Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy

EMBO Molecular Medicine

Dejanovic, Borislav¹  Djémié, Tania²  Grünewald, Nora¹  Suls, Arvid²  Kress, Vanessa¹  Hetsch, Florian⁶  Craiu, Dana⁸  Zemel, Matthew⁵  Gormley, Padhraig⁴  Lal, Dennis⁷  Myers, Candace T⁵  Mefford, Heather C⁵  Palotie, Aarno⁴  Helbig, Ingo³  Meier, Jochen C⁶  De Jonghe, Peter²  Weckhuysen, Sarah²  Schwarz, Guenter¹ 

[1] Institute of Biochemistry University of Cologne Department of Chemistry Cologne Germany;VIB Neurogenetics Group Antwerp Belgium;University Medical Center Schleswig‐Holstein Christian Albrechts University Department of Neuropediatrics Kiel Germany;Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton UK;University of Washington Division of Genetic Medicine Seattle WA USA;Zoological Institute Technische Universität Braunschweig Division Cell Physiology Braunschweig Germany;Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD) University of Cologne Cologne Center for Genomics Cologne Germany;Al Obregia Hospital Pediatric Neurology Clinic Bucharest Romania

关键词: Dravet syndrome;    epileptic encephalopathy;    GABAA receptors;    gephyrin;    molybdenum cofactor;   

DOI  :  10.15252/emmm.201505323

来源: Wiley

【 摘 要 】

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_ARs 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_AR 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.

Synopsis

Aberrant inhibitory synaptic transmission is linked to brain disorders including epilepsy, autism and intellectual disability. A de novo mutation was identified in the gephyrin gene in a patient with epileptic encephalopathy. This mutation disrupts gephyrin postsynaptic and molybdenum cofactor biosynthesis functions.

• Gephyrin-G375D mutation in a patient with Dravet-like syndrome and intellectual disability does not cluster at inhibitory postsynapses and acts dominant-negatively on wild-type gephyrin
• Postsynaptic clustering and inhibitory signaling is diminished by gephyrin-G375D
• The mutation weakens the interaction between gephyrin and inhibitory GABA_A and glycine receptors
• Gephyrin-G375D is enzymatically inactive and unable to synthesize the molybdenum cofactor, thus the mutation affects both gephyrin functions

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

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