Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy
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), a...
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| Format: | Article |
| Language: | English |
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Springer Nature
2015-11-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201505323 |
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| author | Borislav Dejanovic Tania Djémié Nora Grünewald Arvid Suls Vanessa Kress Florian Hetsch Dana Craiu Matthew Zemel Padhraig Gormley Dennis Lal EuroEPINOMICS Dravet working group Candace T Myers Heather C Mefford Aarno Palotie Ingo Helbig Jochen C Meier Peter De Jonghe Sarah Weckhuysen Guenter Schwarz |
| author_facet | Borislav Dejanovic Tania Djémié Nora Grünewald Arvid Suls Vanessa Kress Florian Hetsch Dana Craiu Matthew Zemel Padhraig Gormley Dennis Lal EuroEPINOMICS Dravet working group Candace T Myers Heather C Mefford Aarno Palotie Ingo Helbig Jochen C Meier Peter De Jonghe Sarah Weckhuysen Guenter Schwarz |
| author_sort | Borislav Dejanovic |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-517a9f7bee9740ff96837c4d2eb65e91 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2015-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-517a9f7bee9740ff96837c4d2eb65e912025-08-20T03:43:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842015-11-017121580159410.15252/emmm.201505323Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathyBorislav Dejanovic0Tania Djémié1Nora Grünewald2Arvid Suls3Vanessa Kress4Florian Hetsch5Dana Craiu6Matthew Zemel7Padhraig Gormley8Dennis Lal9EuroEPINOMICS Dravet working groupCandace T Myers10Heather C Mefford11Aarno Palotie12Ingo Helbig13Jochen C Meier14Peter De Jonghe15Sarah Weckhuysen16Guenter Schwarz17Department of Chemistry, Institute of Biochemistry, University of CologneNeurogenetics Group, Department of Molecular Genetics, VIBDepartment of Chemistry, Institute of Biochemistry, University of CologneNeurogenetics Group, Department of Molecular Genetics, VIBDepartment of Chemistry, Institute of Biochemistry, University of CologneDivision Cell Physiology, Zoological Institute, Technische Universität BraunschweigPediatric Neurology Clinic, Al Obregia HospitalDivision of Genetic Medicine, Department of Pediatrics, University of WashingtonWellcome Trust Sanger Institute, Wellcome Trust Genome CampusCologne Center for Genomics, Cologne Excellence Cluster on Cellular Stress Responses in Aging‐Associated Diseases (CECAD), University of CologneDivision of Genetic Medicine, Department of Pediatrics, University of WashingtonDivision of Genetic Medicine, Department of Pediatrics, University of WashingtonWellcome Trust Sanger Institute, Wellcome Trust Genome CampusDepartment of Neuropediatrics, University Medical Center Schleswig‐Holstein, Christian Albrechts UniversityDivision Cell Physiology, Zoological Institute, Technische Universität BraunschweigNeurogenetics Group, Department of Molecular Genetics, VIBNeurogenetics Group, Department of Molecular Genetics, VIBDepartment of Chemistry, Institute of Biochemistry, University of CologneAbstract 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.https://doi.org/10.15252/emmm.201505323Dravet syndromeepileptic encephalopathyGABAA receptorsgephyrinmolybdenum cofactor |
| spellingShingle | Borislav Dejanovic Tania Djémié Nora Grünewald Arvid Suls Vanessa Kress Florian Hetsch Dana Craiu Matthew Zemel Padhraig Gormley Dennis Lal EuroEPINOMICS Dravet working group Candace T Myers Heather C Mefford Aarno Palotie Ingo Helbig Jochen C Meier Peter De Jonghe Sarah Weckhuysen Guenter Schwarz Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy EMBO Molecular Medicine Dravet syndrome epileptic encephalopathy GABAA receptors gephyrin molybdenum cofactor |
| title | Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy |
| title_full | Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy |
| title_fullStr | Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy |
| title_full_unstemmed | Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy |
| title_short | Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy |
| title_sort | simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy |
| topic | Dravet syndrome epileptic encephalopathy GABAA receptors gephyrin molybdenum cofactor |
| url | https://doi.org/10.15252/emmm.201505323 |
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