Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures

Abstract

GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is 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 SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most 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 cases.

Figure 1

Distribution of SLC6A1 Mutations A two-dimensional representation of the 12 SLC6A1 transmembrane domains shown from 1 through 12, left to right, and predicted intracellular and extracellular domains. The six pathogenic mutations identified in this study (red), as well as the previously reported p.Leu151Argfs^∗35 variant (blue) in an individual with intellectual disability and myoclonic-astatic seizures, are highlighted. In three-dimensional space, transmembrane domains 1–5 and 6–12 are folded such that the GABA binding pocket is between transmembrane domains 1 and 6. Thus, the four pathogenic missense substitutions all cluster around the GABA binding pocket and are likely to disrupt GABA transport from the extracellular space into the pre-synaptic terminal.