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SYNGAP1

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https://www.readbyqxmd.com/read/29886190/impact-of-diet-induced-obesity-on-the-mouse-brain-phosphoproteome
#1
Valentina Siino, Antonella Amato, Francesca Di Salvo, Gaetano Felice Caldara, Marcello Filogamo, Peter James, Sonya Vasto
Obesity is closely associated to several diseases such as type 2 diabetes, cardiovascular disease, hepatic steatosis, airway disease, neurodegeneration, biliary diseases and certain cancers. It is, therefore, of importance to assess the role of nutrition in disease prevention as well as its effect in the course of such pathologies. In the present study, we addressed the impact of the exposure to different obesogenic diets in the mice brains phosphoproteome. To analyze if the obesity could be able to modify the protein pattern expression of brain neurons, obesity was induced in two different groups of mice...
May 1, 2018: Journal of Nutritional Biochemistry
https://www.readbyqxmd.com/read/29852413/diagnostic-yield-of-targeted-massively-parallel-sequencing-in-children-with-epileptic-encephalopathy
#2
Kavitha Kothur, Katherine Holman, Elizabeth Farnsworth, Gladys Ho, Michelle Lorentzos, Christopher Troedson, Sachin Gupta, Richard Webster, Peter G Procopis, Manoj P Menezes, Jayne Antony, Simone Ardern-Holmes, Russell C Dale, John Christodoulou, Deepak Gill, Bruce Bennetts
PURPOSE: To report our institutional experience of targeted massively parallel sequencing (MPS) testing in children with epilepsy. METHOD: We retrospectively analysed the yield of targeted epileptic encephalopathy (EE) panel of 71 known EE genes in patients with epilepsy of unknown cause, who underwent clinical triage by a group of neurologists prior to the testing. We compared cost of the EE panel approach compared to traditional evaluation in patients with identified pathogenic variants...
May 28, 2018: Seizure: the Journal of the British Epilepsy Association
https://www.readbyqxmd.com/read/29774215/importance-of-functional-loss-of-fus-in-ftld-als
#3
REVIEW
Shinsuke Ishigaki, Gen Sobue
Fused in sarcoma (FUS) is an RNA binding protein that regulates RNA metabolism including alternative splicing, transcription, and RNA transportation. FUS is genetically and pathologically involved in frontotemporal lobar degeneration (FTLD)/amyotrophic lateral sclerosis (ALS). Multiple lines of evidence across diverse models suggest that functional loss of FUS can lead to neuronal dysfunction and/or neuronal cell death. Loss of FUS in the nucleus can impair alternative splicing and/or transcription, whereas dysfunction of FUS in the cytoplasm, especially in the dendritic spines of neurons, can cause mRNA destabilization...
2018: Frontiers in Molecular Biosciences
https://www.readbyqxmd.com/read/29760947/incorporating-epilepsy-genetics-into-clinical-practice-a-360%C3%A2-evaluation
#4
Stephanie Oates, Shan Tang, Richard Rosch, Rosalie Lear, Elaine F Hughes, Ruth E Williams, Line H G Larsen, Qin Hao, Hans Atli Dahl, Rikke S Møller, Deb K Pal
We evaluated a new epilepsy genetic diagnostic and counseling service covering a UK population of 3.5 million. We calculated diagnostic yield, estimated clinical impact, and surveyed referring clinicians and families. We costed alternative investigational pathways for neonatal onset epilepsy. Patients with epilepsy of unknown aetiology onset < 2 years; treatment resistant epilepsy; or familial epilepsy were referred for counseling and testing. We developed NGS panels, performing clinical interpretation with a multidisciplinary team...
2018: NPJ Genomic Medicine
https://www.readbyqxmd.com/read/29580901/species-conserved-syngap1-phenotypes-associated-with-neurodevelopmental-disorders
#5
REVIEW
Murat Kilinc, Thomas Creson, Camilo Rojas, Massimiliano Aceti, Jacob Ellegood, Thomas Vaissiere, Jason P Lerch, Gavin Rumbaugh
SYNGAP1 loss-of-function variants are causally associated with intellectual disability, severe epilepsy, autism spectrum disorder and schizophrenia. While there are hundreds of genetic risk factors for neurodevelopmental disorders (NDDs), this gene is somewhat unique because of the frequency and penetrance of loss-of-function variants found in patients combined with the range of brain disorders associated with SYNGAP1 pathogenicity. These clinical findings indicate that SYNGAP1 regulates fundamental neurodevelopmental processes that are necessary for brain development...
