title: Aberrant transcriptional networks in step-wise neurogenesis of paroxysmal kinesigenic dyskinesia-induced pluripotent stem cells.
abstract: Paroxysmal kinesigenic dyskinesia (PKD) is an episodic movement disorder with autosomal-dominant inheritance and marked variability in clinical manifestations.Proline-rich transmembrane protein 2 (PRRT2) has been identified as a causative gene of PKD, but the molecular mechanism underlying the pathogenesis of PKD still remains a mystery. The phenotypes and transcriptional patterns of the PKD disease need further clarification. Here, we report the generation and neural differentiation of iPSC lines from two familial PKD patients with c.487C>T (p. Gln163X) and c.573dupT (p. Gly192Trpfs*8) PRRT2 mutations, respectively. Notably, an extremely lower efficiency in neural conversion from PKD-iPSCs than control-iPSCs is observed by a step-wise neural differentiation method of dual inhibition of SMAD signaling. Moreover, we show the high expression level of PRRT2 throughout the human brain and the expression pattern of PRRT2 in other human tissues for the first time. To gain molecular insight into the development of the disease, we conduct global gene expression profiling of PKD cells at four different stages of neural induction and identify altered gene expression patterns, which peculiarly reflect dysregulated neural transcriptome signatures and a differentiation tendency to mesodermal development, in comparison to control-iPSCs. Additionally, functional and signaling pathway analyses indicate significantly different cell fate determination between PKD-iPSCs and control-iPSCs. Together, the establishment of PKD-specific in vitro models and the illustration of transcriptome features in PKD cells would certainly help us with better understanding of the defects in neural conversion as well as further investigations in the pathogenesis of the PKD disease.
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.
authors.forename: Kunshan
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Gu
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Tang
authors.affiliation: Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.|Key Laboratory of Stem Cell Biology, Center for The Excellence in Molecular and Cell Sciences, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Shengdi
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.affiliation: Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China.|Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China.
authors.forename: Siguang
authors.initials: S
authors.lastname: Li
authors.affiliation: Laboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.|Key Laboratory of Stem Cell Biology, Center for The Excellence in Molecular and Cell Sciences, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004421:Dystonia / Q000235:genetics* / Q000503:physiopathology; D053263:Gene Regulatory Networks; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D055495:Neurogenesis / Q000235:genetics*; D059467:Transcriptome
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C569370:PRRT2 protein, human
keywords: induced pluripotent stem cells (iPSCs); neural differentiation; paroxysmal kinesigenic dyskinesia (PKD); proline-rich transmembrane protein 2 (PRRT2); transcriptome analysis