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

Gong M, Li J, Qin Z, Machado Bressan Wilke MV, Liu Y, Li Q, Liu H, Liang C, Morales-Rosado JA, Cohen AS, Hughes SS, Sullivan BR, Waddell V, van den Boogaard MJH, van Jaarsveld RH, van Binsbergen E, van Gassen KL, Wang T, Hiatt SM, Amaral MD, Kelley WV, Zhao J, Feng W, Ren C, Yu Y, Boczek NJ, Ferber MJ, Lahner C, Elliott S, Ruan Y, Mignot C, Keren B, Xie H, Wang X, Popp B, Zweier C, Piard J, Coubes C, Mau-Them FT, Safraou H, Innes AM, Gauthier J, Michaud JL, Koboldt DC, Sylvie O, Willems M, Tan WH, Cogne B, Rieubland C, Braun D, McLean SD, Platzer K, Zacher P, Oppermann H, Evenepoel L, Blanc P, El Khattabi L, Haque N, Dsouza NR, Zimmermann MT, Urrutia R, Klee EW, Shen Y, Du H, Rappaport L, Liu CM, Chen X (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 111

Pages Range: 2392-2410

Journal Issue: 11

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.

Involved external institutions

Vanderbilt University United States (USA) (US) Alberta Children's Hospital Research Institute (ACHRI) Canada (CA) Children's Mercy Hospital United States (USA) (US) Universität Leipzig Germany (DE) Kleinwachau - Sächsisches Epilepsiezentrum Radeberg gGmbH Germany (DE) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Peking University Health Science Center China (CN) Cliniques universitaires Saint-Luc (CHU St-Luc) Belgium (BE) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) HudsonAlpha United States (USA) (US) Hôpital Armand-Trousseau (AP-HP) France (FR) Medical College of Wisconsin (MCW) United States (USA) (US) Capital University of Medical Sciences / 首都医科大学 China (CN) Mayo Clinic United States (USA) (US) Harvard University United States (USA) (US) Institute of Zoology, Chinese Academy of Sciences / 中国科学院动物研究所 China (CN) University of California San Francisco (UCSF) United States (USA) (US) The Maternal and Child Health Hospital of Guangxi Zhuang autonomous region China (CN) Inselspital, Universitätsspital Bern Switzerland (CH) Centre hospitalier régional et universitaire de Besançon (CHRU Besancon) France (FR) Arnaud de Villeneuve France (FR) Centre hospitalier universitaire (CHU) de Dijon Bourgogne France (FR) Centre Hospitalier Universitaire Sainte-Justine, CHU Sainte-Justine Canada (CA) Université de Montréal Canada (CA) University of Missouri–Kansas City (UMKC) United States (USA) (US) Nationwide Children's Hospital United States (USA) (US) Centre hospitalier universitaire de Rennes / CHU Rennes France (FR) Institute for Neurosciences of Montpellier (INM) France (FR) Université de Nantes France (FR) Children's Hospital of San Antonio United States (USA) (US)

How to cite

APA:

Gong, M., Li, J., Qin, Z., Machado Bressan Wilke, M.V., Liu, Y., Li, Q.,... Chen, X. (2024). MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway. American Journal of Human Genetics, 111(11), 2392-2410. https://doi.org/10.1016/j.ajhg.2024.09.006

MLA:

Gong, Maolei, et al. "MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway." American Journal of Human Genetics 111.11 (2024): 2392-2410.

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