SLC6A1 is a recently discovered pathogenic mutation and is only on 13% of panel testing, so the condition is very under-diagnosed. Dr. Dennis Lal’s renowned genomics lab has published an incidence of 1;38,000 births. Please refer to his study in Brain for additional details along with an excel attachment.
Dr. Ingo Helbig at Children’s Hospital of Philadelphia wrote a blog explaining the condition in Beyond the Ion Channel: Click Here and discussing the prevalence: Click Here
SLC6A1 is the 10th most prevalent gene in autism: Click Here
SLC6A1 is the 6th most prevalent gene in epilepsy: Click Here
SLC6A1 is the 6th most prevalent gene in epilepsy: Click Here
Available Point Mutation Mice
Available Knockout Mice
Patient Fibroblasts
Mice/Animals Articles:
- GABA transporter deficiency causes tremor, ataxia, nervousness, and increased GABA-induced tonic conductance in cerebellum
- Electrolyte therapy reduces spike-and-wave discharges in the WAG/Rij rat model of absence epilepsy
- GABAB receptor antagonism abolishes the learning impairments in rats with chronic atypical absence seizures
- GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAA Versus GABAB Receptors in the Hippocampus
- GABA transporter-1 activity modulates hippocampal theta oscillation and theta burst stimulation-induced long-term potentiation.
- Paradoxical role of GABA in a chronic model of petit mal (absence)-iike epilepsy in the rat
- Gamma aminobutyric acid transporter subtype 1 gene knockout mice: a new model for attention deficit/hyperactivity disorder
- Canine distemper virus induces downregulation of GABAA,GABAB, and GAT1 expression in brain tissue of dogs
- Astrocytic GABA transporter 1 deficit in novel SLC6A1 variants mediated epilepsy: Connected from protein destabilization to seizures in mice and humans
- Synaptic scaling of corticostriatal circuits underlies hyperactivity in GABA Transporter-1 deficient mice
- Patient-derived SLC6A1 variant S295L results in an epileptic phenotype similar to haploinsufficient mice
Clinical Articles:
- Defining the Phenotypic Spectrum of SLC6A1 Mutations
- Phenotypic and Genetic Spectrum of Epilepsy with Myoclonic Atonic Seizures
- Endoplasmic reticulum retention and degradation of a mutation in SLC6A1 associated with epilepsy and autism
- Mild Phenotype Associated with SLC6A1 Gene Mutation: A Case Report with Literature Review
- SLC6A1 Mutation and Ketogenic Diet in epilepsy with myoclonic-atonic seizures
- Language Regression in an Atypical SLC6A1 Mutation
- A Missense SLC6A1 Mutation Associated with LGS
- Mild Phenotype Associated with SLC6A1 Gene Mutation: A Case Report with Literature Review
- Overexpression of SLC6A1 Associates with drug resistance and Poor Prognosis in Prostate Cancer
- Methylphenidate treatment of attention deficit hyperactivity disorder in young people with learning disability and difficult-to-treat epilepsy: Evidence of clinical benefit
- De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia
- Genetic mosaicism, intrafamilial phenotypic heterogeneity, and molecular defects of a novel missense SLC6A1 mutation associated with epilepsy and ADHD
- Environmental enrichment implies GAT-1 as a potential therapeutic target for stroke recovery.
- Genetic Mosaicism, Intrafamilial Phenotypic Heterogeneity, and Molecular Defects of a Novel Missense SLC6A1 Mutation Associated with Epilepsy and ADHD
- Intrafamilial Variability in SLC6A1-related Neurodevelopmental Disorders
- SLC6A1 variant pathogenicity, molecular function, and phenotype: a genetic and clinical analysis
- Insights into cognitive and behavioral comorbidities of SLC6A1-related epilepsy: five new cases and literature review
Pharmacological Papers:
- Aggravation of Epilepsy by Anti-Epileptic Drugs
- Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects
- Pharmacological activation of mGlu5 receptors with the positive allosteric modulator, VU0360172 modulates thalamic GABAergic transmission
- Spatiotemporal Regulation of GABA Concentration in Extracellular Space by Gliotransmission Crucial for Extrasynaptic Receptor-Mediated Improvement of Sensory Tuning Performance in Schizophrenia
- Pharmacological activation of mGlu5 receptors with the positive allosteric modulator VU0360172, modulates thalamic GABAergic transmission
Disease Mechanism:
- Endoplasmic Reticulum Retention
- Structure, Function, and Modulation of γ-Aminobutyric Acid Transporter 1 (GAT1) in Neurological Disorders: A Pharmacoinformatic Prospective
- Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures
- SLC6A1 Variants Identified in Epilepsy Patients Reduce
Y‐aminobutyric Acid Transport (.pdf) - GABA Metabolism and Transport: Effects on Synaptic Efficacy
- GABA Transporter GAT1: A Crucial Determinant of GABAB Receptor Activation in Cortical Circuits?
