TY - JOUR
T1 - Phenotypic and functional assessment of two novel KCNQ2 gain-of-function variants Y141N and G239S and effects of amitriptyline treatment
AU - Bayat, Allan
AU - Iavarone, Stefano
AU - Miceli, Francesco
AU - Jakobsen, Anne V
AU - Johannesen, Katrine M
AU - Nikanorova, Marina
AU - Ploski, Rafal
AU - Szymanska, Krystyna
AU - Flamini, Robert
AU - Cooper, Edward C
AU - Weckhuysen, Sarah
AU - Taglialatela, Maurizio
AU - Møller, Rikke S
N1 - Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2024
Y1 - 2024
N2 - While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n = 1) or G239S variant (n = 2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell patch-clamp electrophysiological experiments in Chinese Hamster Ovary cells transiently-transfected with the cDNAs encoding Kv7.2 subunits carrying the Y141N or G239S variants in homomeric or heteromeric configurations with Kv7.2 subunits, revealed that currents from channels incorporating mutant subunits displayed increased current densities and hyperpolarizing shifts of about 10 mV in activation gating; both these functional features are consistent with an in vitro GoF phenotype. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Based on in vitro results, amitriptyline was prescribed in one patient (G239S), prompting a significant improvement in motor, verbal, social, sensory and adaptive behavior skillsduring the two-year-treatment period. Thus, our results suggest that KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures and that treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.
AB - While loss-of-function (LoF) variants in KCNQ2 are associated with a spectrum of neonatal-onset epilepsies, gain-of-function (GoF) variants cause a more complex phenotype that precludes neonatal-onset epilepsy. In the present work, the clinical features of three patients carrying a de novo KCNQ2 Y141N (n = 1) or G239S variant (n = 2) respectively, are described. All three patients had a mild global developmental delay, with prominent language deficits, and strong activation of interictal epileptic activity during sleep. Epileptic seizures were not reported. The absence of neonatal seizures suggested a GoF effect and prompted functional testing of the variants. In vitro whole-cell patch-clamp electrophysiological experiments in Chinese Hamster Ovary cells transiently-transfected with the cDNAs encoding Kv7.2 subunits carrying the Y141N or G239S variants in homomeric or heteromeric configurations with Kv7.2 subunits, revealed that currents from channels incorporating mutant subunits displayed increased current densities and hyperpolarizing shifts of about 10 mV in activation gating; both these functional features are consistent with an in vitro GoF phenotype. The antidepressant drug amitriptyline induced a reversible and concentration-dependent inhibition of current carried by Kv7.2 Y141N and G239S mutant channels. Based on in vitro results, amitriptyline was prescribed in one patient (G239S), prompting a significant improvement in motor, verbal, social, sensory and adaptive behavior skillsduring the two-year-treatment period. Thus, our results suggest that KCNQ2 GoF variants Y141N and G239S cause a mild DD with prominent language deficits in the absence of neonatal seizures and that treatment with the Kv7 channel blocker amitriptyline might represent a potential targeted treatment for patients with KCNQ2 GoF variants.
KW - Amitriptyline
KW - Developmental encephalopathy
KW - Gain of function
KW - Genotype-phenotype
KW - Voltage-gated potassium channel
UR - http://www.scopus.com/inward/record.url?scp=85185223235&partnerID=8YFLogxK
U2 - 10.1016/j.neurot.2023.10.006
DO - 10.1016/j.neurot.2023.10.006
M3 - Journal article
C2 - 38241158
SN - 1878-7479
VL - 21
SP - 1
EP - 9
JO - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
JF - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
IS - 1
M1 - e00296
ER -