology
https://read.qxmd.com/read/30651352/arg78-of-nprl2-catalyzes-gator1-stimulated-gtp-hydrolysis-by-the-rag-gtpases
#7
Kuang Shen, Max L Valenstein, Xin Gu, David M Sabatini
mTOR complex 1 (mTORC1) is a major regulator of cell growth and proliferation that coordinates nutrient inputs with anabolic and catabolic processes. Amino acid signals are transmitted to mTORC1 through the Rag GTPases, which directly recruit mTORC1 onto the lysosomal surface, its site of activation. The Rag GTPase heterodimer has a unique architecture that consists of two GTPase subunits, RagA or RagB bound to RagC or RagD. Their nucleotide-loading states are strictly controlled by several lysosomal or cytosolic protein complexes that directly detect and transmit the amino acid signals...
January 16, 2019: Journal of Biological Chemistry
https://read.qxmd.com/read/30635399/skeletal-muscle-specific-knockout-of-dep-domain-containing-5-increases-mtorc1-signaling-muscle-cell-hypertrophy-and-mitochondrial-respiration
#8
Ted G Graber, Christopher S Fry, Camille R Brightwell, Tatiana Moro, Rosario Maroto, Nisha Bhattari, Craig Porter, Maki Wakamiya, Blake B Rasmussen
mTORC1 regulates protein synthesis, and in turn is regulated by growth factors, energy status, and amino acid availability. In kidney cell (HEK293-T) culture, the GAP activity towards RAG (GATOR1) protein complex suppresses activation of the RAG A/B-RAG C/D heterodimer when amino acids are insufficient. During amino acid sufficiency, the RAG heterodimer recruits mTORC1 to the lysosomal membrane where its interaction with Ras homolog enriched in brain (Rheb) stimulates mTORC1's kinase activity. The DEP domain-containing 5 protein (DEPDC5), a GATOR1 subunit, causes familial focal epilepsy when mutated, and global knockout of the Depdc5 gene is embryonic lethal...
January 11, 2019: Journal of Biological Chemistry
https://read.qxmd.com/read/30531098/-depdc5-a-new-key-to-understand-various-epilepsies
#9
Saeko Ishida
Epilepsy is one of the most frequent neurological disorders characterized by spontaneous and recurrent seizures. Most seizures last for the lifetime and the patients require long term therapies. However, about 30% of the patients are refractory to antiepileptic drugs. Therefore, the need for newer and more effective therapies is urgent. Focal epilepsies, in which the abnormal electrical discharges occur within neuronal networks limited to one hemisphere, accounts for about 60% of all adult idiopathic epilepsy cases...
2018: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
https://read.qxmd.com/read/30427063/gator1-variants-in-chinese-people-with-sporadic-drug-resistant-focal-epilepsy
#10
Weixi Xiong, Lin Tang, Lu Lu, Le Zhang, Yingfeng Xiao, Dong Zhou
OBJECTIVES: GATOR1 (Gap Activity TOward Rags 1) is composed of three different subunits, DEPDC5 (DEP domain-containing protein 5), NPRL2 (nitrogen permease regulator-like 2), and NPRL3 (nitrogen permease regulator-like 3), and variants in these three genes have mostly been reported in familial focal epilepsy. However, very few studies have been carried out on sporadic drug-resistant focal epilepsy patients. In this study, we aimed to identify the frequency of variants in DEPDC5, NPRL2 and NPRL3 in patients with sporadic drug-resistant focal epilepsy...
November 14, 2018: Acta Neurologica Scandinavica
https://read.qxmd.com/read/30289982/pnpla3-and-tm6sf2-variants-as-risk-factors-of-hepatocellular-carcinoma-across-various-etiologies-and-severity-of-underlying-liver-diseases
#11
Jie Yang, Eric Trépo, Pierre Nahon, Qian Cao, Christophe Moreno, Eric Letouzé, Sandrine Imbeaud, Thierry Gustot, Jacques Deviere, Stéphanie Debette, Philippe Amouyel, Paulette Bioulac-Sage, Julien Calderaro, Nathalie Ganne-Carrié, Alexis Laurent, Jean Frédéric Blanc, Erwan Guyot, Angela Sutton, Marianne Ziol, Jessica Zucman-Rossi, Jean-Charles Nault
Few single nucleotide polymorphisms (SNPs) have been reproducibly associated with hepatocellular carcinoma (HCC). Our aim was to test the association between nine SNPs and HCC occurrence. SNPs in genes linked to HCC (DEPDC5, GRIK1, KIF1B, STAT4, MICA, DLC1, DDX18) or to liver damage (PNPLA3-rs738409, TM6SF2-rs58542926) in GWAS were genotyped in discovery cohorts including 1,020 HCC, 2,021 controls with chronic liver disease and 2,484 healthy individuals and replication was performed in prospective cohorts of cirrhotic patients with alcoholic liver disease (ALD, n = 249) and hepatitis C (n = 268)...
