ArticleExperimental neurology2021
Genetic mosaicism, intrafamilial phenotypic heterogeneity, and molecular defects of a novel missense SLC6A1 mutation associated with epilepsy and ADHD.
Article in Experimental neurology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.
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Who cites it
22 citing papers in PubMed, 1 synthesis or guideline pooled it, 27 citations in OpenAlex.
- Comorbidity of epilepsy and attention-deficit/hyperactivity disorder: a systematic review and meta-analysis.Journal of neurology · 2023Pooled it
- Astrocytes in Genetic Epilepsies: Supporting Actor or Key Player?Journal of neuroscience research · 2026Review
- 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
- γ-Aminobutyric Acid Transporter Mutation GAT1 (S295L) Substantially Impairs Neurogenesis in Dentate Gyrus.Brain sciences · 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
- Haploinsufficiency underlies the neurodevelopmental consequences of SLC6A1 variants.American journal of human genetics · 2024Article
- γ-Aminobutyric acid transporter and GABABrain communications · 2024Article
- A transporter's doom or destiny:Frontiers in molecular neuroscience · 2024Review
- Advances in the etiology and neuroimaging of children with attention deficit hyperactivity disorder.Frontiers in pediatrics · 2024Review
- SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.Brain : a journal of neurology · 2023Article
- Synaptic scaling of corticostriatal circuits underlies hyperactivity in GABA Transporter-1 deficient mice.iScience · 2023Article
- Insights into cognitive and behavioral comorbidities ofFrontiers in neuroscience · 2023Article
- Intrafamilial variability inFrontiers in neuroscience · 2023Article
- Next-generation sequencing testing in children with epilepsy reveals novel clinical, diagnostic and therapeutic implications.Frontiers in genetics · 2023Article
- Astrocytic GABA transporter 1 deficit in novel SLC6A1 variants mediated epilepsy: Connected from protein destabilization to seizures in mice and humans.Neurobiology of disease · 2022Article
- Disruption of the Ubiquitin-Proteasome System and Elevated Endoplasmic Reticulum Stress in Epilepsy.Biomedicines · 2022Review
- Molecular and Clinical Repercussions of GABA Transporter 1 Variants Gone Amiss: Links to Epilepsy and Developmental Spectrum Disorders.Frontiers in molecular biosciences · 2022Review
- 4-Phenylbutyrate restored γ-aminobutyric acid uptake and reduced seizures inBrain communications · 2022Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundMutations in SLC6A1, encoding γ-aminobutyric acid (GABA) transporter 1 (GAT-1), have been recently associated with a spectrum of neurodevelopmental disorders ranging from variable epilepsy syndromes, intellectual disability (ID), autism and others. To date, most identified mutations are de novo. We here report a pedigree of two siblings associated with myoclonic astatic epilepsy, attention deficit hyperactivity disorder (ADHD), and ID.
methodsNext-generation sequencing identified a missense mutation in the SLC6A1 gene (c.373G > A(p.Val125Met)) in the sisters but not in their shared mother who is also asymptomatic, suggesting gonadal mosaicism. We have thoroughly characterized the clinical phenotypes: EEG recordings identified features for absence seizures and prominent bursts of occipital intermittent rhythmic delta activity (OIRDA). The molecular pathophysiology underlying the clinical phenotypes was assessed using a multidisciplinary approach including machine learning, confocal microscopy, and high-throughput
resultsThe GAT-1(Val125Met) mutation destabilizes the global protein conformation and reduces transporter protein expression at total and cell surface. The mutant transporter protein was localized intracellularly inside the endoplasmic reticulum (ER) in both HEK293T cells and astrocytes which may directly contribute to seizures in patients. Radioactive
conclusionsThe seizure phenotypes, ADHD, and impaired cognition are likely caused by a partial loss-of-function of GAT-1 due to protein destabilization resulting from the mutation. Reduced GAT-1 function in astrocytes and neurons may consequently alter brain network activities such as increased seizures and reduced attention.
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