March 24, 2018: Molecular and Cellular Neurosciences
https://www.readbyqxmd.com/read/29402231/the-first-international-conference-on-syngap1-related-brain-disorders-a-stakeholder-meeting-of-families-researchers-clinicians-and-regulators
#6
REVIEW
Monica Weldon, Murat Kilinc, J Lloyd Holder, Gavin Rumbaugh
BACKGROUND: Pathologic mutations in SYNGAP1 cause a genetically defined form of intellectual disability (ID) with comorbid epilepsy and autistic features. While only recently discovered, pathogenicity of this gene is a relatively frequent genetic cause of classically undefined developmental delay that progresses to ID with commonly occurring comorbidities. MAIN BODY: A meeting of 150 people was held that included affected individuals and their caregivers, clinicians that treat this and related brain disorders, neuroscientists that study SYNGAP1 biology or the function of related genes, and representatives from government agencies that fund science and approve new medical treatments...
February 5, 2018: Journal of Neurodevelopmental Disorders
https://www.readbyqxmd.com/read/29391390/ulk4-regulates-gabaergic-signaling-and-anxiety-related-behavior
#7
Min Liu, Marie Fitzgibbon, Yanqin Wang, Jamie Reilly, Xiaohong Qian, Timothy O'Brien, Steve Clapcote, Sanbing Shen, Michelle Roche
Excitation/inhibition imbalance has been proposed as a fundamental mechanism in the pathogenesis of neuropsychiatric and neurodevelopmental disorders, in which copy number variations of the Unc-51 like kinase 4 (ULK4) gene encoding a putative Serine/Threonine kinase have been reported in approximately 1/1000 of patients suffering pleiotropic clinical conditions of schizophrenia, depression, autistic spectrum disorder (ASD), developmental delay, language delay, intellectual disability, or behavioral disorder...
February 2, 2018: Translational Psychiatry
https://www.readbyqxmd.com/read/29390993/efficient-strategy-for-the-molecular-diagnosis-of-intractable-early-onset-epilepsy-using-targeted-gene-sequencing
#8
John Hoon Rim, Se Hee Kim, In Sik Hwang, Soon Sung Kwon, Jieun Kim, Hyun Woo Kim, Min Jung Cho, Ara Ko, Song Ee Youn, Jihun Kim, Young Mock Lee, Hee Jung Chung, Joon Soo Lee, Heung Dong Kim, Jong Rak Choi, Seung-Tae Lee, Hoon-Chul Kang
BACKGROUND: We intended to evaluate diagnostic utility of a targeted gene sequencing by using next generation sequencing (NGS) panel in patients with intractable early-onset epilepsy (EOE) and find the efficient analytical step for increasing the diagnosis rate. METHODS: We assessed 74 patients with EOE whose seizures started before 3 years of age using a customized NGS panel that included 172 genes. Single nucleotide variants (SNVs) and exonic and chromosomal copy number variations (CNVs) were intensively examined with our customized pipeline and crosschecked with commercial or pre-built software...
February 1, 2018: BMC Medical Genomics
https://www.readbyqxmd.com/read/29381230/novel-syngap1-variant-in-a-patient-with-intellectual-disability-and-distinctive-dysmorphisms
#9
Yuichi Kimura, Moe Akahira-Azuma, Noriaki Harada, Yumi Enomoto, Yoshinori Tsurusaki, Kenji Kurosawa
We describe a novel de novo heterozygous variant in SYNGAP1 (c.1741C>T, p.R581W), identified through targeted resequencing in an 8-year-old boy with intellectual disability, autism spectrum disorder, distinctive dysmorphic features, and no seizures. Our data strongly suggest that the SYNGAP1 variant is causative of intellectual disability in this patient.
