CTNNB1 syndrome is a rare monogenetic disorder caused by CTNNB1 de novo pathogenic heterozygous loss-of-function variants that result in cognitive and motor disabilities. Treatment is currently lacking; our study addresses this critical need. CTNNB1 encodes β-catenin which is essential for normal brain function via its dual roles in cadherin-based synaptic adhesion complexes and canonical Wnt signal transduction. We have generated a Ctnnb1 germline heterozygous mouse line that displays cognitive and motor deficits, resembling key features of CTNNB1 syndrome in humans. Compared with wild-type littermates, Ctnnb1 heterozygous mice also exhibit decreases in brain β-catenin, β-catenin association with N-cadherin, Wnt target gene expression, and Na/K ATPases, key regulators of changes in ion gradients during high activity. Consistently, hippocampal neuron functional properties and excitability are altered. Most important, we identify a highly selective inhibitor of glycogen synthase kinase (GSK)3α,β that significantly normalizes the phenotypes to closely meet wild-type littermate levels. Our data provide new insights into brain molecular and functional changes, and the first evidence for an efficacious treatment with therapeutic potential for individuals with CTNNB1 syndrome.

中文翻译：

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抑制 GSK3α，β 在 CTNNB1 综合征的临床前小鼠模型中挽救认知表型。


CTNNB1 综合征是一种罕见的单基因疾病，由 CTNNB1 新发致病性杂合子功能丧失变异引起，可导致认知和运动障碍。目前缺乏治疗;我们的研究解决了这一关键需求。CTNNB1 编码 β-catenin，这是正常脑功能所必需的，通过其在基于钙粘蛋白的突触粘附复合物和经典 Wnt 信号转导中的双重作用。我们生成了一种 Ctnnb1 种系杂合小鼠系，该系显示认知和运动缺陷，类似于人类 CTNNB1 综合征的关键特征。与野生型同窝小鼠相比，Ctnnb1 杂合小鼠还表现出脑 β-catenin、β-catenin 与 N-cadherin、Wnt 靶基因表达和 Na/K ATP 酶相关的减少，这些是高活性期间离子梯度变化的关键调节因子。始终如一地，海马神经元的功能特性和兴奋性发生了变化。最重要的是，我们确定了一种高选择性的糖原合成酶激酶 （GSK） 3α 抑制剂，β 它显着使表型正常化，以接近野生型同窝伴侣水平。我们的数据为大脑分子和功能变化提供了新的见解，并为 CTNNB1 综合征患者具有治疗潜力的有效治疗提供了第一个证据。