Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic atonic seizures

Abstract

GAT-1, encoded by SLC6A1, is one of the major GABA transporters in the brain responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six mutations in SLC6A1 in seven individuals. All presented with the syndrome of epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all likely lead to loss-of-function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE , accounting for ∼4% of unsolved MAE.