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

被引：1

作者：

Gong, Maolei ^{[1
,2
,3
,4
]}

Li, Jiayi ^{[5
,6
]}

Qin, Zailong ^{[7
]}

Wilke, Matheus Vernet Machado Bressan ^{[8
]}

Liu, Yijun ^{[1
,2
,3
,9
]}

Li, Qian ^{[1
,2
,3
,9
]}

Liu, Haoran ^{[5
]}

Liang, Chen ^{[5
]}

Morales-Rosado, Joel A. ^{[10
]}

Cohen, Ana S. A. ^{[11
,12
]}

Hughes, Susan S. ^{[12
,13
]}

Sullivan, Bonnie R. ^{[12
,13
]}

Waddell, Valerie ^{[14
]}

van den Boogaard, Marie-Jose H. ^{[15
]}

van Jaarsveld, Richard H. ^{[15
]}

van Binsbergen, Ellen ^{[15
]}

van Gassen, Koen L. ^{[15
]}

Wang, Tianyun ^{[16
,17
]}

Hiatt, Susan M. ^{[18
]}

Amaral, Michelle D. ^{[18
]}

Kelley, Whitley, V ^{[18
]}

Zhao, Jianbo ^{[19
]}

Feng, Weixing ^{[20
]}

Ren, Changhong ^{[21
]}

Yu, Yazhen ^{[22
,23
,24
]}

Boczek, Nicole J. ^{[21
]}

Ferber, Matthew J. ^{[21
]}

Lahner, Carrie ^{[21
]}

Elliott, Sherr ^{[22
,23
,24
]}

Ruan, Yiyan ^{[25
]}

Mignot, Cyril ^{[26
,27
]}

Keren, Boris ^{[26
,27
]}

Xie, Hua ^{[5
]}

Wang, Xiaoyan ^{[28
]}

Popp, Bernt ^{[29
,30
]}

Zweier, Christiane ^{[31
,32
]}

Piard, Juliette ^{[33
,34
]}

Coubes, Christine ^{[35
]}

Mau-Them, Frederic Tran ^{[36
,37
]}

Safraou, Hana ^{[36
,37
]}

Innes, A. Micheil ^{[38
,39
]}

Gauthier, Julie ^{[40
,41
]}

Michaud, Jacques L. ^{[41
,42
]}

Koboldt, Daniel C. ^{[43
]}

Sylvie, Odent ^{[44
,45
]}

Willems, Marjolaine ^{[46
]}

Tan, Wen-Hann ^{[47
]}

Cogne, Benjamin ^{[48
,49
]}

Rieubland, Claudine ^{[31
]}

Braun, Dominique ^{[32
]}

机构：

[1] Chinese Acad Sci, State Key Lab Stem Cell & Reprod Biol, Inst Zool, Beijing, Peoples R China

[2] Beijing Inst Stem Cell & Regenerat Med, Beijing, Peoples R China

[3] Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing, Peoples R China

[4] Peoples Liberat Army Gen Hosp, Med Ctr 9, Beijing, Peoples R China

[5] Capital Inst Pediat, Dept Med Genet, Beijing, Peoples R China

[6] Chinese Acad Med Sci & Peking Union Med Coll, Beijing, Peoples R China

[7] Maternal & Child Hlth Hosp Guangxi Zhuang Autonomo, Birth Defect Prevent Res Inst, Genet & Metab Cent Lab, Nanning, Peoples R China

[8] Mayo Clin, Dept Clin Genom, Rochester, MN USA

[9] Univ Chinese Acad Sci, Savaid Med Sch, Beijing, Peoples R China

[10] Vanderbilt Univ, Med Ctr, Dept Pathol Microbiol & Immunol, Nashville, TN USA

[11] Childrens Mercy Kansas City, Dept Pathol & Lab Med, Genom Med Ctr, Kansas City, MO USA

[12] Univ Missouri Kansas City, Sch Med, Kansas City, MO USA

[13] Childrens Mercy Kansas City, Div Clin Genet, Kansas City, MO USA

[14] Childrens Mercy Kansas City, Dept Neurol, Kansas City, MO USA

[15] Univ Med Ctr Utrecht, Dept Genet, Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands

[16] Peking Univ, Hlth Sci Ctr, Ctr Med Genet, Dept Med Genet,Sch Basic Med Sci,Autism Res Ctr, Beijing, Peoples R China

