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 A. Morales-Rosado; Ana S.A. Cohen; Susan S. Hughes; Bonnie R. Sullivan; Valerie Waddell; Marie José H. van den Boogaard; Richard H. van Jaarsveld; Ellen van Binsbergen; Koen L. van Gassen; Tianyun Wang; Susan M. Hiatt; Michelle D. Amaral; Whitley V. Kelley; Jianbo Zhao; Weixing Feng; Changhong Ren; Yazhen Yu; Nicole J. Boczek; Matthew J. 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 L. Michaud; Daniel C. 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 R. Dsouza; Michael T. Zimmermann; Raul Urrutia; Eric W. Klee; Yiping Shen; Hongzhen Du; Leonard Rappaport; Chang Mei Liu; Xiaoli Chen

doi:10.1016/j.ajhg.2024.09.006

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 A. Morales-Rosado, Ana S.A. Cohen, Susan S. Hughes, Bonnie R. Sullivan, Valerie Waddell, Marie José H. van den Boogaard, Richard H. van Jaarsveld, Ellen van Binsbergen, Koen L. van Gassen, Tianyun Wang, Susan M. Hiatt, Michelle D. AmaralWhitley V. Kelley, Jianbo Zhao, Weixing Feng, Changhong Ren, Yazhen Yu, Nicole J. Boczek, Matthew J. 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 L. Michaud, Daniel C. 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 R. Dsouza, Michael T. Zimmermann, Raul Urrutia, Eric W. Klee, Yiping Shen, Hongzhen Du, Leonard Rappaport, Chang Mei Liu^*, Xiaoli Chen^*

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	2392-2410
Number of pages	19
Journal	American Journal of Human Genetics
Volume	111
Issue number	11
Early online date	16 Oct 2024
DOIs	https://doi.org/10.1016/j.ajhg.2024.09.006
Publication status	Published - 7 Nov 2024

Keywords

ASD
autism spectrum disorder
lithium
LoF
loss-of-function
MARK2 variants
WNT/β-catenin signaling pathway

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10.1016/j.ajhg.2024.09.006Licence: CC BY-NC-ND

PIIS0002929724003665Final published version, 9.3 MBLicence: CC BY-NC-ND

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Gong, M., Li, J., Qin, Z., Machado Bressan Wilke, M. V., Liu, Y., Li, Q., Liu, H., Liang, C., Morales-Rosado, J. A., Cohen, A. S. A., Hughes, S. S., Sullivan, B. R., Waddell, V., van den Boogaard, M. J. H., van Jaarsveld, R. H., van Binsbergen, E., van Gassen, K. L., Wang, T., Hiatt, S. M., ... 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

@article{44e9803e49c649d5971c33bbcd6a8725,

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

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.",

keywords = "ASD, autism spectrum disorder, lithium, LoF, loss-of-function, MARK2 variants, WNT/β-catenin signaling pathway",

author = "Maolei Gong and Jiayi Li and Zailong Qin and {Machado Bressan Wilke}, {Matheus Vernet} and Yijun Liu and Qian Li and Haoran Liu and Chen Liang and Morales-Rosado, {Joel A.} and Cohen, {Ana S.A.} and Hughes, {Susan S.} and Sullivan, {Bonnie R.} and Valerie Waddell and {van den Boogaard}, {Marie Jos{\'e} H.} and {van Jaarsveld}, {Richard H.} and {van Binsbergen}, Ellen and {van Gassen}, {Koen L.} and Tianyun Wang and Hiatt, {Susan M.} and Amaral, {Michelle D.} and Kelley, {Whitley V.} and Jianbo Zhao and Weixing Feng and Changhong Ren and Yazhen Yu and Boczek, {Nicole J.} and Ferber, {Matthew J.} and Carrie Lahner and Sherr Elliott and Yiyan Ruan and Cyril Mignot and Boris Keren and Hua Xie and Xiaoyan Wang and Bernt Popp and Christiane Zweier and Juliette Piard and Christine Coubes and Mau-Them, {Frederic Tran} and Hana Safraou and Innes, {A. Micheil} and Julie Gauthier and Michaud, {Jacques L.} and Koboldt, {Daniel C.} and Odent Sylvie and Marjolaine Willems and Tan, {Wen Hann} and Benjamin Cogne and Claudine Rieubland and Dominique Braun and McLean, {Scott Douglas} and Konrad Platzer and Pia Zacher and Henry Oppermann and Lucie Evenepoel and Pierre Blanc and {El Khattabi}, La{\"i}la and Neshatul Haque and Dsouza, {Nikita R.} and Zimmermann, {Michael T.} and Raul Urrutia and Klee, {Eric W.} and Yiping Shen and Hongzhen Du and Leonard Rappaport and Liu, {Chang Mei} and Xiaoli Chen",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = nov,

