title: PRRT2 mutations lead to neuronal dysfunction and neurodevelopmental defects.
abstract: Mutations in the proline-rich transmembrane protein 2 (PRRT2) gene cause a wide spectrum of neurological diseases, ranging from paroxysmal kinesigenic dyskinesia (PKD) to mental retardation and epilepsy. Previously, seven PKD-related PRRT2 heterozygous mutations were identified in the Taiwanese population: P91QfsX, E199X, S202HfsX, R217PfsX, R217EfsX, R240X and R308C. This study aimed to investigate the disease-causing mechanisms of these PRRT2 mutations. We first documented that Prrt2 was localized at the pre- and post-synaptic membranes with a close spatial association with SNAP25 by synaptic membrane fractionation and immunostaining of the rat neurons. Our results then revealed that the six truncating Prrt2 mutants were accumulated in the cytoplasm and thus failed to target to the cell membrane; the R308C missense mutant had significantly reduced protein expression, suggesting loss-of function effects generated by these mutations. Using in utero electroporation of shRNA into cortical neurons, we further found that knocking down Prrt2 expression in vivo resulted in a delay in neuronal migration during embryonic development and a marked decrease in synaptic density after birth. These pathologic effects and novel disease-causing mechanisms may contribute to the severe clinical symptoms in PRRT2-related diseases.
authors.affiliation: Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Yo-Tsen
authors.initials: YT
authors.lastname: Liu
authors.affiliation: Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.|Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Fang-Shin
authors.initials: FS
authors.lastname: Nian
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Wan-Ju
authors.initials: WJ
authors.lastname: Chou
authors.affiliation: Istitute of Pharmaceutics, Development Center for Biotechnology, New Taipei City, Taiwan.
authors.forename: Chin-Yin
authors.initials: CY
authors.lastname: Tai
authors.affiliation: Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Shang-Yeong
authors.initials: SY
authors.lastname: Kwan
authors.affiliation: Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Chien
authors.initials: C
authors.lastname: Chen
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Kuo
authors.affiliation: Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.
authors.forename: Po-Hsi
authors.initials: PH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chin-Yi
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Huang
authors.affiliation: Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan.|Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan.|Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
authors.affiliation: Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.|Brain Research Center, National Yang-Ming University, Taipei, Taiwan.|Biophotonics and Molecular Imaging Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jin-Wu
authors.initials: JW
authors.lastname: Tsai
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D004421:Dystonia / Q000235:genetics; D004827:Epilepsy / Q000235:genetics; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008813:Mice, Inbred ICR; D009154:Mutation; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013624:Taiwan
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C569370:PRRT2 protein, human; C000609581:PRRT2 protein, mouse; C000625960:Prrt2 protein, rat; D034741:RNA, Small Interfering
keywords: PRRT2; Pathology Section; Taiwan; neuronal migration; paroxysmal kinesigenic dyskinesia (PKD); synaptic development