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A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity

Authors :
Florence Molinari
Laurent Aniksztejn
Mathieu Milh
Jérôme Devaux
Laurent Villard
Affef Abidi
Hélène Becq
Caroline Lacoste
Agathe Roubertie
Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M)
Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Génétique Médicale et Génomique Fonctionnelle (GMGF)
Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
Hôpital Lapeyronie [Montpellier] (CHU)
Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université] (INMED - INSERM U901)
Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Service de pédiatrie et neurologie pédiatrique
Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)
Villard, Laurent
Institut des Neurosciences de Montpellier (INM)
Source :
Epilepsia, Epilepsia, Wiley, 2016, 57 (5), pp.e87-e93. ⟨10.1111/epi.13366⟩, Epilepsia, 2016, 57 (5), pp.e87-e93. ⟨10.1111/epi.13366⟩
Publication Year :
2016
Publisher :
Wiley, 2016.

Abstract

International audience; Mutations in the KCNQ2 gene encoding the voltage-gated potassium channel subunit Kv7.2 cause early onset epileptic encephalopathy (EOEE). Most mutations have been shown to induce a loss of function or to affect the subcellular distribution of Kv7 channels in neurons. Herein, we investigated functional consequences and subcellular distribution of the p.V175L mutation of Kv7.2 (Kv7.2 V175L) found in a patient presenting EOEE. We observed that the mutation produced a 25–40 mV hyperpolarizing shift of the conductance–voltage relationship of both the homomeric Kv7.2 V175L and hetero-meric Kv7.2 V175L /Kv7.3 channels compared to wild-type channels and a 10 mV hyper-polarizing shift of Kv7.2 V175L /Kv7.2/Kv7.3 channels in a 1:1:2 ratio mimicking the patient situation. Mutant channels also displayed faster activation kinetics and an increased current density that was prevented by 1 lM linopirdine. The p.V175L mutation did not affect the protein expression of Kv7 channels and its localization at the axon initial segment. We conclude that p.V175L is a gain of function mutation. This confirms previous observations showing that mutations having opposite consequences on M channels can produce EOEE. These findings alert us that drugs aiming to increase Kv7 channel activity might have adverse effects in EOEE in the case of gain-of-function variants.

Details

ISSN :
00139580
Volume :
57
Database :
OpenAIRE
Journal :
Epilepsia
Accession number :
edsair.doi.dedup.....1bc6e5cb14f9a38eda1d700774fe1d5e