MARK2variants cause autism spectrum disorderviathe downregulation of WNT/β-catenin signaling pathway
Author:
Gong Maolei, Li Jiayi, Liu Yijun, Wilke Matheus Vernet Machado Bressan, Li Qian, Liu Haoran, Liang Chen, Morales-Rosado Joel A, Cohen Ana S.A., Hughes Susan S., Sullivan Bonnie R., Waddell Valerie, van den Boogaard Marie-José H., van Jaarsveld Richard H., van Binsbergen Ellen, van Gassen Koen L, Wang Tianyun, Hiatt Susan M., Amaral Michelle D., Kelley Whitley V., Zhao Jianbo, Feng Weixing, Ren Changhong, Yu Yazhen, Boczek Nicole J, Ferber Matthew J., Lahner Carrie, Elliott Sherr, Ruan Yiyan, Cyril Mignot, Keren Boris, Xie Hua, Wang Xiaoyan, Popp Bernt, Zweier Christiane, Piard Juliette, Coubes Christine, Mau-Them Frederic Tran, Safraou Hana, Innes Micheil, Gauthier Julie, Michaud Jacques, Koboldt Daniel C., Sylvie Odent, Willems MarjolaineORCID, Tan Wen-Hann, Cogne Benjamin, Rieubland Claudine, Braun Dominique, McLean Scott Douglas, Platzer KonradORCID, Zacher Pia, Oppermann Henry, Evenepoel Lucie, Blanc Pierre, Khattabi Laïla El, Haque Neshatul, Dsouza Nikita R., Zimmermann Michael T.ORCID, Urrutia Raul, Klee Eric W, Shen Yiping, Du Hongzhen, Qin Zailong, Liu Chang-Mei, Chen Xiaoli
Abstract
AbstractMARK2, a member of the evolutionarily conserved PAR1/MARK serine/threonine kinase family, has been identified as a novel risk gene for autism spectrum disorder (ASD) based on the enrichment ofde novoloss-of-function (Lof) variants in large-scale sequencing studies of ASD individuals. However, the features shared by affected individuals and the molecular mechanism ofMARK2variants during early neural development remained unclear. Here, we report 31 individuals carrying heterozygousMARK2variants and presenting with ASD, other neurodevelopmental disorders, and typical facial dysmorphisms. Lof variants predominate (81%) in affected individuals, while computational analysis andin vitrotransfection assay also point toMARK2loss resulting from missense variants. Using patient-derived and CRISPR-engineered isogenic induced pluripotent stem cells (iPSCs), andMark2+/-(HET) mice, we show thatMARK2loss leads to systemic neurodevelopmental deficits, including anomalous polarity in neural rosettes, imbalanced proliferation and differentiation in neural progenitor cells (NPCs), abnormal cortical development and ASD-like behaviors in mice. Further using RNA-Seq and lithium treatment, we linkMARK2loss to the downregulated WNT/β-catenin signaling pathway and identify lithium as a potential drug for treatingMARK2-related ASD.
Publisher
Cold Spring Harbor Laboratory
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