• Borislav Dejanovic, Dennis Lal, Claudia B Catarino, Sita Arjune, Abdel A Belaidi, Holger Trucks, Christian Vollmar, Rainer Surges, Wolfram S Kunz, Susanne Motameny, Janine Altmüller, Anna Köhler, Bernd A Neubauer, Epicure Consortium EPICURE Consortium., Peter Nürnberg, Soheyl Noachtar, Günter Schwarz, and Thomas Sander.
• Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 Cologne, Germany.
• Neurobiol. Dis. 2014 Jul 1; 67: 88-96.

AbstractGephyrin 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.Copyright © 2014. Published by Elsevier Inc.

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