October 5, 2018: International Journal of Cancer. Journal International du Cancer
https://read.qxmd.com/read/30182498/genotype-and-phenotype-analysis-using-an-epilepsy-associated-gene-panel-in-chinese-pediatric-epilepsy-patients
#12
Pu Miao, Jianhua Feng, Yufan Guo, Jianda Wang, Xiaoxiao Xu, Ye Wang, Yanfang Li, Liuyan Gao, Chaoguang Zheng, Haiying Cheng
Epilepsy is a common and genetically heterogeneous disorder among children. Advances in next-generation sequencing have revealed that numerous epilepsy genes, helped us improve the understanding of mechanisms underlying epileptogenesis, and guided the development of treatments. We identified 39 candidate variants in 21 genes, including 37 that were pathogenic or likely pathogenic variants according to the American College of Medical Genetics and Genomics scoring system and two variants of uncertain significance that were considered causative after they were associated with clinical characteristics...
September 5, 2018: Clinical Genetics
https://read.qxmd.com/read/30093711/the-landscape-of-epilepsy-related-gator1-variants
#13
Sara Baldassari, Fabienne Picard, Nienke E Verbeek, Marjan van Kempen, Eva H Brilstra, Gaetan Lesca, Valerio Conti, Renzo Guerrini, Francesca Bisulli, Laura Licchetta, Tommaso Pippucci, Paolo Tinuper, Edouard Hirsch, Anne de Saint Martin, Jamel Chelly, Gabrielle Rudolf, Mathilde Chipaux, Sarah Ferrand-Sorbets, Georg Dorfmüller, Sanjay Sisodiya, Simona Balestrini, Natasha Schoeler, Laura Hernandez-Hernandez, S Krithika, Renske Oegema, Eveline Hagebeuk, Boudewijn Gunning, Charles Deckers, Bianca Berghuis, Ilse Wegner, Erik Niks, Floor E Jansen, Kees Braun, Daniëlle de Jong, Guido Rubboli, Inga Talvik, Valentin Sander, Peter Uldall, Marie-Line Jacquemont, Caroline Nava, Eric Leguern, Sophie Julia, Antonio Gambardella, Giuseppe d'Orsi, Giovanni Crichiutti, Laurence Faivre, Veronique Darmency, Barbora Benova, Pavel Krsek, Arnaud Biraben, Anne-Sophie Lebre, Mélanie Jennesson, Shifteh Sattar, Cécile Marchal, Douglas R Nordli, Kristin Lindstrom, Pasquale Striano, Lysa Boissé Lomax, Courtney Kiss, Fabrice Bartolomei, Anne Fabienne Lepine, An-Sofie Schoonjans, Katrien Stouffs, Anna Jansen, Eleni Panagiotakaki, Brigitte Ricard-Mousnier, Julien Thevenon, Julitta de Bellescize, Hélène Catenoix, Thomas Dorn, Martin Zenker, Karen Müller-Schlüter, Christian Brandt, Ilona Krey, Tilman Polster, Markus Wolff, Meral Balci, Kevin Rostasy, Guillaume Achaz, Pia Zacher, Thomas Becher, Thomas Cloppenborg, Christopher J Yuskaitis, Sarah Weckhuysen, Annapurna Poduri, Johannes R Lemke, Rikke S Møller, Stéphanie Baulac
PURPOSE: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. RESULTS: The GATOR1 seizure phenotype consisted mostly in focal seizures (e...
August 10, 2018: Genetics in Medicine: Official Journal of the American College of Medical Genetics
https://read.qxmd.com/read/30087333/tsc1-and-depdc5-regulate-hiv-1-latency-through-the-mtor-signaling-pathway
#14
Shan Jin, Qibin Liao, Jian Chen, Linxia Zhang, Qian He, Huanzhang Zhu, Xiaoyan Zhang, Jianqing Xu
The latent reservoir of HIV-1 presents a major barrier to viral eradication. The mechanism of the establishment and maintenance of the latent viral reservoir is not yet fully understood, which hinders the development of effective curative strategies. In this study, we identified two inhibitory genes, TSC1 and DEPDC5, that maintained HIV-1 latency by suppressing the mTORC1 pathway. We first adapted a genome-wide CRISPR screening approach to identify host factors required for HIV latency in a T-cell-based latency model and discovered two inhibitory genes, TSC1 and DEPDC5, which are potentially involved in HIV-1 latency...
