Pharmacological rescue of mutated Kv3.1 ion-channel linked to progressive myoclonus epilepsies

Progressive myoclonus epilepsyKCNC1variant causes a developmental dendritopathy

“…19 Gating pore currents are best detected in Xenopus laevis oocytes, where large currents are produced. In contrast to reported complete 4 or partial 18 reductions in expression in some experimental conditions, K V 3.1b R320H produced WT-like current amplitude in our conditions (Figure 5A,B). Voltage dependence of activation also did not differ from the WT channels 34 mV, and −4.9 ± 1.3 mV for homomeric mutant, simulated heterozygous condition, and wild-type (WT) channels, respectively (p > .05, two-way analysis of variance [ANOVA] followed by Bonferroni multiple comparison test).…”

“…[15][16][17] The R320H mutation in K V 3.1 removes the highly conserved fourth arginine of the S4 voltage sensor of the channel and produces a dominant negative loss-of-function in both splice variants. 4,5,18 However, the specific effects of R320H are dependent on splice variant and heterologous expression system. 4,5,18 Mutations removing voltage-sensing arginines can introduce pathogenic gating pore currents through the voltage sensor domain (VSD).…”

“…4,5,18 However, the specific effects of R320H are dependent on splice variant and heterologous expression system. 4,5,18 Mutations removing voltage-sensing arginines can introduce pathogenic gating pore currents through the voltage sensor domain (VSD). 19,20 In the Drosophila K V 1 (Shaker), the analogous arginine to histidine mutation of the fourth voltage sensing arginine (K V 1.1 R371H ) introduces a proton-selective pore in the VSD that opens upon depolarization.…”

KCNC1‐related disorders: new de novo variants expand the phenotypic spectrum

“…Another more specific therapeutic strategy might be to directly activate mutant heterotetrameric K V 3 channels. The feasibility of such an approach with a compound called RE01 has been recently reported in vitro …”

Progressive myoclonic epilepsy: myoclonic epilepsy and ataxia due to KCNC1 mutation (MEAK): a case report and review of the literature

“…Many other types of mutations have been described in KCNC1, resulting in different phenotypic N. Barot, et al expression, such as infantile-onset developmental epileptic encephalopathy (DEE) and dysmorphic features without epilepsy (Cameron et al, 2019;Poirier et al, 2017). A recent study found that a small molecular activator of Kv3 channel (RE01) can reverse the neurophysiologic changes from mutation and may guide us towards developing a therapeutic agent for MEAK (Munch et al, 2018).…”