SLC6A1 variants identified in epilepsy patients reduce γ-aminobutyric acid transport

  • Epilepsia. 2018 Sep;59(9):e135-e141. doi: 10.1111/epi.14531.
Kari A Mattison  1  2 ,  Kameryn M Butler  1  2 ,  George Andrew S Inglis  1  2 ,  Oshrat Dayan  3 ,  Hanna Boussidan  3 ,  Vikas Bhambhani  4 ,  Bryan Philbrook  5 ,  Cristina da Silva  6 ,  John J Alexander  1  6 ,  Baruch I Kanner  3 ,  Andrew Escayg  1  2
Affiliations
  • 1. Department of Human Genetics, Emory University, Atlanta, Georgia.
  • 2. Genetics and Molecular Biology Program, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, Georgia.
  • 3. Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University Hadassah Medical School, Jerusalem, Israel.
  • 4. Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.
  • 5. Department of Pediatric Neurology, Emory University, Atlanta, Georgia.
  • 6. EGL Genetics, Tucker, Georgia.
PMID: 30132828 DOI: 10.1111/epi.14531
Abstract

Previous reports have identified SLC6A1 variants in patients with generalized epilepsies, such as myoclonic-atonic epilepsy and childhood absence epilepsy. However, to date, none of the identified SLC6A1 variants has been functionally tested for an effect on GAT-1 transporter activity. The purpose of this study was to determine the incidence of SLC6A1 variants in 460 unselected epilepsy patients and to evaluate the impact of the identified variants on γ-aminobutyric acid (GABA)transport. Targeted resequencing was used to screen 460 unselected epilepsy patients for variants in SLC6A1. Five missense variants, one in-frame deletion, one nonsense variant, and one intronic splice-site variant were identified, representing a 1.7% diagnostic yield. Using a [3 H]-GABA transport assay, the seven identified exonic variants were found to reduce GABA transport activity. A minigene splicing assay revealed that the splice-site variant disrupted canonical splicing of exon 9 in the mRNA transcript, leading to premature protein truncation. These findings demonstrate that SLC6A1 is an important contributor to childhood epilepsy and that reduced GAT-1 function is a common consequence of epilepsy-causing SLC6A1 variants.

Keywords
GAT-1; absence epilepsy; epilepsy genetics; myoclonic-atonic epilepsy; γ-aminobutyric acid transport.