This report describes a fly model of seizure sensitivity using the fly gene SLO2, which encodes an outwardly rectifying potassium channel subunit activated by high intracellular sodium or calcium levels. Dmel\SLO2 is orthologous to human KCNT1 and KCNT2, both of which are implicated in forms of epilepsy (MIM:614959, MIM:615005, OMIM617771:); all of the associated diseases exhibit autosomal dominant inheritance. Multiple genetic reagents have been generated for Dmel\SLO2 including null mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis.
UAS constructs of the human Hsap\KCNT1 gene have been introduced into flies, including wild-type and variants implicated in human disease; see the 'Disease-Implicated Variants' table below. Using a pan-neuronal drivers, expression of each of the disease-implicated variants results in embryonic lethality; expression restricted to GABAergic neurons results in viable adults that exhibit a seizure phenotype. This system has been used to assess epilepsy drugs most commonly administered to patients with KCNT1-epilepsy.
The human KCNT2 gene has not been introduced into flies.
Effects of a null mutation of Dmel\SLO2 have been assessed in combination with Drosophila genetic models of epilepsy and seizure sensitivity; Drosophila disease models used: epilepsy, SCN-alpha-related (FBhh0000289), seizure-sensitivity model, Dmel\jus (FBhh0000314), seizure-sensitive (postulated), ETNK-related (FBhh0000313). Increases in occurrence of induced seizure-like behavior, in the severity of seizure-like behavior, and in the number of individuals that exhibit spontaneous seizures are observed. Results in Drosophila support the hypothesis that SLO-type potassium channels function as a protective mechanism against neuronal overexcitation and Na+ overload.
[updated Mar. 2024 by FlyBase; FBrf0222196]
KCNT1 and KCNT2 encode outwardly rectifying potassium channel subunits that may co-assemble with other Slo-type channel subunits; activated by high intracellular sodium or calcium levels. [Gene Cards, KCNT1, KCNT2; 2021.11.11]
Many to one: 2 human genes to 1 Drosophila gene.
Many to one: 2 human genes to 1 Drosophila gene.
High-scoring ortholog of human KCNT1 and KCNT2 (1 Drosophila to 2 human). Dmel\SLO2 shares 40-42% identity and 53-55% similarity with the human genes.