Soldovieri Maria Virginia, Ambrosino Paolo, Mosca Ilaria, Servettini Ilenio, Pietrunti Francesca, Belperio Giorgio, Syrbe Steffen, Taglialatela Maurizio, Lemke Johannes R
Department of Medicine and Health Science "V. Tiberio", University of Molise, Campobasso, Italy.
Department of Science and Technology, University of Sannio, Benevento, Italy.
Ann Neurol. 2024 Feb;95(2):365-376. doi: 10.1002/ana.26826. Epub 2023 Dec 28.
Variants in several potassium channel genes, including KCNA1 and KCNA2, cause Developmental and Epileptic Encephalopathies (DEEs). We investigated whether variants in KCNA3, another mammalian homologue of the Drosophila shaker family and encoding for Kv1.3 subunits, can cause DEE.
Genetic analysis of study individuals was performed by routine exome or genome sequencing, usually of parent-offspring trios. Phenotyping was performed via a standard clinical questionnaire. Currents from wild-type and/or mutant Kv1.3 subunits were investigated by whole-cell patch-clamp upon their heterologous expression.
Fourteen individuals, each carrying a de novo heterozygous missense variant in KCNA3, were identified. Most (12/14; 86%) had DEE with marked speech delay with or without motor delay, intellectual disability, epilepsy, and autism spectrum disorder. Functional analysis of Kv1.3 channels carrying each variant revealed heterogeneous functional changes, ranging from "pure" loss-of-function (LoF) effects due to faster inactivation kinetics, depolarized voltage-dependence of activation, slower activation kinetics, increased current inactivation, reduced or absent currents with or without dominant-negative effects, to "mixed" loss- and gain-of-function (GoF) effects. Compared to controls, Kv1.3 currents in lymphoblasts from 1 of the proband displayed functional changes similar to those observed upon heterologous expression of channels carrying the same variant. The antidepressant drug fluoxetine inhibited with similar potency the currents from wild-type and 1 of the Kv1.3 GoF variant.
We describe a novel association of de novo missense variants in KCNA3 with a human DEE, and provide evidence that fluoxetine might represent a potential targeted treatment for individuals carrying variants with significant GoF effects. ANN NEUROL 2024;95:365-376.
包括KCNA1和KCNA2在内的多个钾通道基因的变异会导致发育性和癫痫性脑病（DEE）。我们研究了KCNA3（果蝇震颤器家族的另一个哺乳动物同源物，编码Kv1.3亚基）中的变异是否会导致DEE。
通常通过对亲子三联体进行常规外显子组或基因组测序，对研究对象进行基因分析。通过标准临床问卷进行表型分析。在野生型和/或突变型Kv1.3亚基异源表达后，通过全细胞膜片钳研究其电流。
鉴定出14名个体，每人在KCNA3中携带一个新生杂合错义变异。大多数（12/14；86%）患有DEE，伴有明显的语言延迟，有或没有运动延迟、智力残疾、癫痫和自闭症谱系障碍。对携带每个变异的Kv1.3通道进行功能分析，发现功能变化具有异质性，从由于更快的失活动力学、激活的去极化电压依赖性、更慢的激活动力学、电流失活增加、有或没有显性负效应时电流减少或缺失导致的“纯”功能丧失（LoF）效应，到“混合”功能丧失和功能获得（GoF）效应。与对照组相比，一名先证者的淋巴母细胞中的Kv1.3电流显示出与携带相同变异的通道异源表达时观察到的功能变化相似。抗抑郁药氟西汀以相似的效力抑制野生型和一种Kv1.3 GoF变异的电流。
我们描述了KCNA3中的新生错义变异与人类DEE的一种新关联，并提供证据表明氟西汀可能是携带具有显著GoF效应变异个体的潜在靶向治疗药物。《神经病学年鉴》2024；95：365 - 376。
