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

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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:
CreatorsEmailORCIDORCID Put Code
Dejanovic, BorislavUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Djemie, TaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruenewald, NoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suls, ArvidUNSPECIFIEDorcid.org/0000-0003-0328-198XUNSPECIFIED
Kress, VanessaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hetsch, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Craiu, DanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zemel, MatthewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gormley, PadhraigUNSPECIFIEDorcid.org/0000-0002-8908-6968UNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Myers, Candace T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mefford, Heather C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palotie, AarnoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helbig, IngoUNSPECIFIEDorcid.org/0000-0001-8486-0558UNSPECIFIED
Meier, Jochen C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Jonghe, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weckhuysen, SarahUNSPECIFIEDorcid.org/0000-0003-2878-1147UNSPECIFIED
Schwarz, GuenterUNSPECIFIEDorcid.org/0000-0002-2118-9338UNSPECIFIED
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:
KeywordsLanguage
MOLYBDENUM COFACTOR DEFICIENCY; DE-NOVO MUTATIONS; ACID TYPE-A; ESCHERICHIA-COLI MOEA; GLYCINE RECEPTOR; GABA(A) RECEPTOR; INHIBITORY SYNAPSES; PROTEIN GEPHYRIN; MOLECULAR-BASIS; BINDINGMultiple languages
Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/38473

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