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Publication : MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway.

First Author  Gong M Year  2024
Journal  Am J Hum Genet Volume  111
Issue  11 Pages  2392-2410
PubMed ID  39419027 Mgi Jnum  J:358137
Mgi Id  MGI:7779252 Doi  10.1016/j.ajhg.2024.09.006
Citation  Gong M, et al. (2024) MARK2 variants cause autism spectrum disorder via the downregulation of WNT/beta-catenin signaling pathway. Am J Hum Genet
abstractText  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/beta-catenin signaling pathway and identify lithium as a potential drug for treating MARK2-associated ASD.
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