State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; The Ninth Medical Center of PLA General Hospital, Beijing, China.
Department of Medical Genetics, Capital Institute of Pediatrics, Beijing, China; Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Am J Hum Genet. 2024 Nov 7;111(11):2392-2410. doi: 10.1016/j.ajhg.2024.09.006. Epub 2024 Oct 16.
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.
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。虽然大规模测序研究将 MARK2 变体与自闭症谱系障碍（ASD）联系起来，但受 MARK2 变体影响的个体的临床特征和变体谱、突变型人类神经元的早期发育表型以及对神经元发育影响的致病机制仍不清楚。在这里，我们报告了 31 名患有 MARK2 变异体并表现出 ASD、其他神经发育障碍和独特面部特征的个体。受影响个体中主要存在功能丧失（LoF）变异体（81%），而错义变异体的计算分析和体外表达测定支持 MARK2 缺失的作用。使用源自先证者的和 CRISPR 工程化的同源诱导多能干细胞（iPSC），我们表明 MARK2 缺失会导致早期神经元发育和功能缺陷，包括神经玫瑰花结中异常的极性和组织紊乱，以及神经祖细胞（NPC）中增殖和分化失衡。Mark2 小鼠表现出异常的皮质形成和分区以及类似 ASD 的行为。通过使用 RNA 测序（RNA-seq）和锂处理，我们将 MARK2 缺失与 WNT/β-连环蛋白信号通路的下调联系起来，并确定锂是治疗与 MARK2 相关的 ASD 的一种潜在药物。
