title: Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy.
abstract: Gephyrin is a postsynaptic scaffolding protein, essential for the clustering of glycine and γ-aminobutyric acid type-A receptors (GABAARs) at inhibitory synapses. An impairment of GABAergic synaptic inhibition represents a key pathway of epileptogenesis. Recently, exonic microdeletions in the gephyrin (GPHN) gene have been associated with neurodevelopmental disorders including autism spectrum disorder, schizophrenia and epileptic seizures. Here we report the identification of novel exonic GPHN microdeletions in two patients with idiopathic generalized epilepsy (IGE), representing the most common group of genetically determined epilepsies. The identified GPHN microdeletions involve exons 5-9 (Δ5-9) and 2-3 (Δ2-3), both affecting the gephyrin G-domain. Molecular characterization of the GPHN Δ5-9 variant demonstrated that it perturbs the clustering of regular gephyrin at inhibitory synapses in cultured mouse hippocampal neurons in a dominant-negative manner, resulting in a significant loss of γ2-subunit containing GABAARs. GPHN Δ2-3 causes a frameshift resulting in a premature stop codon (p.V22Gfs*7) leading to haplo-insufficiency of the gene. Our results demonstrate that structural exonic microdeletions affecting the GPHN gene constitute a rare genetic risk factor for IGE and other neuropsychiatric disorders by an impairment of the GABAergic inhibitory synaptic transmission.
authors.affiliation: Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 Cologne, Germany.
authors.forename: Borislav
authors.initials: B
authors.lastname: Dejanovic
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany; Department of Neuropediatrics, University Medical Center Giessen and Marburg, 35392 Giessen, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Lal
authors.affiliation: Epilepsy Center, Department of Neurology, University of Munich, 81377 Munich, Germany.
authors.forename: Claudia B
authors.initials: CB
authors.lastname: Catarino
authors.affiliation: Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 Cologne, Germany.
authors.forename: Sita
authors.initials: S
authors.lastname: Arjune
authors.affiliation: Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 Cologne, Germany.
authors.forename: Abdel A
authors.initials: AA
authors.lastname: Belaidi
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; EPICURE Consortium.
authors.forename: Holger
authors.initials: H
authors.lastname: Trucks
authors.affiliation: Epilepsy Center, Department of Neurology, University of Munich, 81377 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Vollmar
authors.affiliation: Department of Epileptology, University Clinics Bonn, 53105 Bonn, Germany; EPICURE Consortium.
authors.forename: Rainer
authors.initials: R
authors.lastname: Surges
authors.affiliation: Department of Epileptology, University Clinics Bonn, 53105 Bonn, Germany; EPICURE Consortium.
authors.forename: Wolfram S
authors.initials: WS
authors.lastname: Kunz
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Motameny
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 Cologne, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Köhler
authors.affiliation: Department of Neuropediatrics, University Medical Center Giessen and Marburg, 35392 Giessen, Germany.
authors.forename: Bernd A
authors.initials: BA
authors.lastname: Neubauer
authors.affiliation: EPICURE Consortium.
authors.lastname: Epicure Consortium
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany; EPICURE Consortium.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Epilepsy Center, Department of Neurology, University of Munich, 81377 Munich, Germany.
authors.forename: Soheyl
authors.initials: S
authors.lastname: Noachtar
authors.affiliation: Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50674 Cologne, Germany; Center for Molecular Medicine (CMMC), University of Cologne, 50931 Cologne, Germany. Electronic address: gschwarz@uni-koeln.de.
authors.forename: Günter
authors.initials: G
authors.lastname: Schwarz
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; EPICURE Consortium. Electronic address: thomas.sander@uni-koeln.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sander
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D004829:Epilepsy, Generalized / Q000235:genetics*; D005091:Exons / Q000235:genetics*; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D017384:Sequence Deletion; D013569:Synapses / Q000378:metabolism*; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C073441:gephyrin
keywords: GPHN; Gephyrin; Idiopathic generalized epilepsy; Microdeletion