Seiffert S et al. (2023), KCNC2 variants of uncertain significance are al...

XB-ART-59829

Front Neurol 2023 Jan 01;14:1212079. doi: 10.3389/fneur.2023.1212079.

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

Seiffert S , Pendziwiat M , Hedrich UBS , Helbig I , Weber Y , Schwarz N .

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Recently, de novo variants in KCNC2, coding for the potassium channel subunit KV3.2, 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 KCNC2 variants of uncertain significance and one variant classified as pathogenic. Electrophysiological studies were performed in Xenopus laevis oocytes. The data presented here support that KCNC2 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 KV3.2, as several patients carrying pathogenic variants in the KCNC2 gene achieved significant seizure reduction or seizure freedom with this drug. However, in our electrophysiological investigations, no change on the behavior of KV3.2 channels could be observed, suggesting that the therapeutic effect of VPA may be explained by other mechanisms.

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Figure 1. Electrophysiological analysis of the KCNC2 variants F382C, I465V, N530H and S333T. (A) Mean current amplitudes of oocytes injected with WT (n = 47), S333T (n = 17) and equal amounts of WT + S333T (n = 13). (B) Mean voltage-dependent activation of KV3.2 channels for WT (n = 47), S333T (n = 17) and equal amounts of WT + S333T (n = 13). Lines illustrate Boltzmann Function fit to the data points. (C) Mean voltage-dependent deactivation time constant of KV3.2 channel WT (n = 46), S333T (n = 17) and WT + S333T (n = 13). (D) Mean current amplitudes of oocytes injected with WT (n = 47), F382C (n = 27) and equal amounts of WT + F382C (n = 23). (E) Mean voltage-dependent activation of KV3.2 channel for WT (n = 47) and equal amounts of WT + F382C (n = 23). Lines illustrate Boltzmann Function fit to the data points. (F) Mean voltage-dependent deactivation time constant of KV3.2 channel WT (n = 46) and WT + F382C (n = 20). (G) Mean current amplitudes of oocytes injected with WT (n = 47), I465V (n = 17) and equal amounts of WT + I465V (n = 15). (H) Mean voltage-dependent activation of KV3.2 channel for WT (n = 47) and equal amounts of WT + I465V (n = 15). Lines illustrate Boltzmann Function fit to the data points. (I) Mean voltage-dependent deactivation time constant of KV3.2 channel WT (n = 46) and WT + I465V (n = 15). (J) Mean current amplitudes of oocytes injected with WT (n = 47), N530H (n = 12) and equal amounts of WT + N530H (n = 18). (K) Mean voltage-dependent activation of KV3.2 channel for WT (n = 47), N530H (n = 12) and equal amounts of WT + N530H (n = 18). Lines illustrate Boltzmann Function fit to the data points. (L) Mean voltage-dependent deactivation time constant of KV3.2 channel WT (n = 46), N530H (n = 12) and WT + N530H (n = 17). All data are shown as means ± SEM. Statistically significant differences are indicated by an asterisk (*p < 0.05).

Figure 2. Application of 30 mM VPA does not affect KV3.2 WT channels. (A) Mean current amplitudes of oocytes injected with WT and recorded as baseline (n = 42), after perfusion with bath solution containing 0 mM VPA (n = 17) and after perfusion with bath solution containing 30 mM VPA (n = 12). (B) Mean voltage-dependent activation of KV3.2 channels for WT (n = 47), after 0 mM VPA (n = 17) and after 30 mM VPA (n = 12). Lines illustrate Boltzmann Function fit to the data points. (C) Mean voltage-dependent deactivation time constants of KV3.2 channels for WT (n = 47), after 0 mM VPA (n = 17) and after 30 mM VPA (n = 12). All data are shown as means ± SEM.

References [+] :

Biervert, A potassium channel mutation in neonatal human epilepsy. 1998, Pubmed, Xenbase