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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
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
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
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
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
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
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
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
Laura A Jansen
No abstract text is available yet for this article.
May 2018: Epilepsy Currents
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
(no author information available yet)
Amino acids promote CUL3-KLHL22-mediated DEPDC5 degradation to relieve mTORC1 inhibition.
July 2018: Cancer Discovery
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
Paul A Dutchak, Sandi J Estill-Terpack, Abigail A Plec, Xiaozheng Zhao, Chendong Yang, Jun Chen, Bookyung Ko, Ralph J Deberardinis, Yonghao Yu, Benjamin P Tu
The conserved GATOR1 complex consisting of NPRL2-NPRL3-DEPDC5 inhibits mammalian target of rapamycin complex 1 (mTORC1) in response to amino acid insufficiency. Here, we show that loss of NPRL2 and GATOR1 function in skeletal muscle causes constitutive activation of mTORC1 signaling in the fed and fasted states. Muscle fibers of NPRL2 knockout animals are significantly larger and show altered fiber-type composition, with more fast-twitch glycolytic and fewer slow-twitch oxidative fibers. NPRL2 muscle knockout mice also have altered running behavior and enhanced glucose tolerance...
May 15, 2018: Cell Reports
Hortense de Calbiac, Adriana Dabacan, Elise Marsan, Hervé Tostivint, Gabrielle Devienne, Saeko Ishida, Eric Leguern, Stéphanie Baulac, Raul C Muresan, Edor Kabashi, Sorana Ciura
Objective: DEPDC5 was identified as a major genetic cause of focal epilepsy with deleterious mutations found in a wide range of inherited forms of focal epilepsy, associated with malformation of cortical development in certain cases. Identification of frameshift, truncation, and deletion mutations implicates haploinsufficiency of DEPDC5 in the etiology of focal epilepsy. DEPDC5 is a component of the GATOR1 complex, acting as a negative regulator of mTOR signaling. Methods: Zebrafish represents a vertebrate model suitable for genetic analysis and drug screening in epilepsy-related disorders...
May 2018: Annals of Clinical and Translational Neurology
Matthew P Anderson
Loss-of-function mutations in a single allele of the gene encoding DEP domain-containing 5 protein (DEPDC5) are commonly linked to familial focal epilepsy with variable foci; however, a subset of patients presents with focal cortical dysplasia that is proposed to result from a second-hit somatic mutation. In this issue of the JCI, Ribierre and colleagues provide several lines of evidence to support second-hit DEPDC5 mutations in this disorder. Moreover, the authors use in vivo, in utero electroporation combined with CRISPR-Cas9 technology to generate a murine model of the disease that recapitulates human manifestations, including cortical dysplasia-like changes, focal seizures, and sudden unexpected death...
June 1, 2018: Journal of Clinical Investigation
Théo Ribierre, Charlotte Deleuze, Alexandre Bacq, Sara Baldassari, Elise Marsan, Mathilde Chipaux, Giuseppe Muraca, Delphine Roussel, Vincent Navarro, Eric Leguern, Richard Miles, Stéphanie Baulac
DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia...
June 1, 2018: Journal of Clinical Investigation
(no author information available yet)
A Rag GTPases-DEPDC5 inhibitory interaction mode suppresses GATOR1 GAP activity.
June 2018: Cancer Discovery
Kuang Shen, Rick K Huang, Edward J Brignole, Kendall J Condon, Max L Valenstein, Lynne Chantranupong, Aimaiti Bomaliyamu, Abigail Choe, Chuan Hong, Zhiheng Yu, David M Sabatini
Nutrients, such as amino acids and glucose, signal through the Rag GTPases to activate mTORC1. The GATOR1 protein complex-comprising DEPDC5, NPRL2 and NPRL3-regulates the Rag GTPases as a GTPase-activating protein (GAP) for RAGA; loss of GATOR1 desensitizes mTORC1 signalling to nutrient starvation. GATOR1 components have no sequence homology to other proteins, so the function of GATOR1 at the molecular level is currently unknown. Here we used cryo-electron microscopy to solve structures of GATOR1 and GATOR1-Rag GTPases complexes...
April 5, 2018: Nature
Maria Stella Vari, Monica Traverso, Tommaso Bellini, Francesca Madia, Francesca Pinto, Pasquale Striano, Carlo Minetti, Federico Zara
The Publisher regrets that this article is an accidental duplication of an article that has already been published in Seizure 50 (2017) 80-82, The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at
April 2018: Seizure: the Journal of the British Epilepsy Association
Somak Roy, William A LaFramboise, Ta-Chiang Liu, Dengfeng Cao, Alyssa Luvison, Caitlyn Miller, Maureen A Lyons, Roderick J O'Sullivan, Amer H Zureikat, Melissa E Hogg, Allan Tsung, Kenneth K Lee, Nathan Bahary, Randall E Brand, Jennifer S Chennat, Kenneth E Fasanella, Kevin McGrath, Marina N Nikiforova, Georgios I Papachristou, Adam Slivka, Herbert J Zeh, Aatur D Singhi
Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed...
June 2018: Gastroenterology
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