IQSEC2 mutation associated with epilepsy, intellectual disability, and autism results in hyperexcitability of patient-derived neurons and deficient synaptic transmission.
IQSEC2 mutation associated with epilepsy, intellectual disability, and autism results in hyperexcitability of patient-derived neurons and deficient synaptic transmission.
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DOI：
10.1038/s41380-021-01281-0
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发表时间：
2021-12
影响因子：
11
通讯作者：
Stern S
中科院分区：
文献类型：
--
作者：
Brant B;Stern T;Shekhidem HA;Mizrahi L;Rosh I;Stern Y;Ofer P;Asleh A;Umanah GKE;Jada R;Levy NS;Levy AP;Stern S
IQSEC2基因突变与抗药性、多灶性婴幼儿和儿童癫痫、自闭症和严重智力残疾(ID)有关。我们利用诱导多能干细胞(IPSC)技术获得海马神经元，以研究IQSEC2介导的疾病的神经病理学。在分化过程中的三个时间点对神经元进行表征，以评估发育进程。我们发现，未成熟的IQSEC2突变型齿状回(DG)颗粒神经元极度兴奋，与CRISPR-Cas9校正的等基因对照相比，表现出更多的钠和钾电流，并显示出与分化和发育相关的基因调控异常。未成熟的IQSEC2突变培养神经元表现出抑制性神经元数量的显著减少，这进一步促进了过度兴奋。随着突变神经元的老化，它们变得不太兴奋，表现出钠电流和钾电流的减少，突触和网络活动率的降低，并显示出参与突触传递和神经元分化的基因调节失调。成熟的IQSEC2突变神经元的活性低于野生型成熟神经元，并且表面AMPA受体的表达减少。我们的研究提供了对严重婴儿癫痫和与该突变相关的神经发育延迟的机械性见解，并提供了一个在体外研究IQSEC2突变的人体模型。
Mutations in the IQSEC2 gene are associated with drug-resistant, multifocal infantile and childhood epilepsy; autism; and severe intellectual disability (ID). We used induced pluripotent stem cell (iPSC) technology to obtain hippocampal neurons to investigate the neuropathology of IQSEC2-mediated disease. The neurons were characterized at three-time points during differentiation to assess developmental progression. We showed that immature IQSEC2 mutant dentate gyrus (DG) granule neurons were extremely hyperexcitable, exhibiting increased sodium and potassium currents compared to those of CRISPR-Cas9-corrected isogenic controls, and displayed dysregulation of genes involved in differentiation and development. Immature IQSEC2 mutant cultured neurons exhibited a marked reduction in the number of inhibitory neurons, which contributed further to hyperexcitability. As the mutant neurons aged, they became hypoexcitable, exhibiting reduced sodium and potassium currents and a reduction in the rate of synaptic and network activity, and showed dysregulation of genes involved in synaptic transmission and neuronal differentiation. Mature IQSEC2 mutant neurons were less viable than wild-type mature neurons and had reduced expression of surface AMPA receptors. Our studies provide mechanistic insights into severe infantile epilepsy and neurodevelopmental delay associated with this mutation and present a human model for studying IQSEC2 mutations in vitro.
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DOI：
10.1073/pnas.83.24.9774
发表时间：
1986-12-01
影响因子：
11.1
作者：
LIPTON, SA
通讯作者：
LIPTON, SA
影响因子：
5.3
作者：
Quraishi, Imran H.;Stern, Shani;Kaczmarek, Leonard K.
通讯作者：
Kaczmarek, Leonard K.
影响因子：
2.9
作者：
Sakagami, Hiroyuki;Sanda, Masashi;Kondo, Hisatake
通讯作者：
Kondo, Hisatake
来自双相情感障碍患者的神经元分为本质上不同的神经元亚群，预测患者对锂的反应
影响因子：
11
作者：
Stern S;Santos R;Marchetto MC;Mendes APD;Rouleau GA;Biesmans S;Wang QW;Yao J;Charnay P;Bang AG;Alda M;Gage FH
通讯作者：
Gage FH
影响因子：
3.7
作者：
Fishbein, Ianai;Segal, Menahem
通讯作者：
Segal, Menahem