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Epilepsia. 2016 May;57(5):e87-93. doi: 10.1111/epi.13366. Epub 2016 Mar 31.

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

Author information

1
CNRS, Aix-Marseille University, CRN2M-UMR7286, Marseille, France.
2
GMGF, Aix-Marseille University, Marseille, France.
3
INSERM, UMR_S 910, Marseille, France.
4
Pediatric Neurology Department, Montpellier University Hospital, Montpellier, France.
5
INSERM U1051, INM Montpellier, Montpellier, France.
6
Mediterranean Neurobiology Institute INMED, Aix-Marseille University, Marseille, France.
7
INSERM, UMR_S 901, Marseille, France.
8
Timone Children Hospital, Pediatric Neurology Department, APHM, Marseille, France.

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.

KEYWORDS:

Axon initial segment; Early onset epileptic encephalopathy; Gain of function; KCNQ2; Linopirdine; M-current

PMID:
27030113
DOI:
10.1111/epi.13366
[Indexed for MEDLINE]
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