ArticleBrain : a journal of neurology2019
Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies.
Article in Brain : a journal of neurology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 49 citations in OpenAlex.
- Excess EEG beta-band oscillations in Dup15q syndrome correlate with clinical severity.Translational psychiatry · 2026Article
- RO4938581, a GABAMolecular psychiatry · 2026Article
- Unraveling the neurotoxic mechanisms of tranexamic acid in epilepsy induction: a network toxicology and molecular docking approach.BMC medicine · 2026Article
- Clinical and genetics spectrum of 392 Chinese patients with genetic epilepsy with febrile seizures plus.Journal of neurology · 2025Article
- Proteostasis regulation of GABABiomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Review
- Understanding paralogous epilepsy-associated GABAProceedings of the National Academy of Sciences of the United States of America · 2024Article
- GABAJournal of neurochemistry · 2024Review
- Article
- Mesomelia-synostoses syndrome: contiguous deletion syndrome, SULF1 haploinsufficiency or enhancer adoption?Molecular cytogenetics · 2024Article
- GABA system as the cause and effect in early development.Neuroscience and biobehavioral reviews · 2024Review
- Region and layer-specific expression of GABAFrontiers in cellular neuroscience · 2024Article
- Epilepsy plus blindness in microdeletion of GABRA1 and GABRG2 in mouse and human.Experimental neurology · 2023Article
- Pathogenic variants of human GABRA1 gene associated with epilepsy: A computational approach.Heliyon · 2023Article
- Vinpocetine improved neuropsychiatric and epileptic outcomes in a patient with a GABRA1 loss-of-function variant.Annals of clinical and translational neurology · 2023Article
- Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum.Physiological reviews · 2023Review
- Distinct Functional Alterations and Therapeutic Options of Two Pathological De Novo Variants of the T292 Residue of GABRA1 Identified in Children with Epileptic Encephalopathy and Neurodevelopmental Disorders.International journal of molecular sciences · 2022Article
- Antiseizure medication in early nervous system development. Ion channels and synaptic proteins as principal targets.Frontiers in pharmacology · 2022Review
- Clinical phenotype and genotype of children with GABAFrontiers in neurology · 2022Article
- Regulation of Inhibitory Signaling at the Receptor and Cellular Level; Advances in Our Understanding of GABAergic Neurotransmission and the Mechanisms by Which It Is Disrupted in Epilepsy.Frontiers in synaptic neuroscience · 2022Review
- Successful use of perampanel in GABRA1-related myoclonic epilepsy with photosensitivity.Epilepsy & behavior reports · 2022Article
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Authors and funding
14 authors at 8 institutions in 2 countries.
Funding
Abstract
We performed next generation sequencing on 1696 patients with epilepsy and intellectual disability using a gene panel with 480 epilepsy-related genes including all GABAA receptor subunit genes (GABRs), and we identified six de novo GABR mutations, two novel GABRA5 mutations (c.880G>T, p.V294F and c.1238C>T, p.S413F), two novel GABRA1 mutations (c.778C>T, p.P260S and c.887T>C, p.L296S/c.944G>T, p.W315L) and two known GABRA1 mutations (c.335G>A, p.R112Q and c.343A>G, p.N115D) in six patients with intractable early onset epileptic encephalopathy. The α5(V294F and S413F) and α1(P260S and L296S/W315L) subunit residue substitutions were all in transmembrane domains, while the α1(R112Q and N115R) subunit residue substitutions were in the N-terminal GABA binding domain. Using multidisciplinary approaches, we compared effects of mutant GABAA receptor α5 and α1 subunits on the properties of recombinant α5β3γ2 and α1β3γ2 GABAA receptors in both neuronal and non-neuronal cells and characterized their effects on receptor clustering, biogenesis and channel function. GABAA receptors containing mutant α5 and α1 subunits all had reduced cell surface and total cell expression with altered endoplasmic reticulum processing, impaired synaptic clustering, reduced GABAA receptor function and decreased GABA binding potency. Our study identified GABRA5 as a causative gene for early onset epileptic encephalopathy and expands the mutant GABRA1 phenotypic spectrum, supporting growing evidence that defects in GABAergic neurotransmission contribute to early onset epileptic encephalopathy phenotypes.
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