17.01.2025

Diverse mechanisms underpinning KCNQ2 encephalopathy

KCNQ2 variants are a significant cause of early-onset epilepsy in children, with a wide spectrum of clinical presentations and outcomes. These variants can lead to diverse phenotypes, ranging from self-limited familial neonatal epilepsy (SLFNE), characterized by good developmental outcomes, to severe developmental and epileptic encephalopathies (DEEs) associated with profound global disability.

Recent research has focused on elucidating the relationship between specific mutations and their functional consequences to better predict developmental outcomes. One particular variant, KCNQ2 G256W, has been identified in a patient with an intermediate severity phenotype. This mutation is located in the pore-gating domain (PGD) turret of the channel, a region previously associated with electrostatic surface charge and toxin binding. Insights from cryo-electron microscopy models suggest that this residue plays a role in stabilizing the open selectivity filter of the channel.

To investigate the pathogenicity of the G256W variant, researchers employed a comprehensive approach, including heterologous expression studies, manual and automated electrophysiology (SyncroPatch 768), and the generation of CRISPR/Cas9 knock-in mouse models. They also created mice with a neighboring frameshift variant to compare the effects of different mutations in vivo.

The study demonstrated that G256W suppresses current in both KCNQ2 homomeric and KCNQ2/KCNQ3 heteromeric channels. Heterozygous G256W knock-in mice exhibit neonatal-onset seizures, increased CA1 pyramidal neuron excitability, and aberrant localization of KCNQ2/KCNQ3 proteins in hippocampal regions. Notably, adult heterozygous mice experience spontaneous seizures and increased mortality.

These findings reveal a previously unrecognized structural role of the KCNQ2 pore turret and its involvement in neurodevelopment and epileptogenesis. The pathogenicity of G256W results from multiplicative effects, including reductions in intrinsic conduction, subcellular targeting, and protein stability.

Find the full article here: Plural molecular and cellular mechanisms of pore domain KCNQ2 encephalopathy

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#ionchannels #channelopathies # KCNQ2