title: Urine-derived induced pluripotent stem cells as a modeling tool for paroxysmal kinesigenic dyskinesia.
abstract: Paroxysmal kinesigenic dyskinesia (PKD) is a monogenic movement disorder with autosomal dominant inheritance. We previously identified the proline-rich transmembrane protein 2 (PRRT2) as a causative gene of PKD. However, the pathogenesis of PKD remains largely unknown so far. In addition, applicable modeling tools to investigate the underlying mechanisms of PKD are still lacking. The combination of disease-specific human induced pluripotent stem cells (iPSCs) and directed cell differentiation offers an ideal platform for disease modeling. In this study, we generated two iPSC lines from the renal epithelial cells of one PKD patient with the hotspot c.649dupC mutation (PKD-iPSCs). These cell lines were positive for alkaline phosphatase Nanog, Tra-1-80, Tra-1-60, SSEA-3 and SSEA-4. Teratomas with three blastoderms including ectoderm, mesoderm, and endoderm were obtained two months after injection of PKD-iPSCs into NOD/SCID mice. The expression of PRRT2 mRNA was decreased in PKD-iPSCs compared with that of the control iPSCs. Furthermore, PKD-iPSCs possessed the differentiation potential of functional glutamatergic, dopaminergic and motor neurons in vitro. Electrophysiological examinations revealed that the current densities of fast activated and deactivated sodium channels as well as voltage gated potassium channels were not different between the neurons from PKD-iPSCs and control iPSCs. Thus, PKD-iPSCs are a feasible modeling tool to investigate the pathogenic mechanisms of PKD.
authors.affiliation: Department of Neurology and Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai 200040, China.
authors.forename: Shu-Zhen
authors.initials: SZ
authors.lastname: Zhang
authors.affiliation: Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou 310009, China.
authors.forename: Hong-Fu
authors.initials: HF
authors.lastname: Li
authors.affiliation: Department of Anatomy, Histology & Embryology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
authors.forename: Li-Xiang
authors.initials: LX
authors.lastname: Ma
authors.affiliation: Institutes of Brain Science, Institute of Neurobiology and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Wen-Jing
authors.initials: WJ
authors.lastname: Qian
authors.affiliation: Institutes of Brain Science, Institute of Neurobiology and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
authors.forename: Zhong-Feng
authors.initials: ZF
authors.lastname: Wang
authors.affiliation: Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and the Collaborative Innovation Center for Brain Science, Zhejiang University School of Medicine, Hangzhou 310009, China zhiyingwu@zju.edu.cn.
authors.forename: Zhi-Ying
authors.initials: ZY
authors.lastname: Wu
keywords: Human induced pluripotent stem cells; Paroxysmal kinesigenic dyskinesia; Proline-rich transmembrane protein 2