Universität zu Köln

Dejanovic, Borislav, Djemie, Tania, Gruenewald, Nora, Suls, Arvid ORCID: 0000-0003-0328-198X, Kress, Vanessa, Hetsch, Florian, Craiu, Dana, Zemel, Matthew, Gormley, Padhraig ORCID: 0000-0002-8908-6968, Lal, Dennis, Myers, Candace T., Mefford, Heather C., Palotie, Aarno, Helbig, Ingo ORCID: 0000-0001-8486-0558, Meier, Jochen C., De Jonghe, Peter, Weckhuysen, Sarah ORCID: 0000-0003-2878-1147 and Schwarz, Guenter ORCID: 0000-0002-2118-9338 (2015). Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy. EMBO Mol. Med., 7 (12). S. 1580 - 1595. HOBOKEN: WILEY. ISSN 1757-4684

Full text not available from this repository.

Abstract

Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition plays an important role in neurological disorders. Gephyrin is a central player at inhibitory postsynapses, directly binds and organizes GABA(A) and glycine receptors (GABA(A)Rs and GlyRs), and is thereby indispensable for normal inhibitory neurotransmission. Additionally, gephyrin catalyzes the synthesis of the molybdenum cofactor (MoCo) in peripheral tissue. We identified a de novo missense mutation (G375D) in the gephyrin gene (GPHN) in a patient with epileptic encephalopathy resembling Dravet syndrome. Although stably expressed and correctly folded, gephyrin-G375D was non-synaptically localized in neurons and acted dominant-negatively on the clustering of wild- type gephyrin leading to a marked decrease in GABA(A)R surface expression and GABAergic signaling. We identified a decreased binding affinity between gephyrin-G375D and the receptors, suggesting that Gly375 is essential for gephyrin-receptor complex formation. Surprisingly, gephyrin-G375D was also unable to synthesize MoCo and activate MoCo-dependent enzymes. Thus, we describe a missense mutation that affects both functions of gephyrin and suggest that the identified defect at GABAergic synapses is the mechanism underlying the patient's severe phenotype.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dejanovic, Borislav UNSPECIFIED UNSPECIFIED UNSPECIFIED Djemie, Tania UNSPECIFIED UNSPECIFIED UNSPECIFIED Gruenewald, Nora UNSPECIFIED UNSPECIFIED UNSPECIFIED Suls, Arvid UNSPECIFIED orcid.org/0000-0003-0328-198X UNSPECIFIED Kress, Vanessa UNSPECIFIED UNSPECIFIED UNSPECIFIED Hetsch, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Craiu, Dana UNSPECIFIED UNSPECIFIED UNSPECIFIED Zemel, Matthew UNSPECIFIED UNSPECIFIED UNSPECIFIED Gormley, Padhraig UNSPECIFIED orcid.org/0000-0002-8908-6968 UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Myers, Candace T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mefford, Heather C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Palotie, Aarno UNSPECIFIED UNSPECIFIED UNSPECIFIED Helbig, Ingo UNSPECIFIED orcid.org/0000-0001-8486-0558 UNSPECIFIED Meier, Jochen C. UNSPECIFIED UNSPECIFIED UNSPECIFIED De Jonghe, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Weckhuysen, Sarah UNSPECIFIED orcid.org/0000-0003-2878-1147 UNSPECIFIED Schwarz, Guenter UNSPECIFIED orcid.org/0000-0002-2118-9338 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-384739
DOI:	10.15252/emmm.201505323
Journal or Publication Title:	EMBO Mol. Med.
Volume:	7
Number:	12
Page Range:	S. 1580 - 1595
Date:	2015
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1757-4684
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MOLYBDENUM COFACTOR DEFICIENCY; DE-NOVO MUTATIONS; ACID TYPE-A; ESCHERICHIA-COLI MOEA; GLYCINE RECEPTOR; GABA(A) RECEPTOR; INHIBITORY SYNAPSES; PROTEIN GEPHYRIN; MOLECULAR-BASIS; BINDING Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/38473