January 30, 2018: Congenital Anomalies
https://www.readbyqxmd.com/read/29190809/molecular-diagnosis-of-patients-with-epilepsy-and-developmental-delay-using-a-customized-panel-of-epilepsy-genes
#10
Laura Ortega-Moreno, Beatriz G Giráldez, Victor Soto-Insuga, Rebeca Losada-Del Pozo, María Rodrigo-Moreno, Cristina Alarcón-Morcillo, Gema Sánchez-Martín, Esther Díaz-Gómez, Rosa Guerrero-López, José M Serratosa
Pediatric epilepsies are a group of disorders with a broad phenotypic spectrum that are associated with great genetic heterogeneity, thus making sequential single-gene testing an impractical basis for diagnostic strategy. The advent of next-generation sequencing has increased the success rate of epilepsy diagnosis, and targeted resequencing using genetic panels is the a most cost-effective choice. We report the results found in a group of 87 patients with epilepsy and developmental delay using targeted next generation sequencing (custom-designed Haloplex panel)...
2017: PloS One
https://www.readbyqxmd.com/read/28883427/tau-exacerbates-excitotoxic-brain-damage-in-an-animal-model-of-stroke
#11
Mian Bi, Amadeus Gladbach, Janet van Eersel, Arne Ittner, Magdalena Przybyla, Annika van Hummel, Sook Wern Chua, Julia van der Hoven, Wei S Lee, Julius Müller, Jasneet Parmar, Georg von Jonquieres, Holly Stefen, Ernesto Guccione, Thomas Fath, Gary D Housley, Matthias Klugmann, Yazi D Ke, Lars M Ittner
Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau-/- ) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau...
September 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28867142/exonic-mosaic-mutations-contribute-risk-for-autism-spectrum-disorder
#12
Deidre R Krupp, Rebecca A Barnard, Yannis Duffourd, Sara A Evans, Ryan M Mulqueen, Raphael Bernier, Jean-Baptiste Rivière, Eric Fombonne, Brian J O'Roak
Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Initial re-evaluation of published single-nucleotide variant (SNV) de novo mutations showed evidence consistent with putative PMMs for 11% of mutations...
September 7, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28721930/pharmacoresistant-epileptic-eyelid-twitching-in-a-child-with-a-mutation-in-syngap1
#13
Tetsuya Okazaki, Yoshiaki Saito, Rika Hiraiwa, Shinji Saitoh, Masachika Kai, Kaori Adachi, Yoko Nishimura, Eiji Nanba, Yoshihiro Maegaki
SYNGAP1 gene mutation has been associated with epilepsy which is often drug resistant, with seizure types including eyelid myoclonia. However, detailed descriptions, including ictal video-EEG, have not been reported. We report the case of a 4-year-old boy who developed recurrent epileptic eyelid twitching at 1 year and 5 months of age. Seizures gradually increased in frequency to more than 50 times per day and manifested with upward eye deviation, motion arrest, loss of consciousness, and eyelid twitching lasting for five seconds...
September 1, 2017: Epileptic Disorders: International Epilepsy Journal with Videotape
https://www.readbyqxmd.com/read/28706196/synaptic-gap-and-gef-complexes-cluster-proteins-essential-for-gtp-signaling
#14
Brent Wilkinson, Jing Li, Marcelo P Coba
GTPase-activating proteins (GAPs) and guanine exchange factors (GEFs) play essential roles in regulating the activity of small GTPases. Several GAPs and GEFs have been shown to be present at the postsynaptic density (PSD) within excitatory glutamatergic neurons and regulate the activity of glutamate receptors. However, it is not known how synaptic GAP and GEF proteins are organized within the PSD signaling machinery, if they have overlapping interaction networks, or if they associate with proteins implicated in contributing to psychiatric disease...
July 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28584888/autism-spectrum-disorder-neuropathology-and-animal-models
#15
REVIEW
Merina Varghese, Neha Keshav, Sarah Jacot-Descombes, Tahia Warda, Bridget Wicinski, Dara L Dickstein, Hala Harony-Nicolas, Silvia De Rubeis, Elodie Drapeau, Joseph D Buxbaum, Patrick R Hof
Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations, and significance of each...