[17] Peking Univ, Key Lab Neurosci, Minist Educ, Natl Hlth Commiss China, Beijing 100083, Peoples R China

[18] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

[19] Capital Med Univ, Dept Neurol, Beijing Childrens Hosp, Beijing, Peoples R China

[20] Capital Univ Med Sci, Beijing Tiantan Hosp, Dept Pediat, Beijing, Peoples R China

[21] Mayo Clin, Dept Lab Med & Pathol, Genom Lab, Rochester, MN USA

[22] Univ Calif San Francisco, Inst Human Genet, Dept Neurol, San Francisco, CA USA

[23] Univ Calif San Francisco, Inst Human Genet, Dept Pediat, San Francisco, CA USA

[24] Univ Calif San Francisco, Weill Inst Neurosci, San Francisco, CA USA

[25] Maternal & Child Hlth Hosp Guangxi Zhuang Autonomo, Guangxi Clin Res Ctr Pediat Dis, Nanning, Peoples R China

[26] Ctr Univ Paris, Paris, France

[27] Hop Trousseau, Ctr Reference Deficiences Intellectuelles Causes R, Paris, France

[28] Capital Inst Pediat, Childrens Hosp, Dept Childrens Nutr Res Ctr, Beijing, Peoples R China

[29] Univ Leipzig Hosp & Clin, Inst Human Genet, Leipzig, Germany

[30] Charite Univ Med Berlin, Berlin Inst Hlth, Ctr Funct Genom, Hess Str 4A, Berlin, Germany

[31] Univ Bern, Bern Univ Hosp, Dept Human Genet, Inselspital, Bern, Switzerland

[32] Friedrich Alexander Univ Erlangen Nurnberg FAU, Univ Hosp Erlangen, Inst Human Genet, Erlangen, Germany

[33] ANSES, Lab Lyon, Ctr Hosp Reg Univ, Lyon, France

[34] Univ Bourgogne Franche Comte, UMR 1231 GAD, Inserm, Dijon, France

[35] Hop Arnaud de Villeneuve, Dept Genet Med Malad Rares & Med Personnalisee, Cedex, Dijon, France

[36] UF6254 Innovat Diagnost Genom Malad Rares, Dijon, France

[37] Inserm UMR1231 GAD, F-21000 Dijon, France

[38] Univ Calgary, Dept Med Genet & Pediat, Calgary, AB, Canada

[39] Univ Calgary, Alberta Childrens Hosp Res Inst, Cumming Sch Med, Calgary, AB, Canada

[40] Ctr Hosp Univ Sainte Justine, Mol Diagnost Lab, Montreal, PQ, Canada

[41] Univ Montreal, Dept Pediat, Montreal, PQ, Canada

[42] CHU Sainte Justine Res Ctr, Montreal, PQ, Canada

[43] Nationwide Childrens Hosp, Inst Genom Med, Columbus, OH USA

[44] CHU Rennes, Serv Genet Clin, ERN ITHACA, Rennes, France

[45] Univ Rennes, CNRS, IGDR Inst Genet & Dev Rennes, INSERM,UMR 6290,ERL U1305, Rennes, France

[46] Montpellier Univ, Med Genet Dept Rare Dis & Personalized Med, Reference Ctr AD SOOR, AnDDI RARE,Inserm U1298,INM,Ctr Hosp Univ Montpell, Montpellier, France

[47] Harvard Med Sch, Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA

[48] Nantes Univ, Serv Genet Med, CHU Nantes, Nantes, France

[49] Nantes Univ, Inst thorax, CHU Nantes, CNRS,INSERM, Nantes, France

[50] Childrens Hosp San Antonio, Div Clin Genet, San Antonio, TX USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2024年 / 111卷 / 11期

基金：

北京市自然科学基金;

关键词：

NEURODEVELOPMENTAL DISORDERS; BIPOLAR DISORDER; BETA-CATENIN; PROTEIN; INDIVIDUALS; NETWORK; GENE; CELL; DIFFERENTIATION; MARK2/PAR-1;

D O I：

10.1016/j.ajhg.2024.09.006

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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/b-catenin signaling pathway and identify lithium as a potential drug for treating MARK2-associated ASD.

引用

页数：20

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