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Neurobiol Dis. 2014 Jul;67:88-96. doi: 10.1016/j.nbd.2014.02.001. Epub 2014 Feb 19.

Exonic microdeletions of the gephyrin gene impair GABAergic synaptic inhibition in patients with idiopathic generalized epilepsy.

Author information

1
Department of Chemistry, Institute of Biochemistry, University of Cologne, 50674 Cologne, Germany.
2
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.
3
Epilepsy Center, Department of Neurology, University of Munich, 81377 Munich, Germany.
4
Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; EPICURE Consortium.
5
Department of Epileptology, University Clinics Bonn, 53105 Bonn, Germany; EPICURE Consortium.
6
Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
7
Department of Neuropediatrics, University Medical Center Giessen and Marburg, 35392 Giessen, Germany.
8
EPICURE Consortium.
9
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.
10
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.
11
Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; EPICURE Consortium. Electronic address: thomas.sander@uni-koeln.de.

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.

KEYWORDS:

GPHN; Gephyrin; Idiopathic generalized epilepsy; Microdeletion

PMID:
24561070
DOI:
10.1016/j.nbd.2014.02.001
[Indexed for MEDLINE]

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