SLC 6A1 SLC SLC 6A1 variants identified in epilepsy patients reduce γ‐aminobutyric acid transport

摘要

Summary Previous reports have identified SLC 6A1 variants in patients with generalized epilepsies, such as myoclonic‐atonic epilepsy and childhood absence epilepsy. However, to date, none of the identified SLC 6A1 variants has been functionally tested for an effect on GAT ‐1 transporter activity. The purpose of this study was to determine the incidence of SLC 6A1 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 SLC 6A1 . 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 SLC 6A1 is an important contributor to childhood epilepsy and that reduced GAT ‐1 function is a common consequence of epilepsy‐causing SLC 6A1 variants.