Our Symposium was a great success and SC6A1 is steadily making progress due to the diligent work of our attendees. We thank everyone who showed up and made this event happen! The video and sound quality of the recording is poor due to a hotel power outage.  Below is a summary of our presenters, discussion overview and links to our slides.


“The Clinical Presentation of SLC6A1” – Katie Helbig

Helbig gave a thorough overview of what is currently known of SLC6A1 as a disorder, specifically in the clinical setting. Starting with Carvill’s research study in 2015 and then Johannesen’s 2018 study, she shared the following findings:

  • There are currently 41 unique SLC6A1 variants reported in HGMD (Human Gene Mutation Database) and 39, likely, pathogenic SLC6A1 variants in ClinVar (similar public database)
    • The most common variant type is a de novo missense mutation.
  • Epilepsy is present in 81% of individuals; meaning, SLC6A1 is not exclusively an epilepsy syndrome—which it is often characterized as.
    • Of these, 65% of individuals can become seizure free with AEDs.
    • Furthermore, generalized seizures are the most common type.
  • There are developmental delays in 91% of individuals.
  • Less observed traits include ataxia/tremor, autism, ADHD, aggression, and hypotonia.
  • Further research is needed for genotype-phenotype correlations.
    Helbig Slides (download)

“Characterization of Variant Tolerant and Intolerant Sites of SLC6A1” – Dennie’s Lal, PhD

Dr. Lal and his team have been compiling variant sequences from genetic databases so that digital models can be created with pathogenic zones. Specifically, Dr. Lal presented his findings on genes closely related to SLC6A1 and suggested that these pathogenic zones could correlate to SLC6A1. Here are his key take-aways:

  • A genetic variant does not always equal pathogenic, meaning every SLC6A1 mutation does not equal a clinical case.
  • Spacial scoring can identify regions that likely correlate with pathogenic states.
    • V2PMapper can create digital protein models with highlighted pathogenic regions
  • SLC6A1 protein structure has not been experimentally determined, but it can be compared to similar genes.
    • By using the data of 13 SLC6A* known disorders (ie. SLC6A8, SLC6A3, etc.), a likely model of SLC6A1 can be created.
      • This SLC6A1 model could then aid identification of SLC6A1 variants that correlate with pathogenic states.
      • This conclusion is possible because these related disorders have nearly identical structures in key regions of the protein (structure = function). Instead, these genes vary in where they are expressed.
    • Further clinical data of patients is needed to further compare results and functional data.
      Lal Slides (download)

“Mechanisms of SLC6A1 Dysfunction” – Andrew Escayg, PhD

Dr. Escayg presented information on specific SLC6A1 variants and their cellular effects by utilizing past research strategies for genes like SCN1A and the 2018 research of Mattison and Butler.

  • Escayg’s lab relies heavily upon EGL Genetics to screen patients and their genetics.
    • Children with severe epilepsy are most commonly referred through this resource.
  • SLC6A1 encodes the GAT 1 GABA transporter, and GAT1 mutations reduce GABA transport, thus affecting neuronal excitability.
    • One common variant, SLC6A1 c.850-2A>G, causes exon skipping, but additional mechanisms were not discussed.
  • Escayg agreed that no genotype-phenotype correlations are currently present.
    Escayg slides (download)

“Mouse & Stem Cell Models for SLC6A1” – Katy Kang, PhD

Dr. Kang presented the raw findings of multiple, on-going experiments aimed at identifying the underlying pathophysiology and mechanism-based therapies for SLC6A1 mutations.

  • In broad terms, Dr. Kang’s research works by identifying mutations in epilepsy patients, then characterizing these mutations through recombinant receptor Petri cultures, then generating and characterizing knockin mice with heterozygous mutations, and then correlating these findings with human pathophysiology. After all of this, mechanism-based therapy can be developed.
  • From this process, Dr. Kang shared where GAT1 is expressed at the circuitry, cellular, protein, mRNA, and genetic levels.
  • Next, she discussed common phenotypes of mutations in SLC6A1, in particular, epilepsy and intellectual disability.
  • Furthermore, she compared outcomes of SLC6A1 knockin mice to GABR mice—sharing that SLC6A1 mice have better survival rates.
  • She also discussed the advantages and disadvantages of using global and conditional knockin mice procedures.
    • By using conditional knockin, more precise information can be found.
  • Alongside her current mouse models, Dr. Kang hopes to validate her findings in human iPSC derived neurons and organoids.
    • Is currently using the skin cells of a Angelman syndrome patient to explore this step.
      Kang slides (download)

“Zebrafish Models for SLC6A1” – Camila Esguerra, PhD

Dr. Esguerra utilizes the Zebrafish model to study the causes of brain disorders, in particular, epilepsy. She explained the benefits of using this model for research and how it’s been used in SCN1A, a related epileptic disorder.

  • Esguerra’s lab regularly uses Zebrafish for phenotypic analysis and drug screening.
  • Mutant Zebrafish mimicked the phenotype of patients with the same SCN1A disorder.
  • Behavioral larval locomotor assay allowed her lab to track movements and make conclusions on behavior.
    • Altered shoaling (grouping) behavior suggested autism
      Esguerra slides (download)

“Pharmacological Thoughts for SLC6A1” – Michael Rogawski, PhD

Dr. Rogawski summarized known pharmacological therapies that could aid gene therapy for SLC6A1. By analyzing the action of pharmacological molecules like tiagabine and PTZ on GABA a&b receptors, conclusions on excess extracellular GABA could be made. For example, preconvulsive states and mild seizures occurred in PTZ treated neurons. Dr. Rogawski also discussed the structure for GABA a&b structures to explain the mechanism of action of these molecules.
Rogawski slides (download)

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