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

作者：Devaux Jerome; Abidi Affef; Roubertie Agathe; Molinari Florence; Becq Helene; Lacoste Caroline; Villard Laurent; Milh Mathieu; Aniksztejn Laurent

来源：Epilepsia, 2016, 57(5): E87-E93.

DOI：10.1111/epi.13366

<jats:title>Summary</jats:title><jats:p>Mutations in the <jats:italic><jats:styled-content style="fixed-case">KCNQ</jats:styled-content>2</jats:italic> gene encoding the voltage‐gated potassium channel subunit Kv7.2 cause early onset epileptic encephalopathy (<jats:styled-content style="fixed-case">EOEE</jats:styled-content>). 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 <jats:italic>p.V175L</jats:italic> mutation of Kv7.2 (Kv7.2<jats:sup>V175L</jats:sup>) found in a patient presenting <jats:styled-content style="fixed-case">EOEE</jats:styled-content>. We observed that the mutation produced a 25–40 mV hyperpolarizing shift of the conductance–voltage relationship of both the homomeric Kv7.2<jats:sup>V175L</jats:sup> and heteromeric Kv7.2<jats:sup>V175L</jats:sup>/Kv7.3 channels compared to wild‐type channels and a 10 <jats:styled-content style="fixed-case">mV</jats:styled-content> hyperpolarizing shift of Kv7.2<jats:sup>V175L</jats:sup>/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 μ<jats:sc>m</jats:sc> 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 <jats:styled-content style="fixed-case">EOEE</jats:styled-content>. These findings alert us that drugs aiming to increase Kv7 channel activity might have adverse effects in <jats:styled-content style="fixed-case">EOEE</jats:styled-content> in the case of gain‐of‐function variants.</jats:p>

• 出版日期2016-5