Plural molecular and cellular mechanisms of pore domain encephalopathy.

🤖 Plain-English Summary

variants in children with neurodevelopmental impairment are difficult to assess due to their heterogeneity and unclear pathogenic mechanisms. These studies provide evidence for an unexpected and novel role for the KCNQ2 pore turret and introduce a valid animal model of encephalopathy.

🔑 Key Findings

• We describe a child with neonatal-onset epilepsy, developmental impairment of intermediate severity, and G256W heterozygosity.
• Analyzing prior KCNQ2 channel cryoelectron microscopy models revealed G256 as a node of an arch-shaped non-covalent bond network linking S5, the pore turret, and the ion path.
• Co-expression with G256W dominantly suppressed conduction by wild-type subunits in heterologous cells.

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