ArticleExperimental neurology2019
A missense mutation in SLC6A1 associated with Lennox-Gastaut syndrome impairs GABA transporter 1 protein trafficking and function.
Article in Experimental neurology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44 citing papers in PubMed, 53 citations in OpenAlex.
- Article
- 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
- Unraveling 4-Phenylbutyrate's Therapeutic Role in SLC6A1 Disorders: Pharmacochaperoning Over HDAC Inhibition.Annals of clinical and translational neurology · 2026Article
- 4-Phenylbutyrate rescues neurobehavioral phenotypes in SLC6A1-related encephalopathy.Epilepsy research · 2026Article
- Unraveling Lennox-Gastaut Syndrome: From Molecular Pathogenesis to Precision Diagnosis and Targeted Therapy Evolving Therapeutic Strategies.International journal of molecular sciences · 2026Review
- Haploinsufficiency of brain-specific kinase BRSK1 causes epilepsy and neurodevelopmental disorders.Epilepsia · 2025Article
- Human Medial Ganglionic Eminence Organoids Robustly Generate Parvalbumin Interneurons and Fast-Spiking Neurons and Reveal Migratory Deficits inbioRxiv : the preprint server for biology · 2025Article
- High-throughput imaging of GABA fluorescence as a functional assay for variants in the neurodevelopmental gene,bioRxiv : the preprint server for biology · 2025Article
- Missense variants in SLC9A6 cause partial epilepsy without neurodevelopmental delay.Orphanet journal of rare diseases · 2025Article
- Precision Therapeutics in Lennox-Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy.Children (Basel, Switzerland) · 2025Review
- 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
- Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants.American journal of human genetics · 2024Article
- Article
- A transporter's doom or destiny:Frontiers in molecular neuroscience · 2024Review
- Gene therapy for neurotransmitter-related disorders.Journal of inherited metabolic disease · 2024Review
- γ-Aminobutyric acid transporter and GABABrain communications · 2024Article
- SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.Brain : a journal of neurology · 2023Article
- Patient-derived SLC6A1 variant S295L results in an epileptic phenotype similar to haploinsufficient mice.Epilepsia · 2023Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
Abstract
backgroundMutations in SLC6A1 have been associated mainly with myoclonic atonic epilepsy (MAE) and intellectual disability. We identified a novel missense mutation in a patient with Lennox-Gastaut syndrome (LGS) characterized by severe seizures and developmental delay.
methodsExome Sequencing was performed in an epilepsy patient cohort. The impact of the mutation was evaluated by
resultsWe discovered a heterozygous missense mutation (c700G to A [pG234S) in the SLC6A1 encoding GABA transporter 1 (GAT-1). Structural modeling suggests the mutation destabilizes the global protein conformation. With transient expression of enhanced yellow fluorescence protein (YFP) tagged rat GAT-1 cDNAs, we demonstrated that the mutant GAT-1(G234S) transporter had reduced total protein expression in both rat cortical neurons and HEK 293 T cells. With a high-throughput flow cytometry assay and live cell surface biotinylation, we demonstrated that the mutant GAT-1(G234S) had reduced cell surface expression.
conclusionsThis mutation caused instability of the mutant transporter protein, which resulted in reduced cell surface and total protein levels. The mutation also caused reduced GABA uptake in addition to reduced protein expression, leading to reduced GABA clearance, and altered GABAergic signaling in the brain. The impaired trafficking and reduced GABA uptake function may explain the epilepsy phenotype in the patient.
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