PDF(Pubmed)
Abstract：
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.
摘要：
KCNC2中编码电压门控钾（K）通道亚基Kv3.2的从头杂合变体是最近描述的发育性和癫痫性脑病（DEE）的原因。KCNC2c.374G>A中的从头变体（p。Cys125Tyr）是通过DEE患者的外显子组测序鉴定的。相对于野生型Kv3.2,Kv3.2-p。Cys125Tyr诱导K电流在激活的电压依赖性中表现出较大的超极化偏移，加速激活,与开放构象的相对稳定一致的延迟失活，随着电流密度的增加。利用Kv3.1的低温电子显微镜（cryo-EM）结构，分子动力学模拟表明，T1域的α-6螺旋中变体Tyr125和Tyr156之间的强π-π堆叠相互作用促进了开放构象的相对稳定通道，这是观察到的功能增益的基础。表达Kv3的小白蛋白阳性大脑皮层快速尖峰γ-氨基丁酸能（GABA能）中间神经元（PV-IN）的多室计算模型证明了Kv3.2-Cys125Tyr变体如何调节大脑皮层回路中的神经元兴奋性和抑制障碍，以解释所产生的癫痫。
