ArticleNeurobiology of disease2014
Three epilepsy-associated GABRG2 missense mutations at the γ+/β- interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents.
Article in Neurobiology of disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 44 citations in OpenAlex.
- GABASynapse (New York, N.Y.) · 2026Review
- Proteostasis regulation of GABABiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Review
- Repetitive Transcranial Magnetic Stimulation-Mediated Neuroprotection in the 5xFAD Mouse Model of Alzheimer's Disease Through GABRG2 and SNAP25 Modulation.Molecular neurobiology · 2025Article
- GABAJournal of neurochemistry · 2024Review
- Review
- GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics.Journal of translational medicine · 2024Review
- Established and emerging GABAFrontiers in pharmacology · 2024Review
- Article
- Clptm1, a new target in suppressing epileptic seizure by regulating GABAThe Kaohsiung journal of medical sciences · 2023Article
- Variable Expression of GABAA Receptor Subunit Gamma 2 Mutation in a Nuclear Family Displaying Developmental and Encephalopathic Phenotype.International journal of molecular sciences · 2022Review
- Disruption of the Ubiquitin-Proteasome System and Elevated Endoplasmic Reticulum Stress in Epilepsy.Biomedicines · 2022Review
- Association of ultra-rare coding variants with genetic generalized epilepsy: A case-control whole exome sequencing study.Epilepsia · 2022Article
- Regulation of Inhibitory Signaling at the Receptor and Cellular Level; Advances in Our Understanding of GABAergic Neurotransmission and the Mechanisms by Which It Is Disrupted in Epilepsy.Frontiers in synaptic neuroscience · 2022Review
- Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice.Cell death & disease · 2021Article
- Dravet syndrome-associated mutations inBrain communications · 2021Article
- Pathophysiology of and therapeutic options for a GABRA1 variant linked to epileptic encephalopathy.Molecular brain · 2019Article
- Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies.Brain : a journal of neurology · 2019Article
- Alterations in GABAFrontiers in cellular neuroscience · 2019Article
- GABA type a receptor trafficking and the architecture of synaptic inhibition.Developmental neurobiology · 2018Review
- Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy.The Journal of pharmacology and experimental therapeutics · 2018Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
We compared the effects of three missense mutations in the GABAA receptor γ2 subunit on GABAA receptor assembly, trafficking and function in HEK293T cells cotransfected with α1, β2, and wildtype or mutant γ2 subunits. The mutations R82Q and P83S were identified in families with genetic epilepsy with febrile seizures plus (GEFS+), and N79S was found in a single patient with generalized tonic-clonic seizures (GTCS). Although all three mutations were located in an N-terminal loop that contributes to the γ+/β- subunit-subunit interface, we found that each mutation impaired GABAA receptor assembly to a different extent. The γ2(R82Q) and γ2(P83S) subunits had reduced α1β2γ2 receptor surface expression due to impaired assembly into pentamers, endoplasmic reticulum (ER) retention and degradation. In contrast, γ2(N79S) subunits were efficiently assembled into GABAA receptors with only minimally altered receptor trafficking, suggesting that N79S was a rare or susceptibility variant rather than an epilepsy mutation. Increased structural variability at assembly motifs was predicted by R82Q and P83S, but not N79S, substitution, suggesting that R82Q and P83S substitutions were less tolerated. Membrane proteins with missense mutations that impair folding and assembly often can be "rescued" by decreased temperatures. We coexpressed wildtype or mutant γ2 subunits with α1 and β2 subunits and found increased surface and total levels of both wildtype and mutant γ2 subunits after decreasing the incubation temperature to 30°C for 24h, suggesting that lower temperatures increased GABAA receptor stability. Thus epilepsy-associated mutations N79S, R82Q and P83S disrupted GABAA receptor assembly to different extents, an effect that could be potentially rescued by facilitating protein folding and assembly.
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