day = "7",

doi = "10.1016/j.ajhg.2024.09.006",

language = "English",

volume = "111",

pages = "2392--2410",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "11",

}

Gong, M, Li, J, Qin, Z, Machado Bressan Wilke, MV, Liu, Y, Li, Q, Liu, H, Liang, C, Morales-Rosado, JA, Cohen, ASA, 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, 'MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway', American Journal of Human Genetics, vol. 111, no. 11, pp. 2392-2410. https://doi.org/10.1016/j.ajhg.2024.09.006

TY - JOUR

T1 - MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway

AU - Gong, Maolei

AU - Li, Jiayi

AU - Qin, Zailong

AU - Machado Bressan Wilke, Matheus Vernet

AU - Liu, Yijun

AU - Li, Qian

AU - Liu, Haoran

AU - Liang, Chen

AU - Morales-Rosado, Joel A.

AU - Cohen, Ana S.A.

AU - Hughes, Susan S.

AU - Sullivan, Bonnie R.

AU - Waddell, Valerie

AU - van den Boogaard, Marie José H.

AU - van Jaarsveld, Richard H.

AU - van Binsbergen, Ellen

AU - van Gassen, Koen L.

AU - Wang, Tianyun

AU - Hiatt, Susan M.

AU - Amaral, Michelle D.

AU - Kelley, Whitley V.

AU - Zhao, Jianbo

AU - Feng, Weixing

AU - Ren, Changhong

AU - Yu, Yazhen

AU - Boczek, Nicole J.

AU - Ferber, Matthew J.

AU - Lahner, Carrie

AU - Elliott, Sherr

AU - Ruan, Yiyan

AU - Mignot, Cyril

AU - Keren, Boris

AU - Xie, Hua

AU - Wang, Xiaoyan

AU - Popp, Bernt

AU - Zweier, Christiane

AU - Piard, Juliette

AU - Coubes, Christine

AU - Mau-Them, Frederic Tran

AU - Safraou, Hana

AU - Innes, A. Micheil

AU - Gauthier, Julie

AU - Michaud, Jacques L.

AU - Koboldt, Daniel C.

AU - Sylvie, Odent

AU - Willems, Marjolaine

AU - Tan, Wen Hann

AU - Cogne, Benjamin

AU - Rieubland, Claudine

AU - Braun, Dominique

AU - McLean, Scott Douglas

AU - Platzer, Konrad

AU - Zacher, Pia

AU - Oppermann, Henry

AU - Evenepoel, Lucie

AU - Blanc, Pierre

AU - El Khattabi, Laïla

AU - Haque, Neshatul

AU - Dsouza, Nikita R.

AU - Zimmermann, Michael T.

AU - Urrutia, Raul

AU - Klee, Eric W.

AU - Shen, Yiping

AU - Du, Hongzhen

AU - Rappaport, Leonard

AU - Liu, Chang Mei

AU - Chen, Xiaoli

PY - 2024/11/7

Y1 - 2024/11/7

N2 - 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.

AB - 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.

KW - ASD

KW - autism spectrum disorder

KW - lithium

KW - LoF

KW - loss-of-function

KW - MARK2 variants

KW - WNT/β-catenin signaling pathway

UR - http://www.scopus.com/inward/record.url?scp=85207372821&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2024.09.006

DO - 10.1016/j.ajhg.2024.09.006

M3 - Article

C2 - 39419027

AN - SCOPUS:85207372821

SN - 0002-9297

VL - 111

SP - 2392

EP - 2410

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 11

ER -

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

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