ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2010
Slow degradation and aggregation in vitro of mutant GABAA receptor gamma2(Q351X) subunits associated with epilepsy.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 47 citations in OpenAlex.
- New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms.The Journal of biological chemistry · 2013Trial
- Artificial intelligence in the assessment of epilepsy-related genetic mutations: Learned from GABAEpilepsia open · 2026Review
- The p.R321C mutation in the p62 protein is associated with abnormalities in the central nervous system.Scientific reports · 2025Article
- GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics.Journal of translational medicine · 2024Review
- Modulating Endoplasmic Reticulum Chaperones and Mutant Protein Degradation in GABRG2(Q390X) Associated with Genetic Epilepsy with Febrile Seizures Plus and Dravet Syndrome.International journal of molecular sciences · 2024Article
- Article
- 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
- 4-Phenylbutyrate restored γ-aminobutyric acid uptake and reduced seizures inBrain communications · 2022Article
- Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons.Brain : a journal of neurology · 2021Article
- Genetic mosaicism, intrafamilial phenotypic heterogeneity, and molecular defects of a novel missense SLC6A1 mutation associated with epilepsy and ADHD.Experimental neurology · 2021Article
- Epileptic Mechanisms Shared by Alzheimer's Disease: Viewed via the Unique Lens of Genetic Epilepsy.International journal of molecular sciences · 2021Review
- Impaired State-Dependent Potentiation of GABAergic Synaptic Currents Triggers Seizures in a Genetic Generalized Epilepsy Model.Cerebral cortex (New York, N.Y. : 1991) · 2021Article
- Endoplasmic reticulum stress increases inflammatory cytokines in an epilepsy mouse model Gabrg2Epilepsia · 2020Article
- Endoplasmic reticulum retention and degradation of a mutation in SLC6A1 associated with epilepsy and autism.Molecular brain · 2020Article
- A missense mutation in SLC6A1 associated with Lennox-Gastaut syndrome impairs GABA transporter 1 protein trafficking and function.Experimental neurology · 2019Article
- Synaptic clustering differences due to different GABRB3 mutations cause variable epilepsy syndromes.Brain : a journal of neurology · 2019Article
- Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy.The Journal of pharmacology and experimental therapeutics · 2018Review
- Article
- De novo GABRG2 mutations associated with epileptic encephalopathies.Brain : a journal of neurology · 2017Article
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Authors and funding
5 authors at 1 institution in 2 countries.
Funding
Abstract
The GABA(A) receptor γ2 subunit nonsense mutation Q351X has been associated with the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus, which includes a spectrum of seizures types from febrile seizures to Dravet syndrome. Although most genetic epilepsy syndromes are mild and remit with age, Dravet syndrome has a more severe clinical course with refractory seizures associated with developmental delay and cognitive impairment. The basis for the broad spectrum of seizure phenotypes is uncertain. We demonstrated previously that the GABA(A) receptor γ2 subunit gene Q351X mutation suppressed biogenesis of wild-type partnering α1 and β2 subunits in addition to its loss of function. Here we show that γ2S(Q351X) subunits have an additional impairment of biogenesis. Mutant γ2(Q351X) subunits were degraded more slowly than wild-type γ2 subunits and formed SDS-resistant, high-molecular-mass complexes or aggregates in multiple cell types, including neurons. The half-life of γ2S(Q351X) subunits was ∼4 h, whereas that of γ2S subunits was ∼2 h. Mutant subunits formed complexes rapidly after synthesis onset. Using multiple truncated subunits, we demonstrated that aggregate formation was a general phenomenon for truncated γ2S subunits and that their Cys-loop cysteines were involved in aggregate formation. Protein aggregation is a hallmark of neurodegenerative diseases, but the effects of the mutant γ2S(Q351X) subunit aggregates on neuronal function and survival are unclear. Additional validation of the mutant subunit aggregation in vivo and determination of the involved signaling pathways will help reveal the pathological effects of these mutant subunit aggregates in the pathogenesis of genetic epilepsy syndromes.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.