# 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.

## Key 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.