Background: Increasing evidence indicates a robust correlation between epilepsy and variants of the Kv7.2 () channel, which is critically involved in directing M-currents and regulating neuronal excitability within the nervous system. With the advancement of next-generation sequencing, the identification of variants has surged. Nonetheless, their functional impacts are still being determined, introducing uncertainty into the diagnostic process for affected families and potentially hindering their ability to participate in targeted precision medicine trials. This study aims to elucidate the pathogenicity of these novel variants and explore potential therapeutic interventions.
Methods: Whole-cell patch-clamp recordings, western blotting, and immunofluorescent staining were performed to elucidate the functional consequences of the identified variants. Moreover, coimmunoprecipitation techniques were conducted to explore protein interactions, thus facilitating a deeper understanding of the underlying pathogenetic mechanisms contributing to the disease. Ultimately, the effects of pharmacological interventions were evaluated in vitro using the patch-clamp technique.
Results: Herein, we identified 12 novel variants, further expanding the mutational spectrum of . Our investigation revealed that one gain-of-function variant (p.L102V (c.304C>G)) and three loss-of-function variants (p.H328Q (c.984C>G), p.A336V (c.1007C>T) and p.D563Efs*22 (c.1688_1689insACTT)) had different impacts on the binding of calmodulin and phosphati-dylinositol-4,5-bisphosphate, potentially altering their localisation and protein stability. Furthermore, the application of ML213, unlike Retigabine and ICA-069673, led to a significant increase in the current of p.H328Q.
Conclusion: This study expanded the mutational spectrum of and analysed the genetic and functional consequences, as well as the pharmacological rescue, of four variants. These findings offer valuable insights into the precise medicine of -related epilepsy.
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