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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Novel treatments in epilepsy guided by genetic diagnosis
Carla Marini,Maria Giardino +1 more
TL;DR: The therapeutic implications following a specific genetic diagnosis and the correlation between genetic findings, pathophysiological mechanism and tailored seizure treatment emphasizing the impact on current clinical practice are discussed.
Journal ArticleDOI
Immunotherapy for GRIN2A and GRIN2D-related epileptic encephalopathy
TL;DR: Immunotherapy may lead to a clinical and electrographic improvement in patients with GRIN-related developmental-epileptic encephalopathies, and the potential role of autoimmunity in GRin-related disorders are needed.
Posted ContentDOI
NMDAR-mediated transcriptional control of gene expression in the specification of interneuron subtype identity
Vivek Mahadevan,Apratim Mitra,Yajun Zhang,Areg Peltekian,Ramesh Chittajallu,Caraoline Esnault,Dragan Maric,Christopher T. Rhodes,Kenneth A. Pelkey,Ryan K. Dale,Timothy J. Petros,Chris J. McBain +11 more
TL;DR: It is shown that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates subtype-specific transcriptional regulation of gene expression in MGE-derived interneurons, leading to altered subtype identities.
Journal ArticleDOI
Regulation of the NMDA receptor by its cytoplasmic domains: (How) is the tail wagging the dog?
TL;DR: In this paper, the carboxyl terminal domain (CTD) of N-methyl-d-aspartate receptors (NMDARs) has been studied and the authors discuss the many important functions of the CTD in regulating NMDA membrane and synaptic targeting, stabilization, degradation targeting, allosteric modulation and metabotropic signaling.
Dissertation
Next-generation sequencing analyses in human disease and population genomics
TL;DR: A novel method for ranking variants in the presence of phenotypic and genetic heterogeneity is introduced, and its diagnostic utility explored across syndromic CLP patients, as this thesis demonstrates many applications of NGS technology and highlights the common limitations involved in the analysis and interpretation of variants revealed from high throughput NGS analysis.
References
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