ArticleNeurobiology of disease2022
Astrocytic GABA transporter 1 deficit in novel SLC6A1 variants mediated epilepsy: Connected from protein destabilization to seizures in mice and humans.
Article in Neurobiology of disease, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 29 citations in OpenAlex.
- Article
- Astrocytes in Genetic Epilepsies: Supporting Actor or Key Player?Journal of neuroscience research · 2026Review
- 4 Phenylbutyrate Plus Gene augmentation: A Dual Therapy To Rescue of SLC6A1 Variant Associated Developmental And Epileptic Encephalopathy.bioRxiv : the preprint server for biology · 2026Article
- Artificial intelligence in the assessment of epilepsy-related genetic mutations: Learned from GABAEpilepsia open · 2026Review
- 4-Phenylbutyrate rescues neurobehavioral phenotypes in SLC6A1-related encephalopathy.Epilepsy research · 2026Article
- Comprehensive Clinical, Diagnostic, and In Silico Assessment of a Novel 1p36.33p36.32 Copy Number Variant.Journal of cellular and molecular medicine · 2026Article
- Multiple Chemical Sensitivity and the SLC Gene Superfamily: A Case-Control Study.International journal of molecular sciences · 2025Article
- Gene therapies alleviate absence epilepsy associated withbioRxiv : the preprint server for biology · 2025Article
- Dynamics and conditions for inhibitory synaptic current to induce bursting and spreading depolarization in pyramidal neurons.Scientific reports · 2025Article
- 4-Phenylbutyrate restored GABA uptake, mitigated seizures in SLC6A1 and SLC6A11 microdeletions/3p- syndrome: From cellular models to human patients.Epilepsy research · 2025Article
- Endoplasmic reticulum protein retention and disturbed proteostasis is a common pathology for a subset of autism: evidence from mutations in GABAFrontiers in molecular neuroscience · 2025Review
- Modulating Endoplasmic Reticulum Chaperones and Mutant Protein Degradation in GABRG2(Q390X) Associated with Genetic Epilepsy with Febrile Seizures Plus and Dravet Syndrome.International journal of molecular sciences · 2024Article
- Article
- A transporter's doom or destiny:Frontiers in molecular neuroscience · 2024Review
- γ-Aminobutyric acid transporter and GABABrain communications · 2024Article
- Patient-derived SLC6A1 variant S295L results in an epileptic phenotype similar to haploinsufficient mice.Epilepsia · 2023Article
- GABAInternational journal of molecular sciences · 2023Article
- Heterozygous GABAEpilepsia · 2023Article
- Genetic mechanisms in generalized epilepsies.Acta epileptologica · 2023Review
- Experimental and Bioinformatic Insights into the Effects of Epileptogenic Variants on the Function and Trafficking of the GABA Transporter GAT-1.International journal of molecular sciences · 2023Article
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Authors and funding
15 authors at 6 institutions in 2 countries.
Funding
Abstract
objectiveMutations in γ-aminobutyric acid (GABA) transporter 1 (GAT-1)-encoding SLC6A1 have been associated with myoclonic atonic epilepsy and other phenotypes. We determined the patho-mechanisms of the mutant GAT-1, in order to identify treatment targets.
methodsWe conducted whole-exome sequencing of patients with myoclonic atonic epilepsy (MAE) and characterized the seizure phenotypes and EEG patterns. We studied the protein stability and structural changes with homology modeling and machine learning tools. We characterized the function and trafficking of the mutant GAT-1 with
resultsWe identified four novel SLC6A1 variants associated with MAE and 2 to 4 Hz spike-wave discharges as a common EEG feature. Machine learning tools predicted that the variant proteins are destabilized. The variant protein had reduced expression and reduced GABA uptake due to endoplasmic reticular retention. The consistent observation was made in cortical and thalamic astrocytes from variant-knockin mice and human iPSC-derived astrocytes. The Slc6a
interpretationSLC6A1 variants in various locations of the protein peptides can cause MAE with similar seizure phenotypes and EEG features. Reduced GABA uptake is due to decreased functional GAT-1, which, in thalamic astrocytes, could result in increased extracellular GABA accumulation and enhanced tonic inhibition, leading to seizures and abnormal EEGs.
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