The KCNC2 p.Cys125Tyr variant induces a gain of function in Kv3.2 channels, stabilizing the open conformation and impairing neuronal excitability in fast-spiking interneurons to explain the epilepsy.
De novo heterozygous variants in KCNC2 encoding the voltage-gated potassium (K + ) channel subunit Kv3.2 are a recently described cause of developmental and epileptic encephalopathy (DEE). A de novo variant in KCNC2 c.374G > A (p.Cys125Tyr) was identified via exome sequencing in a patient with DEE. Relative to wild-type Kv3.2, Kv3.2-p.Cys125Tyr induces K + currents exhibiting a large hyperpolarizing shift in the voltage dependence of activation, accelerated activation, and delayed deactivation consistent with a relative stabilization of the open conformation, along with increased current density. Leveraging the cryogenic electron microscopy (cryo-EM) structure of Kv3.1, molecular dynamic simulations suggest that a strong π-π stacking interaction between the variant Tyr125 and Tyr156 in the α-6 helix of the T1 domain promotes a relative stabilization of the open conformation of the channel, which underlies the observed gain of function. A multicompartment computational model of a Kv3-expressing parvalbumin-positive cerebral cortex fast-spiking γ-aminobutyric acidergic (GABAergic) interneuron (PV-IN) demonstrates how the Kv3.2-Cys125Tyr variant impairs neuronal excitability and dysregulates inhibition in cerebral cortex circuits to explain the resulting epilepsy.
Clatot et al. (Tue,) conducted a other in Developmental and epileptic encephalopathy (DEE) (n=1). KCNC2 c.374G>A (p.Cys125Tyr) variant vs. Wild-type Kv3.2 was evaluated on K+ current properties and neuronal excitability. The KCNC2 p.Cys125Tyr variant induces a gain of function in Kv3.2 channels, stabilizing the open conformation and impairing neuronal excitability in fast-spiking interneurons to explain the epilepsy.