- Synaptic GABA release prevents GABA transporter type-1 reversal during excessive network activity
- Molecular Characterization of Neurotransmitter Transporters
- Relax, Cool Down and Scaffold: How to Restore Surface Expression of Folding-Deficient Mutant GPCRs and SLC6 Transporters
- GABA uptake transporters support dopamine release in dorsal striatum with maladaptive downregulation in a parkinsonism model
- Common molecular mechanisms of SLC6A1 variant- mediated neurodevelopmental disorders in astrocytes and neurons
- Structural basis of GABA reuptake inhibition
- Yo GABA GABA! Convergent Mechanisms Driven by Gain-of-Function GABRD and Loss-of-Function SLC6A1 Variants Implicate Elevated GABAergic Tone in Generalized Epilepsies
- PDZ interaction of the GABA transporter GAT1 with the syntenin-1 in Neuro-2a cells
- TorC1 and Nitrogen Catabolite Repression Control of Integrated GABA Shunt and Retrograde Pathway Gene Expression
- The lignin-degrading abilities of Gelatoporia subvermispora gat1 and pex1 mutants generated via CRISPR/Cas9
- Ketone bodies promote stroke recovery via GAT-1-dependent cortical network remodeling
Other Disease Correlations:
- Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism
- Inhibitory co-transmission from midbrain dopamine neurons relies on presynaptic GABA uptake
- Activation of GABA receptor attenuates intestinal inflammation by modulating enteric glial cells function through inhibiting NF-κB pathway
Cell Based Screening (iPSC, High Throughput, etc):
- Generation of pure GABAergic neurons by transcription factor programming
- Library Screening Strategy Combining the Concepts of MS Binding Assays and Affinity Selection Mass Spectrometry
- A Genetically Encoded Flourescent Sensor for In Vivo Imaging of GABA
Absence Seizure Literature:
- Clinical and Experimental Insight into Pathophysiology, Comorbidity and Therapy of Absence Seizures
- Dynamics of epileptic activity in a peculiar case of childhood absence epilepsy and correlation with thalamic levels of GABA
- Current and Emerging Treatments for Absence Seizures in Young Patients
- Daily Rhythms of Seizure Activity and Behavior in a Model of Atypical Absence Epilepsy
- Enhanced tonic GABAA inhibition in typical absence epilepsy
- GABAB Receptor and Absence Epilepsy
- Attenuation of transcriptional and signaling responses limits viability of ρ0 Saccharomyces cerevisiae during periods of glucose deprivation
- Augmentation of Tonic GABA(A) Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABA(A) Receptors
- Astrocytic GABA transporter GAT-1 dysfunction in experimental absence seizures
- Essential Roles of GABA Transporter-1 in Controlling Rapid Eye Movement Sleep and in Increased Slow Wave Activity after Sleep Deprivation
- Clinical and Nenrophysiologic Spectrum Associated With Atypical Absence Seizures in Children With Intractable Epilepsy
- Too Much Inhibition Leads To Excitation in Absence Epilepsy
- Astrocytic GABA transporter 1 deficit in novel SLC6A1 variants mediated epilepsy: Connected from protein destabilization to seizures in mice and humans
Quality of Life Measurements:
Glycerol Phenylbutyrate:
- 4-phenylbutyrate restored GABA uptake and reduced seizures in SLC6A1 variants-mediated disorders
- Chemical Chaperone Therapy for Developmental and Epileptic Encephalopathies (DEEs) – Identifying Candidates Via Literature Review
- 4-Phenylbutyrate restored γ-aminobutyric acid uptake and reduced seizures in SLC6A1 patient variant-bearing cell and mouse models
- Experimental and Bioinformatic Insights into the Effects of Epileptogenic Variants on the Function and Trafficking of the GABA Transporter GAT-1
Other:
- EuroEPINOMICS Functional Genomic Variation in the Epilepsies
- Dissecting the phenotypic and genetic spectrum of early childhood-onset generalized epilepsies
- The Role of Neuroinflammation in Evolution of Childhood Epilepsy
- Terpene Trilactones from Ginkgo biloba Are Antagonists of Cortical Glycine and GABAA Receptors*
- A comparison of the transport kinetics of glycine transporter 1 and glycine transporter 2.
- Development of Positron Emission Tomography (PET) Radiotracers for the GABA Transporter 1 (GAT1)
- Gene Therapy: Novel Approaches to Targeting Monogenic Epilepsies
- Myoclonic-Atonic Epilepsy Caused by a Novel de Novo Heterozygous Missense Variant in the SLC6A1 Gene: Brief Discussion of the Literature and Detailed Case Description of a Severely Intellectually Disabled Adult Male Patient.
- A draft conceptual model of SLC6A1 neurodevelopmental disorder
- A case of epilepsy with myoclonic atonic seizures caused by SLC6A1 gene mutation due to balanced chromosomal translocation
- A call to arms against ultra-rare diseases
Other Helpful Links: