Journal ArticleDOI
Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes
Johannes R. Lemke,Dennis Lal,Eva M. Reinthaler,Isabelle Steiner,Michael Nothnagel,Michael Alber,Kirsten Geider,Bodo Laube,Michael Schwake,Katrin Finsterwalder,Andre Franke,Markus Schilhabel,Johanna A. Jähn,Hiltrud Muhle,Rainer Boor,Wim Van Paesschen,Roberto Caraballo,Natalio Fejerman,Sarah Weckhuysen,Peter De Jonghe,Jan Larsen,Rikke S. Møller,Helle Hjalgrim,Laura Addis,Shan Tang,Elaine Hughes,Deb K. Pal,Kadi Veri,Ulvi Vaher,Tiina Talvik,Petia Dimova,Rosa Guerrero López,José M. Serratosa,Tarja Linnankivi,Anna-Elina Lehesjoki,Susanne Ruf,Markus Wolff,Sarah E. Buerki,Gabriele Wohlrab,Judith Kroell,Alexandre N. Datta,Barbara Fiedler,Gerhard Kurlemann,Gerhard Kluger,Andreas Hahn,D Edda Haberlandt,Christina Kutzer,Jürgen Sperner,Felicitas Becker,Yvonne G. Weber,Martha Feucht,Hannelore Steinböck,Birgit Neophythou,Gabriel M. Ronen,Ursula Gruber-Sedlmayr,Julia Geldner,Robert J. Harvey,Per Hoffmann,Per Hoffmann,Stefan Herms,Stefan Herms,Janine Altmüller,Mohammad R. Toliat,Holger Thiele,Peter Nürnberg,Christian Wilhelm,Ulrich Stephani,Ingo Helbig,Holger Lerche,Fritz Zimprich,Bernd A. Neubauer,Saskia Biskup,Saskia Biskup,Sarah von Spiczak +73 more
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TLDR
Results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.Abstract:
Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fisher's exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fisher's exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.read more
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Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.
Kasper B. Hansen,Lonnie P. Wollmuth,Derek Bowie,Hiro Furukawa,Frank S. Menniti,Alexander I. Sobolevsky,Geoffrey T. Swanson,Sharon A. Swanger,Ingo H. Greger,Terunaga Nakagawa,Chris J. McBain,Vasanthi Jayaraman,Chian-Ming Low,Mark L. Dell’Acqua,Jeffrey S. Diamond,Chad R. Camp,Riley E. Perszyk,Hongjie Yuan,Stephen F. Traynelis +18 more
TL;DR: In this paper, the authors review insights from more than 3 decades of iGluR studies with an emphasis on the progress that has occurred in the past decade, covering structure, function, pharmacology, roles in neurophysiology, and therapeutic implications for all classes of receptors assembled from the subunits encoded by the 18 ionotropic glutamate receptor genes.
Journal ArticleDOI
International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions
Nicola Specchio,Elaine C. Wirrell,Ingrid E. Scheffer,Rima Nabbout,Kate Riney,Pauline Samia,Marilisa M. Guerreiro,Sam Gwer,Sameer M. Zuberi,Jo M. Wilmshurst,Elissa G. Yozawitz,Ronit M. Pressler,E. C. Hirsch,Samuel Wiebe,JH Cross,Emilio Perucca,Solomon L. Moshé,Paolo Tinuper,Stéphane Auvin +18 more
TL;DR: The childhood onset epilepsy syndromes are described, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations.
Journal ArticleDOI
Delineating the GRIN1 phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy
Johannes R. Lemke,Kirsten Geider,Katherine L. Helbig,Henrike O. Heyne,Hannah Schütz,Julia Hentschel,Carolina Courage,Christel Depienne,Caroline Nava,Delphine Héron,Rikke S. Møller,Helle Hjalgrim,Dennis Lal,Bernd A. Neubauer,Peter Nürnberg,Holger Thiele,Gerhard Kurlemann,Georgianne L. Arnold,Vikas Bhambhani,Deborah Bartholdi,Christeen Ramane J. Pedurupillay,Doriana Misceo,Eirik Frengen,Petter Strømme,Dennis J. Dlugos,Emily S. Doherty,Emilia K. Bijlsma,Claudia A. L. Ruivenkamp,Mariëtte J.V. Hoffer,Amy Goldstein,Deepa S. Rajan,Vinodh Narayanan,Keri Ramsey,Newell Belnap,Isabelle Schrauwen,Ryan Richholt,Bobby P. C. Koeleman,Joaquim Sa,Carla Mendonça,Carolien G.F. de Kovel,Sarah Weckhuysen,Katia Hardies,Peter De Jonghe,Linda De Meirleir,Mathieu Milh,Catherine Badens,Marine Lebrun,Tiffany Busa,Christine Francannet,Amélie Piton,Erik Riesch,Saskia Biskup,Heinrich Vogt,Thomas Dorn,Ingo Helbig,Jacques L. Michaud,Bodo Laube,Steffen Syrbe +57 more
TL;DR: De novo GRIN1 mutations are associated with severe intellectual disability with cortical visual impairment as well as oculomotor and movement disorders being discriminating phenotypic features.
Journal ArticleDOI
Positive Allosteric Modulators of GluN2A-Containing NMDARs with Distinct Modes of Action and Impacts on Circuit Function
David H. Hackos,Patrick J. Lupardus,Teddy Grand,Yelin Chen,Tzu-Ming Wang,Paul Reynen,Amy Gustafson,Heidi J.A. Wallweber,Matthew Volgraf,Benjamin D. Sellers,Jacob Schwarz,Pierre Paoletti,Morgan Sheng,Qiang Zhou,Jesse E. Hanson +14 more
TL;DR: The identification of a new NMDAR modulatory site and characterization of GluN2A-selective PAMs provide powerful molecular tools to dissect N MDAR function and demonstrate the feasibility of a therapeutically desirable type of NMD AR enhancement.
Journal ArticleDOI
Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains
Sharon A. Swanger,Wenjuan Chen,Gordon Wells,Pieter B. Burger,Anel Tankovic,Subhrajit Bhattacharya,Katie L. Strong,Chun Hu,Hirofumi Kusumoto,Jing Zhang,David R. Adams,John Millichap,Slavé Petrovski,Stephen F. Traynelis,Hongjie Yuan +14 more
TL;DR: Assessing genetic variation across GluN2 domains determined that the agonist binding domain, transmembrane domain, and the linker regions between these domains were particularly intolerant to functional variation, which allowed investigations of pharmacologic strategies to correct NMDAR function to be investigated.
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