Potassium current inactivation as a novel pathomechanism for KCNQ2 developmental and epileptic encephalopathy

TL;DR

A new mechanism involving potassium channel inactivation is identified in a genetic disorder causing neonatal epilepsy and developmental issues.

Contribution

The study reveals current inactivation as a novel pathomechanism for KCNQ2 developmental and epileptic encephalopathy.

Findings

The A265V variant in KCNQ2 causes reduced maximal current density in potassium channels.

The variant leads to a voltage-dependent inactivation process during depolarizing pulses.

The effects of the mutation are modulated by coexpression with other Kv7 subunits.

Abstract

De novo variants in KCNQ2 cause neonatal onset developmental and epileptic encephalopathy (KCNQ2‐DEE; Online Mendelian Inheritance in Man #613720), most often by loss‐of‐function in vitro effects. In this study, we describe a neonatal onset DEE proband carrying a recurrent de novo KCNQ2 variant (c.794C>T; p.A265V) affecting the pore domain of KCNQ2‐encoded Kv7.2 subunits. Whole‐cell patch‐clamp measurement in a mammalian heterologous expression system revealed that, when compared to wild‐type Kv7.2 channels, channels containing Kv7.2 A265V subunits displayed (1) reduced maximal current density; (2) decreased voltage‐dependence of activation; and (3) an unusual inactivation process, with a 50% current reduction during 1–2‐s depolarizing pulses at voltages > 0 mV. These effects were proportional to the number of mutant subunits incorporated in heteromeric channels, being overall less dramatic upon coexpression with Kv7.2 or Kv7.2 + Kv7.3 subunits. These results reveal current inactivation as a novel pathogenetic mechanism for KCNQ2‐DEE caused by a recurrent variant affecting a critical pore residue, further highlighting the importance of in vitro functional assessment for a better understanding of disease molecular pathophysiology.

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