ArticleNeurobiology of disease2012
The GABRG2 nonsense mutation, Q40X, associated with Dravet syndrome activated NMD and generated a truncated subunit that was partially rescued by aminoglycoside-induced stop codon read-through.
Article in Neurobiology of disease, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.
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Who cites it
25 citing papers in PubMed, 1 synthesis or guideline pooled it, 46 citations in OpenAlex.
- Do All Roads Lead to Rome? Genes Causing Dravet Syndrome and Dravet Syndrome-Like Phenotypes.Frontiers in neurology · 2022Pooled it
- Spotlight on mechanism of sudden unexpected death in epilepsy in Dravet syndrome.Translational psychiatry · 2025Review
- GABAJournal of neurochemistry · 2024Review
- GABRG2 mutations in genetic epilepsy with febrile seizures plus: structure, roles, and molecular genetics.Journal of translational medicine · 2024Review
- Molecular mechanism of hyperactivation conferred by a truncation of TRPA1.Nature communications · 2023Article
- Features and factors that dictate if terminating ribosomes cause or counteract nonsense-mediated mRNA decay.The Journal of biological chemistry · 2022Review
- Rare variants in GABRG2 associated with sleep-related hypermotor epilepsy.Journal of neurology · 2022Article
- Variable Expression of GABAA Receptor Subunit Gamma 2 Mutation in a Nuclear Family Displaying Developmental and Encephalopathic Phenotype.International journal of molecular sciences · 2022Review
- Phenotypic Spectrum and Prognosis of Epilepsy Patients WithFrontiers in molecular neuroscience · 2022Article
- Neocortex- and hippocampus-specific deletion of Gabrg2 causes temperature-dependent seizures in mice.Cell death & disease · 2021Article
- Dravet syndrome-associated mutations inBrain communications · 2021Article
- Targeted knockout of GABA-A receptor gamma 2 subunit provokes transient light-induced reflex seizures in zebrafish larvae.Disease models & mechanisms · 2019Article
- γ2 GABAFrontiers in cellular neuroscience · 2018Review
- Common Ribs of Inhibitory Synaptic Dysfunction in the Umbrella of Neurodevelopmental Disorders.Frontiers in molecular neuroscience · 2018Review
- De novo GABRG2 mutations associated with epileptic encephalopathies.Brain : a journal of neurology · 2017Article
- Molecular Pathogenic Basis for GABRG2 Mutations Associated With a Spectrum of Epilepsy Syndromes, From Generalized Absence Epilepsy to Dravet Syndrome.JAMA neurology · 2016Review
- Nonsense mutations in the rhodopsin gene that give rise to mild phenotypes trigger mRNA degradation in human cells by nonsense-mediated decay.Experimental eye research · 2016Article
- Novel GABRG2 mutations cause familial febrile seizures.Neurology. Genetics · 2015Article
- Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases.Molecular pharmacology · 2015Review
- Translational read-through of the RP2 Arg120stop mutation in patient iPSC-derived retinal pigment epithelium cells.Human molecular genetics · 2015Article
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The GABRG2 nonsense mutation, Q40X, is associated with the severe epilepsy syndrome, Dravet syndrome, and is predicted to generate a premature translation-termination codon (PTC) in the GABA(A) receptor γ2 subunit mRNA in a position that codes for the first amino acid of the mutant subunit. We determined the effects of the mutation on γ2 subunit mRNA and protein synthesis and degradation, as well as on α1β2γ2 GABA(A) receptor assembly, trafficking and surface expression in HEK cells. Using bacterial artificial chromosome (BAC) constructs, we found that γ2(Q40X) subunit mRNA was degraded by nonsense mediated mRNA decay (NMD). Undegraded mutant mRNA was translated to a truncated peptide, likely the signal peptide, which was cleaved further. We also found that mutant γ2(Q40X) subunits did not assemble into functional receptors, thus decreasing GABA-evoked current amplitudes. The GABRG2(Q40X) mutation is one of several epilepsy-associated nonsense mutations that have the potential to be rescued by reading through the PTC, thus restoring full-length protein translation. As a first approach, we investigated the use of the aminoglycoside, gentamicin, to rescue translation of intact mutant subunits by inducing mRNA read-through. In the presence of gentamicin, synthesis of full length γ2 subunits was partially restored, and surface biotinylation and whole cell recording experiments suggested that rescued γ2 subunits could corporate into functional, surface GABA(A) receptors, indicating a possible direction for future therapy.
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