title: A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity.
abstract: 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 heteromeric Kv7.2(V175L) /Kv7.3 channels compared to wild-type channels and a 10 mV hyperpolarizing 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 μm 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.
authors.affiliation: CNRS, Aix-Marseille University, CRN2M-UMR7286, Marseille, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Devaux
authors.affiliation: GMGF, Aix-Marseille University, Marseille, France.|INSERM, UMR_S 910, Marseille, France.
authors.forename: Affef
authors.initials: A
authors.lastname: Abidi
authors.affiliation: Pediatric Neurology Department, Montpellier University Hospital, Montpellier, France.|INSERM U1051, INM Montpellier, Montpellier, France.
authors.forename: Agathe
authors.initials: A
authors.lastname: Roubertie
authors.affiliation: Mediterranean Neurobiology Institute INMED, Aix-Marseille University, Marseille, France.|INSERM, UMR_S 901, Marseille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Molinari
authors.affiliation: Mediterranean Neurobiology Institute INMED, Aix-Marseille University, Marseille, France.|INSERM, UMR_S 901, Marseille, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Becq
authors.affiliation: GMGF, Aix-Marseille University, Marseille, France.|INSERM, UMR_S 910, Marseille, France.|Timone Children Hospital, Pediatric Neurology Department, APHM, Marseille, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lacoste
authors.affiliation: GMGF, Aix-Marseille University, Marseille, France.|INSERM, UMR_S 910, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Villard
authors.affiliation: GMGF, Aix-Marseille University, Marseille, France.|INSERM, UMR_S 910, Marseille, France.|Timone Children Hospital, Pediatric Neurology Department, APHM, Marseille, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Milh
authors.affiliation: Mediterranean Neurobiology Institute INMED, Aix-Marseille University, Marseille, France.|INSERM, UMR_S 901, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Aniksztejn
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000378:metabolism; D000927:Anticonvulsants / Q000494:pharmacology; D016466:CHO Cells; D002219:Carbamates / Q000494:pharmacology; D003412:Cricetulus; D004558:Electric Stimulation; D005260:Female; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051658:KCNQ2 Potassium Channel / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010655:Phenylenediamines / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013036:Spasms, Infantile / Q000235:genetics*
chemical_list: D017487:Ankyrins; D000927:Anticonvulsants; D002219:Carbamates; D007211:Indoles; D051658:KCNQ2 Potassium Channel; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D011725:Pyridines; C101866:ezogabine; C061017:linopirdine
keywords: Axon initial segment; Early onset epileptic encephalopathy; Gain of function; KCNQ2; Linopirdine; M-current