August 8, 2018: Emerging Microbes & Infections
https://read.qxmd.com/read/30080265/somatic-depdc5-deletion-recapitulates-electroclinical-features-of-human-focal-cortical-dysplasia-type-iia
#15
Shuntong Hu, Robert C Knowlton, Brendon O Watson, Katarzyna M Glanowska, Geoffrey G Murphy, Jack M Parent, Yu Wang
Epileptogenic mechanisms in focal cortical dysplasia (FCD) remain elusive, as no animal models faithfully recapitulate FCD seizures, which have distinct electrographic features and a wide range of semiologies. Given that DEPDC5 plays significant roles in focal epilepsies with FCD, we used in utero electroporation with clustered regularly interspaced short palindromic repeats gene deletion to create focal somatic Depdc5 deletion in the rat embryonic brain. Animals developed spontaneous seizures with focal pathological and electroclinical features highly clinically relevant to FCD IIA, paving the way toward understanding its pathogenesis and developing mechanistic-based therapies...
July 2018: Annals of Neurology
https://read.qxmd.com/read/30034362/molecular-genetic-characterization-of-patients-with-focal-epilepsy-using-a-customized-targeted-resequencing-gene-panel
#16
Meng-Han Tsai, Chung-Kin Chan, Ying-Chao Chang, Chih-Hsiang Lin, Chia-Wei Liou, Wen-Neng Chang, Ching-Ching Ng, Kheng-Seang Lim, Daw-Yang Hwang
Objective: Focal epilepsy is the most common subtype of epilepsies in which the influence of underlying genetic factors is emerging but remains largely uncharacterized. The purpose of this study is to determine the contribution of currently known disease-causing genes in a large cohort ( n = 593) of common focal non-lesional epilepsy patients. Methods: The customized focal epilepsy gene panel (21 genes) was based on multiplex polymerase chain reaction (PCR) and sequenced by Illumina MiSeq platform. Results: Eleven variants (1...
2018: Frontiers in Neurology
https://read.qxmd.com/read/29950950/delving-deeper-into-depdc5
#17
COMMENT
Laura A Jansen
No abstract text is available yet for this article.
May 2018: Epilepsy Currents
https://read.qxmd.com/read/29861134/non-canonical-mtor-independent-role-of-depdc5-in-regulating-gabaergic-network-development
#18
Amrutha Swaminathan, Rahma Hassan-Abdi, Solène Renault, Aleksandra Siekierska, Raphaëlle Riché, Meijiang Liao, Peter A M de Witte, Constantin Yanicostas, Nadia Soussi-Yanicostas, Pierre Drapeau, Éric Samarut
Mutations in DEPDC5 are causal factors for a broad spectrum of focal epilepsies, but the underlying pathogenic mechanisms are still largely unknown. To address this question, a zebrafish depdc5 knockout model showing spontaneous epileptiform events in the brain, increased drug-induced seizure susceptibility, general hypoactivity, premature death at 2-3 weeks post-fertilization, as well as the expected hyperactivation of mTOR signaling was developed. Using this model, the role of DEPDC5 in brain development was investigated using an unbiased whole-transcriptomic approach...
June 18, 2018: Current Biology: CB
https://read.qxmd.com/read/29802162/klhl22-promotes-mtorc1-activation-and-breast-tumorigenesis
#19
(no author information available yet)
Amino acids promote CUL3-KLHL22-mediated DEPDC5 degradation to relieve mTORC1 inhibition.
July 2018: Cancer Discovery
https://read.qxmd.com/read/29769719/klhl22-activates-amino-acid-dependent-mtorc1-signalling-to-promote-tumorigenesis-and-ageing
#20
Jie Chen, Yuhui Ou, Yanyan Yang, Wen Li, Ye Xu, Yuntao Xie, Ying Liu
The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that responds to a diverse set of environmental cues, including amino acids1,2 . Deregulation of mTORC1 has been linked with metabolic diseases, cancer and ageing2-4 . In response to amino acids, mTORC1 is recruited by the Rag GTPases to the lysosome, its site of activation5,6 . The GATOR1 complex, consisting of DEPDC5, NPRL3 and NPRL2, displays GAP activity to inactivate Rag GTPases under amino-acid-deficient conditions 7 ...
May 2018: Nature
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