SLC6A1 variants identified in epilepsy patients reduce γ-aminobutyric acid transport.
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.
['Mattison|Kari A|KA|', 'Butler|Kameryn M|KM|', 'Inglis|George Andrew S|GAS|', 'Dayan|Oshrat|O|', 'Boussidan|Hanna|H|', 'Bhambhani|Vikas|V|', 'Philbrook|Bryan|B|', 'da Silva|Cristina|C|', 'Alexander|John J|JJ|', 'Kanner|Baruch I|BI|', 'Escayg|Andrew|A|']
D015331:Cohort Studies D004252:DNA Mutational Analysis D004827:Epilepsy D005260:Female D050485:GABA Plasma Membrane Transport Proteins D005786:Gene Expression Regulation D020022:Genetic Predisposition to Disease D057809:HEK293 Cells D006367:HeLa Cells D006801:Humans D008297:Male D009154:Mutation D012333:RNA, Messenger D014162:Transfection D014316:Tritium D005680:gamma-Aminobutyric Acid
γ-aminobutyric acid transport myoclonic-atonic epilepsy absence epilepsy GAT-1 epilepsy genetics