Abstracts

This is a Late Breaking abstract

Rationale: The solute carrier family 6, member 1 (SLC6A1) gene encodes the gamma aminobutyric acid (GABA) transporter type 1 (GAT1) protein and contributes to maintaining homeostasis of excitatory and inhibitory neurotransmitters. GAT1 mediates the reuptake of the inhibitory neurotransmitter GABA at the synapse which is essential to protect from seizure activity. SLC6A1 has recently been implicated in a spectrum of neurological disorders. The clinical phenotype presents as a dominant disorder that is pleiotropic and shows variable expressivity of symptoms including developmental delay, epilepsy, intellectual disability, motor dysfunction, and autism spectrum disorder. Seizure types range from absence seizures to myoclonic atonic seizures and that are resistant to standard therapeutics in many of the patients. Furthermore, GAT1 is a potential therapeutic target for other forms of epilepsy. Previous research has identified GAT1 loss-of-function as the mechanism of pathogenesis in SLC6A1 related disorders. In this study, we are using the Drosophila melanogaster model organism to identify patient variant mechanisms.  

Methods: We recruited 15 patients through the Brain Gene Registry with rare SLC6A1 related disorders and completed a genotype-phenotype correlative study to identify patients who were responsive and non-responsive to current therapeutics. To evaluate variants specific effects i, I created patient specific personalized constructs to insert into the Drosophila genome to express our variants of interest. I expressed these patient variants in the Drosophila Gat protein to evaluate allele specific effects. To evaluate variant function in flies, I characterized phenotypes associated with loss of the Gat protein.

Results: Seizures were reported in 9/10 patients and the average number of therapeutics attempted was 4.6 per patient. Valproic acid was the most effective therapeutic among the patient cohort and resulted in a partial reduction in seizures. I found that Gat deficient flies are bang sensitive analogous to seizure activity in humans, exhibit motor dysfunction, and have a reduced lifespan. I will use these assays to evaluate variant specific effects in Drosophila and I will attempt to suppress seizure phenotypes with valproic acid and GAT1 agonists.

Conclusions: We have identified phenotypes associated with Gat loss-of-function which will provide a baseline to evaluate variant associated phenotypes. Our short-term goal is to evaluate phenotypes associated with each variant and correlate this with our patient phenotypes. Our long-term goal is to apply these personalized patient specific models to predict variant response to therapeutics. Identifying therapeutics that will be most effective in suppressing seizure phenotypes by genotype will eliminate several rounds of trial and error for the patients and result in improved outcome for those living with SLC6A1 related disorders.

Funding: This project is supported by startup funds (SEED) to Dr. Michael Wangler from the department of Molecular and Human Genetics (MHG) at Baylor College of Medicine (BCM).