Document Type
Article
Publication Date
11-7-2024
Identifier
DOI: 10.1016/j.ajhg.2024.09.006
Abstract
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.
Journal Title
American journal of human genetics
Volume
111
Issue
11
First Page
2392
Last Page
2410
MeSH Keywords
Autism Spectrum Disorder; Humans; Wnt Signaling Pathway; Animals; Mice; Female; Male; Protein Serine-Threonine Kinases; Child; Induced Pluripotent Stem Cells; Down-Regulation; Neural Stem Cells; Child, Preschool; beta Catenin; Adolescent; Cell Differentiation; Neurons
Keywords
ASD; LoF; MARK2 variants; WNT/β-catenin signaling pathway; autism spectrum disorder; lithium; loss-of-function
Recommended Citation
Gong M, Li J, Qin Z, et al. MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway. Am J Hum Genet. 2024;111(11):2392-2410. doi:10.1016/j.ajhg.2024.09.006
Comments
This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.
Publisher's Link: https://doi.org/10.1016/j.ajhg.2024.09.006