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

Maolei Gong; Jiayi Li; Zailong Qin; Matheus Vernet Machado Bressan Wilke; Yijun Liu; Qian Li; Haoran Liu; Chen Liang; Joel Morales-Rosado; Ana S.A. Cohen; Susan Hughes; Bonnie Sullivan; Valerie Waddell; Marie-José van den Boogaard; Richard van Jaarsveld; Ellen van Binsbergen; Koen van Gassen; Tianyun Wang; Susan Hiatt; Michelle Amaral; Whitley Kelley; Jianbo Zhao; Weixing Feng; Changhong Ren; Yazhen Yu; Nicole Boczek; Matthew Ferber; Carrie Lahner; Sherr Elliott; Yiyan Ruan; Cyril Mignot; Boris Keren; Hua Xie; Xiaoyan Wang; Bernt Popp; Christiane Zweier; Juliette Piard; Christine Coubes; Frederic Tran Mau-Them; Hana Safraou; A. Micheil Innes; Julie Gauthier; Jacques Michaud; Daniel Koboldt; Odent Sylvie; Marjolaine Willems; Wen-Hann Tan; Benjamin Cogne; Claudine Rieubland; Dominique Braun; Scott Douglas Mclean; Konrad Platzer; Pia Zacher; Henry Oppermann; Lucie Evenepoel; Pierre Blanc; Laïla El Khattabi; Neshatul Haque; Nikita Dsouza; Michael Zimmermann; Raul Urrutia; Eric Klee; Yiping Shen; Hongzhen Du; Leonard Rappaport; Chang-Mei Liu; Xiaoli Chen

doi:10.1016/j.ajhg.2024.09.006

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

Journal article

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

Maolei Gong, Jiayi Li, Zailong Qin, Matheus Vernet Machado Bressan Wilke, Yijun Liu, Qian Li, Haoran Liu, Chen Liang, Joel Morales-Rosado, Ana S.A. Cohen, …

American Journal of Human Genetics, Vol.111(11), pp.2392-2410

11/2024

DOI: https://doi.org/10.1016/j.ajhg.2024.09.006

PMCID: PMC11568763

PMID: 39419027

Abstract

ASD

LoF

MARK2 variants

WNT/β-catenin signaling pathway

Autism spectrum disorder

Lithium

Loss-of-function

Adolescent

Animals

Induced Pluripotent Stem Cells* / metabolism

Male

Mice

Neural Stem Cells / metabolism

Neurons / metabolism

Protein Serine-Threonine Kinases* / genetics

Protein Serine-Threonine Kinases* / metabolism

Wnt Signaling Pathway* / genetics

beta Catenin / genetics

beta Catenin / metabolism

Autism Spectrum Disorder* / genetics

Autism Spectrum Disorder* / metabolism

Cell Differentiation / genetics

Child

Child, Preschool

Down-Regulation / genetics

Female

Humans

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.

