2. Academic Validation
  3. SLC6A1 variants identified in epilepsy patients reduce γ-aminobutyric acid transport

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

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.

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