2. Academic Validation
  3. Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy

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

  • EMBO Mol Med. 2015 Dec;7(12):1580-94. doi: 10.15252/emmm.201505323.
Borislav Dejanovic 1,  Tania Djémié 2,  Nora Grünewald 3,  Arvid Suls 4,  Vanessa Kress 3,  Florian Hetsch 5,  Dana Craiu 6,  Matthew Zemel 7,  Padhraig Gormley 8,  Dennis Lal 9,  EuroEPINOMICS Dravet working group,  Candace T Myers 7,  Heather C Mefford 7,  Aarno Palotie 10,  Ingo Helbig 11,  Jochen C Meier 5,  Peter De Jonghe 12,  Sarah Weckhuysen 13,  Guenter Schwarz 14
Affiliations

Affiliations

  • 1 Department of Chemistry, Institute of Biochemistry University of Cologne, Cologne, Germany b.dejanovic@uni-koeln.de sarahweck@hotmail.com gschwarz@uni-koeln.de.
  • 2 Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium Laboratory of Neurogenetics, Institute Born-Bunge University of Antwerp, Antwerp, Belgium.
  • 3 Department of Chemistry, Institute of Biochemistry University of Cologne, Cologne, Germany.
  • 4 Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium Laboratory of Neurogenetics, Institute Born-Bunge University of Antwerp, Antwerp, Belgium GENOMED, Center for Medical Genetics, University of Antwerp, Antwerp, Belgium.
  • 5 Division Cell Physiology, Zoological Institute Technische Universität Braunschweig, Braunschweig, Germany.
  • 6 Pediatric Neurology Clinic, Al Obregia Hospital, Bucharest, Romania Department of Neurology, Pediatric Neurology, Psychiatry, Child and Adolescent Psychiatry, and Neurosurgery, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
  • 7 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
  • 8 Wellcome Trust Sanger Institute Wellcome Trust Genome Campus, Hinxton, UK Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) University of Cologne, Cologne, Germany Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 9 Cologne Center for Genomics, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) University of Cologne, Cologne, Germany Department of Neuropediatrics, University Medical Faculty Giessen and Marburg, Giessen, Germany.
  • 10 Wellcome Trust Sanger Institute Wellcome Trust Genome Campus, Hinxton, UK Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
  • 11 Department of Neuropediatrics, University Medical Center Schleswig-Holstein Christian Albrechts University, Kiel, Germany Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 12 Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium Laboratory of Neurogenetics, Institute Born-Bunge University of Antwerp, Antwerp, Belgium Division of Neurology, Antwerp University Hospital, Antwerp, Belgium.
  • 13 Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium Laboratory of Neurogenetics, Institute Born-Bunge University of Antwerp, Antwerp, Belgium Inserm U 1127 CNRS UMR 7225 Sorbonne Universités UPMC Univ Paris 06 UMR S 1127 Institut du Cerveau et de la Moelle épinière, ICM, Paris, France Centre de reference épilepsies rares, Epilepsy unit, AP-HP Groupe hospitalier Pitié-Salpêtrière, F-75013, Paris, France b.dejanovic@uni-koeln.de sarahweck@hotmail.com gschwarz@uni-koeln.de.
  • 14 Department of Chemistry, Institute of Biochemistry University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) University of Cologne, Cologne, Germany b.dejanovic@uni-koeln.de sarahweck@hotmail.com gschwarz@uni-koeln.de.
PMID: 26613940 DOI: 10.15252/emmm.201505323
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 GABAA and glycine receptors (GABAARs 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 GABAAR 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.

Keywords

Dravet syndrome; GABAA receptors; epileptic encephalopathy; gephyrin; molybdenum cofactor.

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