Abstract, originally published in Brain Communications
Advances in gene discovery have identified genetic variants in the solute carrier family 6 member 1 (SLC6A1) gene as a monogenic cause of neurodevelopmental disorders, including epilepsy with myoclonic atonic seizures, autism spectrum disorder, and intellectual disability. The SLC6A1 gene encodes for the GABA transporter protein type 1 (GAT1), which is responsible for the reuptake of the neurotransmitter GABA, the primary inhibitory neurotransmitter in the central nervous system, from the extracellular space. GABAergic inhibition is essential to counterbalance neuronal excitation, and when significantly disrupted, it negatively impacts brain development leading to developmental differences and seizures. Aggregation of patient variants and observed clinical manifestations expand understanding of the genotypic and phenotypic spectrum of this disorder. Here, we assess genetic and phenotypic features in 116 individuals with SLC6A1 variants, the vast majority of which are likely to lead to GAT1 loss-of-function. The knowledge acquired will guide therapeutic decisions and the development of targeted therapies that selectively enhance transporter function and may improve symptoms. We analyzed the longitudinal and cell type-specific expression of SLC6A1 in humans and localization of patient and control missense variants in a novel GAT1 protein structure model. In this update, we discuss the progress made in understanding and treating SLC6A1-related disorders thus far, through the concerted efforts of clinicians, scientists, and family support groups.