October 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28576131/analysis-of-31-year-old-patient-with-syngap1-gene-defect-points-to-importance-of-variants-in-broader-splice-regions-and-reveals-developmental-trajectory-of-syngap1-associated-phenotype-case-report
#16
Darina Prchalova, Marketa Havlovicova, Katalin Sterbova, Viktor Stranecky, Miroslava Hancarova, Zdenek Sedlacek
BACKGROUND: Whole exome sequencing is a powerful tool for the analysis of genetically heterogeneous conditions. The prioritization of variants identified often focuses on nonsense, frameshift and canonical splice site mutations, and highly deleterious missense variants, although other defects can also play a role. The definition of the phenotype range and course of rare genetic conditions requires long-term clinical follow-up of patients. CASE PRESENTATION: We report an adult female patient with severe intellectual disability, severe speech delay, epilepsy, autistic features, aggressiveness, sleep problems, broad-based clumsy gait and constipation...
June 2, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28524815/anchoring-high-concentrations-of-syngap-at-postsynaptic-densities-via-liquid-liquid-phase-separation
#17
Menglong Zeng, Guanhua Bai, Mingjie Zhang
SynGAP, encoded by SYNGAP1, is a Ras/Rap GTPase activator specifically expressed in the nervous systems. SynGAP is one of the most abundant proteins in the postsynaptic densities (PSDs) of excitatory synapses and acts as a critical synaptic activity brake by tuning down synaptic GTPase activities. Mutations of SYNGAP1 have been frequently linked to brain disorders including intellectual disability, autisms, and seizure. SynGAP has been shown to undergo fast dispersions from synapses in response to stimulations, a strategy that neurons use to control the specific activities of the enzyme within the tiny, semi-open compartments in dendritic spines...
May 19, 2017: Small GTPases
https://www.readbyqxmd.com/read/27942422/expansion-of-the-rasopathies
#18
William E Tidyman, Katherine A Rauen
The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of cell cycle, differentiation, growth, cell senescence and apoptosis, all of which are critical to normal development. A class of neurodevelopmental disorders, RASopathies, is caused by germline mutations in genes of the Ras/MAPK pathway. Through the use of whole exome sequencing and targeted sequencing of selected genes in cohorts of panel-negative RASopathy patients, several new genes have been identified. These include: RIT1, SOS2, RASA2, RRAS and SYNGAP1, that likely represent new, albeit rare, causative RASopathy genes...
September 2016: Current Genetic Medicine Reports
https://www.readbyqxmd.com/read/27897003/de-novo-mutations-in-autism-implicate-the-synaptic-elimination-network
#19
Guhan Ram Venkataraman, Chloe O'Connell, Fumiko Egawa, Dorna Kashef-Haghighi, Dennis P Wall
Autism has been shown to have a major genetic risk component; the architecture of documented autism in families has been over and again shown to be passed down for generations. While inherited risk plays an important role in the autistic nature of children, de novo (germline) mutations have also been implicated in autism risk. Here we find that autism de novo variants verified and published in the literature are Bonferroni-significantly enriched in a gene set implicated in synaptic elimination. Additionally, several of the genes in this synaptic elimination set that were enriched in protein-protein interactions (CACNA1C, SHANK2, SYNGAP1, NLGN3, NRXN1, and PTEN) have been previously confirmed as genes that confer risk for the disorder...
2017: Pacific Symposium on Biocomputing
https://www.readbyqxmd.com/read/27827368/decrease-of-syngap1-in-gabaergic-cells-impairs-inhibitory-synapse-connectivity-synaptic-inhibition-and-cognitive-function
#20
Martin H Berryer, Bidisha Chattopadhyaya, Paul Xing, Ilse Riebe, Ciprian Bosoi, Nathalie Sanon, Judith Antoine-Bertrand, Maxime Lévesque, Massimo Avoli, Fadi F Hamdan, Lionel Carmant, Nathalie Lamarche-Vane, Jean-Claude Lacaille, Jacques L Michaud, Graziella Di Cristo
Haploinsufficiency of the SYNGAP1 gene, which codes for a Ras GTPase-activating protein, impairs cognition both in humans and in mice. Decrease of Syngap1 in mice has been previously shown to cause cognitive deficits at least in part by inducing alterations in glutamatergic neurotransmission and premature maturation of excitatory connections. Whether Syngap1 plays a role in the development of cortical GABAergic connectivity and function remains unclear. Here, we show that Syngap1 haploinsufficiency significantly reduces the formation of perisomatic innervations by parvalbumin-positive basket cells, a major population of GABAergic neurons, in a cell-autonomous manner...
November 9, 2016: Nature Communications
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