Dejanovic, Boris Lav, Lal, Dennis, Catarino, Claudia B., Arjune, Sita, Belaidi, Abdel A., Trucks, Holger, Vollmar, Christian ORCID: 0000-0002-4630-7484, Surges, Rainer ORCID: 0000-0002-3177-8582, Kunz, Wolfram S. ORCID: 0000-0003-1113-3493, Motameny, Susanne, Altmueller, Janine, Koehler, Anna, Neubauer, Bernd A., Nuernberg, Peter, Noachtar, Soheyl, Schwarz, Gunter and Sander, Thomas (2014). Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy. Neurobiol. Dis., 67. S. 88 - 97. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1095-953X

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Abstract

Gephyrin is a postsynaptic scaffolding protein, essential for the clustering of glycine and gamma-aminobutyric acid type-A receptors (GABA(A)Rs) 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 (ICE), representing the most common group of genetically determined epilepsies. The identified GPHN microdeletions involve exons 5-9 (Delta 5-9) and 2-3 (Delta 2-3), both affecting the gephyrin G-domain. Molecular characterization of the GPHN Delta 5-9 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 gamma(2)-subunit containing GABAARs. GPHN Delta 2-3 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. (C) 2014 Published by Elsevier Inc.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dejanovic, Boris LavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Catarino, Claudia B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arjune, SitaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Belaidi, Abdel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trucks, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vollmar, ChristianUNSPECIFIEDorcid.org/0000-0002-4630-7484UNSPECIFIED
Surges, RainerUNSPECIFIEDorcid.org/0000-0002-3177-8582UNSPECIFIED
Kunz, Wolfram S.UNSPECIFIEDorcid.org/0000-0003-1113-3493UNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koehler, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neubauer, Bernd A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noachtar, SoheylUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schwarz, GunterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-435425
DOI: 10.1016/j.nbd.2014.02.001
Journal or Publication Title: Neurobiol. Dis.
Volume: 67
Page Range: S. 88 - 97
Date: 2014
Publisher: ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication: SAN DIEGO
ISSN: 1095-953X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MOLYBDENUM COFACTOR DEFICIENCY; TRANSCRANIAL MAGNETIC STIMULATION; CLUSTERING PROTEIN GEPHYRIN; MOTOR CORTEX EXCITABILITY; GABA(A) RECEPTOR SUBTYPES; DIRECT BINDING; NEURODEVELOPMENTAL DISEASE; 16P13.11 PREDISPOSE; GAMMA-2 SUBUNIT; DOWN-REGULATIONMultiple languages
NeurosciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/43542

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