ACTL6B is a component of the neuronal BRG1/brm‐associated factor (nBAF) complex, which is required for chromatin remodeling in postmitotic neurons. We recently reported biallelic pathogenic variants in ACTL6B in patients diagnosed with early infantile epileptic encephalopathy, subtype 76 (EIEE‐76), presenting with severe, global developmental delay, epileptic encephalopathy, cerebral atrophy, and abnormal central nervous system myelination. However, the pathophysiological mechanisms underlying their phenotype is unknown. Here, we investigate the molecular pathogenesis of ACTL6B p.(Val421_Cys425del) using in silico 3D protein modeling predictions and patient‐specific induced pluripotent stem cell‐derived neurons. We found neurons derived from EIEE‐76 patients showed impaired accumulation of ACTL6B compared to unaffected relatives, caused by reduced protein stability. Furthermore, EIEE‐76 patient‐derived neurons had dysregulated nBAF target gene expression, including genes important for neuronal development and disease. Multielectrode array system analysis unveiled elevated electrophysiological activity of EIEE‐76 patients‐derived neurons, consistent with the patient phenotype. Taken together, our findings validate a new model for EIEE‐76 and reveal how reduced ACTL6B expression affects neuronal function.

中文翻译：

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癫痫相关 ACTL6B 变体在人类诱导的多能干细胞模型中捕获神经元过度兴奋

ACTL6B 是神经元 BRG1/brm 相关因子 (nBAF) 复合物的一个组成部分，它是有丝分裂后神经元染色质重塑所必需的。我们最近在诊断为早期婴儿癫痫性脑病 76 亚型 (EIEE-76) 的患者中报告了ACTL6B的双等位基因致病变异，表现为严重的整体发育迟缓、癫痫性脑病、脑萎缩和中枢神经系统髓鞘形成异常。然而，其表型背后的病理生理机制尚不清楚。在这里，我们使用计算机研究了 ACTL6B p.(Val421_Cys425del) 的分子发病机制3D 蛋白质建模预测和患者特异性诱导多能干细胞衍生神经元。我们发现来自 EIEE-76 患者的神经元与未受影响的亲属相比，由于蛋白质稳定性降低，ACTL6B 的积累受损。此外，EIEE-76 患者来源的神经元具有失调的 nBAF 靶基因表达，包括对神经元发育和疾病重要的基因。多电极阵列系统分析揭示了 EIEE-76 患者衍生神经元的电生理活性升高，与患者表型一致。总之，我们的研究结果验证了 EIEE-76 的新模型，并揭示了 ACTL6B 表达降低如何影响神经元功能。