Microtubule affinity-regulating kinase 2 (MARK2) contributes to establishing neuronal polarity and developing dendritic spines. Although large-scale sequencing studies have associated MARK2 variants with autism spectrum disorder (ASD), the clinical features and variant spectrum in affected individuals with MARK2 variants, early developmental phenotypes in mutant human neurons, and the pathogenic mechanism underlying effects on neuronal development have remained unclear. Here, we report 31 individuals with MARK2 variants and presenting with ASD, other neurodevelopmental disorders, and distinctive facial features. Loss-of-function (LoF) variants predominate (81%) in affected individuals, while computational analysis and in vitro expression assay of missense variants supported the effect of MARK2 loss. Using proband-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs), we show that MARK2 loss leads to early neuronal developmental and functional deficits, including anomalous polarity and dis-organization in neural rosettes, as well as imbalanced proliferation and differentiation in neural progenitor cells (NPCs). Mark2+/− mice showed abnormal cortical formation and partition and ASD-like behavior. Through the use of RNA sequencing (RNA-seq) and lithium treatment, we link MARK2 loss to downregulation of the WNT/β-catenin signaling pathway and identify lithium as a potential drug for treating MARK2-associated ASD.

中文翻译：

---

MARK2 变体通过下调 WNT/β-catenin 信号通路导致自闭症谱系障碍


微管亲和调节激酶 2 （MARK2） 有助于建立神经元极性和发育树突棘。尽管大规模测序研究将 MARK2 变异与自闭症谱系障碍 （ASD） 相关联，但具有 MARK2 变异的受影响个体的临床特征和变异谱、突变人类神经元的早期发育表型以及对神经元发育影响的潜在致病机制仍不清楚。在这里，我们报告了 31 例具有 MARK2 变异并表现为 ASD 、其他神经发育障碍和独特面部特征的个体。功能丧失 （LoF） 变体在受影响的个体中占主导地位 （81%），而错义变体的计算分析和 体外表达测定支持 MARK2 缺失的影响。使用先证者衍生和 CRISPR 工程的同基因诱导多能干细胞 （iPSC），我们表明 MARK2 缺失导致早期神经元发育和功能缺陷，包括神经玫瑰花结中的异常极性和杂乱无章，以及神经祖细胞 （NPC） 的不平衡增殖和分化。Mark2 + / - 小鼠表现出异常的皮质形成和分配以及 ASD 样行为。通过使用 RNA 测序 （RNA-seq） 和锂处理，我们将 MARK2 丢失与 WNT/β-catenin 信号通路的下调联系起来，并确定锂是治疗 MARK2 相关 ASD 的潜在药物。