Universität zu Köln

Macha, Arthur, Liebsch, Filip ORCID: 0000-0002-0955-8065, Fricke, Steffen, Hetsch, Florian, Neuser, Franziska, Johannes, Lena, Kress, Vanessa, Djemie, Tania, Santamaria-Araujo, Jose A., Vilain, Catheline, Aeby, Alec, Van Bogaert, Patrick, Dejanovic, Borislav, Weckhuysen, Sarah ORCID: 0000-0003-2878-1147, Meier, Jochen C. and Schwarz, Guenter (2022). Biallelic gephyrin variants lead to impaired GABAergic inhibition in a patient with developmental and epileptic encephalopathy. Hum. Mol. Genet., 31 (6). S. 901 - 914. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2083

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Abstract

Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition is linked to epilepsy. Gephyrin (Geph) is the principal scaffolding protein at inhibitory synapses and is essential for postsynaptic clustering of glycine (GlyRs) and GABA type A receptors. Consequently, gephyrin is crucial for maintaining the relationship between excitation and inhibition in normal brain function and mutations in the gephyrin gene (GPHN) are associated with neurodevelopmental disorders and epilepsy. We identified bi-allelic variants in the GPHN gene, namely the missense mutation c.1264G > A and splice acceptor variant c.1315-2A > G, in a patient with developmental and epileptic encephalopathy. We demonstrate that the splice acceptor variant leads to nonsense-mediated mRNA decay. Furthermore, the missense variant (D422N) alters gephyrin structure, as examined by analytical size exclusion chromatography and circular dichroism-spectroscopy, thus leading to reduced receptor clustering and sensitivity towards calpain-mediated cleavage. In addition, both alterations contribute to an observed reduction of inhibitory signal transmission in neurons, which likely contributes to the pathological encephalopathy.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Macha, Arthur UNSPECIFIED UNSPECIFIED UNSPECIFIED Liebsch, Filip UNSPECIFIED orcid.org/0000-0002-0955-8065 UNSPECIFIED Fricke, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Hetsch, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Neuser, Franziska UNSPECIFIED UNSPECIFIED UNSPECIFIED Johannes, Lena UNSPECIFIED UNSPECIFIED UNSPECIFIED Kress, Vanessa UNSPECIFIED UNSPECIFIED UNSPECIFIED Djemie, Tania UNSPECIFIED UNSPECIFIED UNSPECIFIED Santamaria-Araujo, Jose A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vilain, Catheline UNSPECIFIED UNSPECIFIED UNSPECIFIED Aeby, Alec UNSPECIFIED UNSPECIFIED UNSPECIFIED Van Bogaert, Patrick UNSPECIFIED UNSPECIFIED UNSPECIFIED Dejanovic, Borislav UNSPECIFIED UNSPECIFIED UNSPECIFIED Weckhuysen, Sarah UNSPECIFIED orcid.org/0000-0003-2878-1147 UNSPECIFIED Meier, Jochen C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Guenter UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-689364
DOI:	10.1093/hmg/ddab298
Journal or Publication Title:	Hum. Mol. Genet.
Volume:	31
Number:	6
Page Range:	S. 901 - 914
Date:	2022
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2083
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN SECONDARY STRUCTURE; CIRCULAR-DICHROISM SPECTRA; GLYCINE RECEPTOR; BINDING; PHOSPHORYLATION; COLLYBISTIN; MUTATION; DOMAIN; GENES; ALPHA Multiple languages Biochemistry & Molecular Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/68936