ArticleThe Journal of physiology2011
The GABRA6 mutation, R46W, associated with childhood absence epilepsy, alters 6β22 and 6β2 GABA(A) receptor channel gating and expression.
Article in The Journal of physiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 41 citations in OpenAlex.
- Genetic analysis of benign familial epilepsies in the first year of life in a Chinese cohort.Journal of human genetics · 2018Trial
- GABASynapse (New York, N.Y.) · 2026Review
- GABAFrontiers in neuroscience · 2021Article
- Dravet syndrome-associated mutations inBrain communications · 2021Article
- Abnormal expression of GABABiology open · 2020Article
- Novel and de novo mutations in pediatric refractory epilepsy.Molecular brain · 2018Article
- Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy.The Journal of pharmacology and experimental therapeutics · 2018Review
- Common Ribs of Inhibitory Synaptic Dysfunction in the Umbrella of Neurodevelopmental Disorders.Frontiers in molecular neuroscience · 2018Review
- GABAScientific reports · 2017Article
- Ion Channel Genes and Epilepsy: Functional Alteration, Pathogenic Potential, and Mechanism of Epilepsy.Neuroscience bulletin · 2017Review
- De novo GABRG2 mutations associated with epileptic encephalopathies.Brain : a journal of neurology · 2017Article
- Genetic and epigenetic mechanisms of epilepsy: a review.Neuropsychiatric disease and treatment · 2017Review
- Epileptic encephalopathy de novo GABRB mutations impair γ-aminobutyric acid type A receptor function.Annals of neurology · 2016Article
- Article
- Dodecyl maltopyranoside enabled purification of active human GABA type A receptors for deep and direct proteomic sequencing.Molecular & cellular proteomics : MCP · 2015Article
- A novel variant in GABRB2 associated with intellectual disability and epilepsy.American journal of medical genetics. Part A · 2014Article
- Three epilepsy-associated GABRG2 missense mutations at the γ+/β- interface disrupt GABAA receptor assembly and trafficking by similar mechanisms but to different extents.Neurobiology of disease · 2014Article
- Downregulation of GABAA receptor protein subunits α6, β2, δ, ε, γ2, θ, and ρ2 in superior frontal cortex of subjects with autism.Journal of autism and developmental disorders · 2014Article
- Mapping genetic modifiers of survival in a mouse model of Dravet syndrome.Genes, brain, and behavior · 2014Article
- Channelopathies.Korean journal of pediatrics · 2014Review
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
A GABA(A) receptor α6 subunit mutation, R46W, was identified as a susceptibility gene that may contribute to the pathogenesis of childhood absence epilepsy (CAE), but the molecular basis for alteration of GABA(A) receptor function is unclear. The R46W mutation is located in a region homologous to a GABA(A) receptor γ2 subunit missense mutation, R82Q, that is associated with CAE and febrile seizures in humans. To determine how this mutation reduces GABAergic inhibition, we expressed wild-type (α6β2γ2L and α6β2δ) and mutant (α6(R46W)β2γ2L and α6(R46W)β2δ) receptors in HEK 293T cells and characterize their whole-cell and single-channel currents, and surface and total levels. We demonstrated that gating and assembly of both α6(R46W)β2γ2L and α6(R46W)β2δ receptors were impaired. Compared to wild-type currents, α6(R46W)β2γ2L and α6(R46W)β2δ receptors had a reduced current density, α6(R46W)β2γ2L currents desensitized to a greater extent and deactivated at a slower rate, α6(R46W)β2δ receptors did not desensitize but deactivated faster and both α6(R46W)β2γ2L and α6(R46W)β2δ single-channel current mean open times and burst durations were reduced. Surface levels of coexpressed α6(R46W), β2 and δ, but not γ2L, subunits were decreased. 'Heterozygous' coexpression of α6(R46W) and α6 subunits with β2 and γ2L subunits produced intermediate macroscopic current amplitudes by increasing incorporation of wild-type and decreasing incorporation of mutant subunits into receptors trafficked to the surface. Finally, these findings suggest that similar to the γ2(R82Q) mutation, the CAE-associated α6(R46W) mutation could cause neuronal disinhibition and thus increase susceptibility to generalized seizures through a reduction of αβγ and αβδ receptor function and expression.
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