ArticleBrain : a journal of neurology2018
De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy.
Article in Brain : a journal of neurology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
59 citing papers in PubMed, 2 syntheses or guidelines pooled it, 114 citations in OpenAlex.
- Biomarkers and Tourette syndrome: a systematic review and meta-analysis.Frontiers in neurology · 2024Pooled it
- Cys-loop receptors on cannabinoids: All high?Frontiers in physiology · 2022Pooled it
- Imputation of fluid intelligence scores reduces ascertainment bias and increases power for analyses of common and rare variants.Nature genetics · 2026Article
- Excess EEG beta-band oscillations in Dup15q syndrome correlate with clinical severity.Translational psychiatry · 2026Article
- Association Analysis ofBiology · 2026Article
- RO4938581, a GABAMolecular psychiatry · 2026Article
- A novel iPSC model of Bryant-Li-Bhoj neurodevelopmental/neurodegenerative syndrome demonstrates the role of histone H3.3 in chromatin dynamics, neuronal differentiation, and maturation.Journal of translational medicine · 2026Article
- Unraveling the neurotoxic mechanisms of tranexamic acid in epilepsy induction: a network toxicology and molecular docking approach.BMC medicine · 2026Article
- Carvone derived cannabidiol enantiomers as novel anticonvulsants.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- GABRA2-related encephalopathy: Identification of two phenotypes with distinctive electroclinical features.Epilepsia · 2025Article
- ENX-101, a GABAEpilepsia · 2025Article
- Proteostasis regulation of GABABiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Review
- A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient.Annals of clinical and translational neurology · 2025Article
- Heritability and Genome-Wide Association Study of Dog Behavioral Phenotypes in a Commercial Breeding Cohort.Genes · 2024Article
- Understanding paralogous epilepsy-associated GABAProceedings of the National Academy of Sciences of the United States of America · 2024Article
- GABAJournal of neurochemistry · 2024Review
- Impaired axon initial segment structure and function in a model ofProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Mesomelia-synostoses syndrome: contiguous deletion syndrome, SULF1 haploinsufficiency or enhancer adoption?Molecular cytogenetics · 2024Article
- The Chromatin Organization Close to SNP rs12913832, Involved in Eye Color Variation, Is Evolutionary Conserved in Vertebrates.International journal of molecular sciences · 2024Article
- Gene Expression of GABABrain sciences · 2024Article
Corrections and comments
- Commented on by
- Commented on by
- Commented on by
Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
GABAA receptors are ligand-gated anion channels that are important regulators of neuronal inhibition. Mutations in several genes encoding receptor subunits have been identified in patients with various types of epilepsy, ranging from mild febrile seizures to severe epileptic encephalopathy. Using whole-genome sequencing, we identified a novel de novo missense variant in GABRA5 (c.880G > C, p.V294L) in a patient with severe early-onset epilepsy and developmental delay. Targeted resequencing of 279 additional epilepsy patients identified 19 rare variants from nine GABAA receptor genes, including a novel de novo missense variant in GABRA2 (c.875C > A, p.T292K) and a recurrent missense variant in GABRB3 (c.902C > T, p.P301L). Patients with the GABRA2 and GABRB3 variants also presented with severe epilepsy and developmental delay. We evaluated the effects of the GABRA5, GABRA2 and GABRB3 missense variants on receptor function using whole-cell patch-clamp recordings from human embryonic kidney 293T cells expressing appropriate α, β and γ subunits. The GABRA5 p.V294L variant produced receptors that were 10-times more sensitive to GABA but had reduced maximal GABA-evoked current due to increased receptor desensitization. The GABRA2 p.T292K variant reduced channel expression and produced mutant channels that were tonically open, even in the absence of GABA. Receptors containing the GABRB3 p.P301L variant were less sensitive to GABA and produced less GABA-evoked current. These results provide the first functional evidence that de novo variants in the GABRA5 and GABRA2 genes contribute to early-onset epilepsy and developmental delay, and demonstrate that epilepsy can result from reduced neuronal inhibition via a wide range of alterations in GABAA receptor function.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.