AUTHOR=Seiffert Simone , Pendziwiat Manuela , Hedrich Ulrike B. S. , Helbig Ingo , Weber Yvonne , Schwarz Niklas 

TITLE=KCNC2 variants of uncertain significance are also associated to various forms of epilepsy

JOURNAL=Frontiers in Neurology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1212079

DOI=10.3389/fneur.2023.1212079

ISSN=1664-2295

ABSTRACT=<p>Recently, <italic>de novo</italic> variants in <italic>KCNC2</italic>, coding for the potassium channel subunit K<sub>V</sub>3.2, have been described as causative for various forms of epilepsy including genetic generalized epilepsy (GGE) and developmental and epileptic encephalopathy (DEE). Here, we report the functional characteristics of three additional <italic>KCNC2</italic> variants of uncertain significance and one variant classified as pathogenic. Electrophysiological studies were performed in <italic>Xenopus laevis</italic> oocytes. The data presented here support that <italic>KCNC2</italic> variants with uncertain significance may also be causative for various forms of epilepsy, as they show changes in the current amplitude and activation and deactivation kinetics of the channel, depending on the variant. In addition, we investigated the effect of valproic acid on K<sub>V</sub>3.2, as several patients carrying pathogenic variants in the <italic>KCNC2</italic> gene achieved significant seizure reduction or seizure freedom with this drug. However, in our electrophysiological investigations, no change on the behavior of K<sub>V</sub>3.2 channels could be observed, suggesting that the therapeutic effect of VPA may be explained by other mechanisms.</p>