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

Jérôme Devaux (1) , Affef Abidi (2) , Agathe Roubertie (3, 4) , Florence Molinari (5, 2) , Hélène Becq (5, 2) , Caroline Lacoste (2, 6) , Laurent Villard (2, 5) , Mathieu Milh (2, 6) , Laurent Aniksztejn (5, 2)

1 CRN2M - Centre de recherche en neurobiologie - neurophysiologie de Marseille
2 GMGF - Génétique Médicale et Génomique Fonctionnelle
3 INM - Institut des Neurosciences de Montpellier
4 CHU - Hôpital Lapeyronie [Montpellier]
5 INMED - INSERM U901 - Institut de Neurobiologie de la Méditerranée [Aix-Marseille Université]
6 Service de pédiatrie et neurologie pédiatrique

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.

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

Domains: Life Sciences [q-bio]; Genetics; Life Sciences [q-bio]; Human health and pathology; Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]

Jérôme Devaux, Affef Abidi, Agathe Roubertie, Florence Molinari, Hélène Becq, et al.. A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity. Epilepsia, 2016, 57 (5), pp.e87 - e93. ⟨10.1111/epi.13366⟩. ⟨hal-01668018⟩