Gong, MaoleiMaoleiGongLi, JiayiJiayiLiQin, ZailongZailongQinMachado Bressan Wilke, Matheus VernetMatheus VernetMachado Bressan WilkeLiu, YijunYijunLiuLi, QianQianLiLiu, HaoranHaoranLiuLiang, ChenChenLiangMorales-Rosado, Joel AJoel AMorales-RosadoCohen, Ana S AAna S ACohenHughes, Susan SSusan SHughesSullivan, Bonnie RBonnie RSullivanWaddell, ValerieValerieWaddellvan den Boogaard, Marie-José HMarie-José Hvan den Boogaardvan Jaarsveld, Richard HRichard Hvan Jaarsveldvan Binsbergen, EllenEllenvan Binsbergenvan Gassen, Koen LKoen Lvan GassenWang, TianyunTianyunWangHiatt, Susan MSusan MHiattAmaral, Michelle DMichelle DAmaralKelley, Whitley VWhitley VKelleyZhao, JianboJianboZhaoFeng, WeixingWeixingFengRen, ChanghongChanghongRenYu, YazhenYazhenYuBoczek, Nicole JNicole JBoczekFerber, Matthew JMatthew JFerberLahner, CarrieCarrieLahnerElliott, SherrSherrElliottRuan, YiyanYiyanRuanMignot, CyrilCyrilMignotKeren, BorisBorisKerenXie, HuaHuaXieWang, XiaoyanXiaoyanWangPopp, BerntBerntPoppZweier, ChristianeChristianeZweierPiard, JulietteJuliettePiardCoubes, ChristineChristineCoubesMau-Them, Frederic TranFrederic TranMau-ThemSafraou, HanaHanaSafraouInnes, A MicheilA MicheilInnesGauthier, JulieJulieGauthierMichaud, Jacques LJacques LMichaudKoboldt, Daniel CDaniel CKoboldtSylvie, OdentOdentSylvieWillems, MarjolaineMarjolaineWillemsTan, Wen-HannWen-HannTanCogne, BenjaminBenjaminCogneRieubland, ClaudineClaudineRieublandBraun, DominiqueDominiqueBraunMcLean, Scott DouglasScott DouglasMcLeanPlatzer, KonradKonradPlatzerZacher, PiaPiaZacherOppermann, HenryHenryOppermannEvenepoel, LucieLucieEvenepoelBlanc, PierrePierreBlancEl Khattabi, LaïlaLaïlaEl KhattabiHaque, NeshatulNeshatulHaqueDsouza, Nikita RNikita RDsouzaZimmermann, Michael TMichael TZimmermannUrrutia, RaulRaulUrrutiaKlee, Eric WEric WKleeShen, YipingYipingShenDu, HongzhenHongzhenDuRappaport, LeonardLeonardRappaportLiu, Chang-MeiChang-MeiLiuChen, XiaoliXiaoliChen2024-11-202024-11-202024-11-07https://boris-portal.unibe.ch/handle/20.500.12422/189357Microtubule 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.enASDLoFMARK2 variantsWNT/β-catenin signaling pathwayautism spectrum disorderlithiumloss-of-function600 - Technology::610 - Medicine & healtharticle10.48620/764233941902710.1016/j.ajhg.2024.09.006