ArticlePloS one2016
Deleterious Rare Variants Reveal Risk for Loss of GABAA Receptor Function in Patients with Genetic Epilepsy and in the General Population.
Article in PloS one, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 19 papers.
What it found
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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.
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Who cites it
19 citing papers in PubMed, 35 citations in OpenAlex.
- GABAJournal of neurochemistry · 2024Review
- Trace amine associated receptor 1: predicted effects of single nucleotide variants on structure-function in geographically diverse populations.Human genomics · 2024Article
- Genetic Background of Epilepsy and Antiepileptic Treatments.International journal of molecular sciences · 2023Review
- Pathogenic variants of human GABRA1 gene associated with epilepsy: A computational approach.Heliyon · 2023Article
- Article
- Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies.Nature communications · 2022Article
- Gabra2 is a genetic modifier of Dravet syndrome in mice.Mammalian genome : official journal of the International Mammalian Genome Society · 2021Article
- Dravet syndrome-associated mutations inBrain communications · 2021Article
- Rare variants in the GABAMolecular genetics & genomic medicine · 2020Article
- Differential Coassembly of α1-GABAThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Clinical Characterization of 2 Siblings with a Homozygous SPAST Variant.The American journal of case reports · 2020Article
- Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies.Brain : a journal of neurology · 2019Article
- Functional genomics of epilepsy-associated mutations in the GABAThe Journal of biological chemistry · 2019Article
- Neurobiology and Therapeutic Potential of α5-GABA Type A Receptors.Frontiers in molecular neuroscience · 2019Article
- De novo variants in GABRA2 and GABRA5 alter receptor function and contribute to early-onset epilepsy.Brain : a journal of neurology · 2018Article
- γ2 GABAFrontiers in cellular neuroscience · 2018Review
- GABAScientific reports · 2017Article
- No Gain, Less Pain: GABRB3 Mutations in Epileptic Encephalopathy.Epilepsy currentsArticle
- Article
Corrections and comments
- Erratum issued
Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Genetic epilepsies (GEs) account for approximately 50% of all seizure disorders, and familial forms include mutations in single GABAA receptor subunit genes (GABRs). In 144 sporadic GE cases (GECs), exome sequencing of 237 ion channel genes identified 520 GABR variants. Among these variants, 33 rare variants in 11 GABR genes were present in 24 GECs. To assess functional risk of variants in GECs, we selected 8 variants found in GABRA, 3 in GABRB, and 3 in GABRG and compared them to 18 variants found in the general population for GABRA1 (n = 9), GABRB3 (n = 7), and GABRG2 (n = 2). To identify deleterious variants and gain insight into structure-function relationships, we studied the gating properties, surface expression and structural perturbations of the 32 variants. Significant reduction of GABAA receptor function was strongly associated with variants scored as deleterious and mapped within the N-terminal and transmembrane domains. In addition, 12 out of 17 variants mapped along the β+/α- GABA binding interface, were associated with reduction in channel gating and were predicted to cause structural rearrangements of the receptor by in silico simulations. Missense or nonsense mutations of GABRA1, GABRB3 and GABRG2 primarily impair subunit biogenesis. In contrast, GABR variants affected receptor function by impairing gating, suggesting that different mechanisms are operating in GABR epilepsy susceptibility variants and disease-causing mutations. The functional impact of single GABR variants found in individuals with sporadic GEs warrants the use of molecular diagnosis and will ultimately improve the treatment of genetic epilepsies by using a personalized approach.
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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.