An epilepsy-associated ACTL6B variant captures neuronal hyperexcitability in a human induced pluripotent stem cell model.
An epilepsy-associated ACTL6B variant captures neuronal hyperexcitability in a human induced pluripotent stem cell model.
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DOI：
10.1002/jnr.24747
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发表时间：
2021-01
影响因子：
4.2
通讯作者：
Miranda HC
中科院分区：
文献类型：
--
作者：
Ahn LY;Coatti GC;Liu J;Gumus E;Schaffer AE;Miranda HC
ACTL6B是神经元BRG1/BRM相关因子(NBAF)复合体的一个组成部分，是有丝分裂后神经元染色质重塑所必需的。我们最近报道了早期婴儿癫痫脑病76亚型(EIEE-76)患者的ACTL6B双等位致病变异，表现为严重的全球发育迟缓、癫痫脑病、脑萎缩和中枢神经系统髓鞘异常。然而，其表型背后的病理生理机制尚不清楚。在这里，我们研究了ACTL6B pp.(Val421_Cys425del)的分子发病机制，并使用计算机3D蛋白质模型预测和患者特定诱导的多能干细胞来源的神经元。我们发现，与未受影响的亲属相比，来自EIEE-76患者的神经元显示出ACTL6B的受损积累，这是由于蛋白质稳定性降低所致。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至关重要的基因。多电极阵列系统分析揭示了EIEE-76患者来源的神经元的电生理活性增加，与患者的表型一致。综上所述，我们的发现验证了EIEE-76的新模型，并揭示了ACTL6B表达减少如何影响神经元功能。携带ACTL6B(Val421_Cys425del)突变体的患者诱导的多能干细胞来源的神经元在体外表现出ACTL6B蛋白的表达减少和稳定性降低，自发神经元活动增加。
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. Neurons derived from patient induced pluripotent stem cells harboring ACTL6B p.(Val421_Cys425del) variant display reduced expression and stability of ACTL6B protein and increased spontaneous neuronal activity in vitro.
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影响因子：
8.8
作者：
Wainger BJ;Kiskinis E;Mellin C;Wiskow O;Han SS;Sandoe J;Perez NP;Williams LA;Lee S;Boulting G;Berry JD;Brown RH Jr;Cudkowicz ME;Bean BP;Eggan K;Woolf CJ
通讯作者：
Woolf CJ
DOI：
10.1038/s41436-018-0138-x
发表时间：
2019-03
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Maddirevula S;Alzahrani F;Al-Owain M;Al Muhaizea MA;Kayyali HR;AlHashem A;Rahbeeni Z;Al-Otaibi M;Alzaidan HI;Balobaid A;El Khashab HY;Bubshait DK;Faden M;Yamani SA;Dabbagh O;Al-Mureikhi M;Jasser AA;Alsaif HS;Alluhaydan I;Seidahmed MZ;Alabbasi BH;Almogarri I;Kurdi W;Akleh H;Qari A;Al Tala SM;Alhomaidi S;Kentab AY;Salih MA;Chedrawi A;Alameer S;Tabarki B;Shamseldin HE;Patel N;Ibrahim N;Abdulwahab F;Samira M;Goljan E;Abouelhoda M;Meyer BF;Hashem M;Shaheen R;AlShahwan S;Alfadhel M;Ben-Omran T;Al-Qattan MM;Monies D;Alkuraya FS
通讯作者：
Alkuraya FS
使用诱导多能干细胞进行癫痫发作责任测试的体外模型。
影响因子：
4.3
作者：
Grainger AI;King MC;Nagel DA;Parri HR;Coleman MD;Hill EJ
通讯作者：
Hill EJ
影响因子：
5.3
作者：
Fichera, Marco;Failla, Pinella;Elia, Maurizio
通讯作者：
Elia, Maurizio
双相情感障碍患者过度兴奋的神经元对锂的不同反应。
影响因子：
64.8
作者：
Mertens, Jerome;Wang, Qiu-Wen;Yao, Jun
通讯作者：
Yao, Jun