Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Dejanovic, Boris Lav UNSPECIFIED UNSPECIFIED UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Catarino, Claudia B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Arjune, Sita UNSPECIFIED UNSPECIFIED UNSPECIFIED Belaidi, Abdel A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Trucks, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Vollmar, Christian UNSPECIFIED orcid.org/0000-0002-4630-7484 UNSPECIFIED Surges, Rainer UNSPECIFIED orcid.org/0000-0002-3177-8582 UNSPECIFIED Kunz, Wolfram S. UNSPECIFIED orcid.org/0000-0003-1113-3493 UNSPECIFIED Motameny, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, Janine UNSPECIFIED UNSPECIFIED UNSPECIFIED Koehler, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Neubauer, Bernd A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Noachtar, Soheyl UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Gunter UNSPECIFIED UNSPECIFIED UNSPECIFIED Sander, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Keywords Language 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-REGULATION Multiple languages Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43542