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Title: MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway
Creators - without role: Maolei Gong - Chinese Academy of Sciences
Jiayi Li - Capital Institute of Pediatrics
Zailong Qin - Guangxi Maternal and Child Health Hospital
Matheus Vernet Machado Bressan Wilke - Mayo Clinic
Yijun Liu - Institute of Zoology
Qian Li - Chinese Academy of Sciences
Haoran Liu - Capital Institute of Pediatrics
Chen Liang - Capital Institute of Pediatrics
Joel Morales-Rosado - Vanderbilt University Medical Center
Ana S.A. Cohen - University of Missouri–Kansas City
Susan Hughes - University of Missouri–Kansas City
Bonnie Sullivan - University of Missouri–Kansas City
Valerie Waddell - Children's Mercy Hospital
Marie-José van den Boogaard - University Medical Center [Utrecht]
Richard van Jaarsveld - University Medical Center Utrecht
Ellen van Binsbergen - Heidelberg University
Koen van Gassen - University Medical Center [Utrecht]
Tianyun Wang - National Health and Family Planning Commission
Susan Hiatt - HudsonAlpha Institute for Biotechnology
Michelle Amaral - HudsonAlpha Institute for Biotechnology
Whitley Kelley - HudsonAlpha Institute for Biotechnology
Jianbo Zhao - Beijing Children’s Hospital
Weixing Feng - Beijing Children’s Hospital
Changhong Ren - Capital University
Yazhen Yu - Capital University
Nicole Boczek - Mayo Clinic
Matthew Ferber - Mayo Clinic
Carrie Lahner - Mayo Clinic
Sherr Elliott - University of California, San Francisco
Yiyan Ruan - Guangxi Maternal and Child Health Hospital
Cyril Mignot - Sorbonne Université
Boris Keren - Sorbonne Université
Hua Xie - Capital Institute of Pediatrics
Xiaoyan Wang - Children's Hospital of Capital Institute of Pediatrics
Bernt Popp - Berlin Institute of Health at Charité - Universitätsmedizin Berlin
Christiane Zweier - Friedrich-Alexander-Universität Erlangen-Nürnberg
Juliette Piard - Centre Hospitalier Universitaire de Besançon
Christine Coubes - Hôpital Arnaud de Villeneuve
Frederic Tran Mau-Them - Université de Bourgogne
Hana Safraou - Laboratoire Innovations Technologiques pour la Détection et le Diagnostic
A. Micheil Innes - Alberta Children's Hospital
Julie Gauthier - Centre Hospitalier Universitaire Sainte-Justine
Jacques Michaud - Centre Hospitalier Universitaire Sainte-Justine
Daniel Koboldt - Nationwide Children's Hospital
Odent Sylvie - Institut de génétique et de développement de Rennes
Marjolaine Willems - Université de Montpellier, Institut des Neurosciences de Montpellier - INM
Wen-Hann Tan - Harvard Medical School
Benjamin Cogne - Centre Hospitalier Universitaire de Nantes
Claudine Rieubland - University Hospital of Bern
Dominique Braun - University Hospital of Bern
Scott Douglas Mclean - Children's Hospital of San Antonio
Konrad Platzer - Leipzig University
Pia Zacher - Epilepsiezentrum Kleinwachau Gemeinnützige
Henry Oppermann - Leipzig University
Lucie Evenepoel - Cliniques Universitaires Saint-Luc
Pierre Blanc - Institut du Cerveau
Laïla El Khattabi - Institut du Cerveau
Neshatul Haque - Medical College of Wisconsin
Nikita Dsouza - Medical College of Wisconsin
Michael Zimmermann - Medical College of Wisconsin
Raul Urrutia - Medical College of Wisconsin
Eric Klee - Mayo Clinic in Florida
Yiping Shen - Boston Children's Hospital
Hongzhen Du - Chinese Academy of Sciences [Beijing]
Leonard Rappaport - Boston Children's Hospital
Chang-Mei Liu - Chinese Academy of Sciences [Beijing]
Xiaoli Chen - Chinese Academy of Sciences
Publication Details: American Journal of Human Genetics, Vol.111(11), pp.2392-2410
Grant note: This work was supported by grants from the National Key Research and Development Program of China (project 2021YFA1101402), the Strategic Priority Research Program of the Chinese Academy of Sciences (nos. XDA16010300/XDA16021400), and the Open Project Program of the State Key Laboratory of Stem Cell and Reproductive Biology. This study was also supported by grants from the National Science Foundation of China (82371868, 82271428, 31900690, 82201314, and 82471194), Beijing Natural Science Foundation (7202019), Beijing Finance Bureau (CIP2024-0040), and Guangxi Science and Technology Program Project (Guike AB17195011).
Identifiers: 9937726309311
Academic Unit: Institut des Neurosciences de Montpellier - INM
Language: English
Resource Type: Journal article
Local Fields: inserm-04957371