# Kcnq2 R213 knock-in mice reveal variant- and region-specific mechanisms underlying self-limited familial neonatal-infantile epilepsy and early infantile developmental and epileptic encephalopathy

## TL;DR

This study uses mouse models to show how two genetic variants in KCNQ2 cause different types of neonatal epilepsy and brain development issues.

## Contribution

The study introduces two novel Kcnq2 knock-in mouse models to reveal variant-specific mechanisms of neonatal epilepsies.

## Key findings

- Kcnq2R213Q/+ mice show severe symptoms like seizures, shortened lifespan, and cortical neuron migration delays.
- Kcnq2R213W/+ mice display milder symptoms with transient seizures and preserved cortical function.
- RNA sequencing shows p.R213Q upregulates genes related to endoplasmic reticulum stress and synaptic regulation.

## Abstract

KCNQ2 variants cause a spectrum of neonatal epilepsies, ranging from self-limited familial neonatal-infantile epilepsy (SeLFNIE) to early infantile developmental and epileptic encephalopathy (EIDEE). Two distinct missense variants at the same residue, p.R213W and p.R213Q, are associated with SeLFNIE and EIDEE, respectively. This study aimed to elucidate the in vivo effects of these variants on brain development and neuronal excitability using two knock-in mouse models, Kcnq2R213W/+ and Kcnq2R213Q/+. We assessed survival, seizure susceptibility, histological and molecular phenotypes, and electrophysiological properties in cortical and hippocampal neurons, and conducted RNA sequencing analyses of cortical tissue to identify transcriptional alterations. Kcnq2R213Q/+ mice exhibited tonic–clonic seizures, shortened lifespan, delayed cortical neuron migration, abnormal elongation of the axon initial segment in cortical neurons, and dentate gyrus-specific gliosis. In contrast, Kcnq2R213W/+ mice showed a milder phenotype with transient seizures and largely preserved cortical function. RNA sequencing analyses revealed that p.R213Q selectively upregulated genes involved in endoplasmic reticulum stress and synaptic regulation, together with compensatory upregulation of potassium channel subunits. These findings demonstrate that the two Kcnq2 variants lead to distinct neurodevelopmental phenotypes, attributable not only to differential impairment of the M-current but also to aberrant cortical development and stress response pathways. In particular, p.R213Q induces sustained cortical hyperexcitability and axon initial segment abnormalities, whereas p.R213W results in the milder phenotype. The established knock-in models provide powerful tools for elucidating disease mechanisms of EIDEE and SeLFNIE, and developing targeted therapies for KCNQ2-related epilepsies.

The online version contains supplementary material available at 10.1186/s40478-026-02264-4.