title: PRRT2 truncated mutations lead to nonsense-mediated mRNA decay in Paroxysmal Kinesigenic Dyskinesia.
abstract: OBJECTIVE
  Paroxysmal Kinesigenic Dyskinesia (PKD) is an episodic involuntary movement disorder characterized by recurrent and brief involuntary movements. Proline-rich transmembrane protein 2 (PRRT2) has been identified as the causative gene for PKD, Benign familial infantile convulsions (BFIC) and Infantile convulsions with choreoathetosis (ICCA). As well, PRRT2 mutations have been detected in patients with PED or PNKD. To date, most of the mutations have been found to be nonsense.
  
  
  METHODS
  We used inhibitors of nonsense-mediated mRNA decay (NMD) pathway --emetine dihydrochloride hydrate and cycloheximide and silencing regulator of nonsense transcripts 1(UPF1) with immortalized lymphoblasts to detect whether the truncated mutations lead to NMD, a type of mRNA surveillance in every eukaryotic cell proved so far and that generally degrades mRNA containing premature translation termination codons (PTCs). In addition, we transfected the SH-SY5Y cells with wild-type and mutant PRRT2 plasmids to identify the PRRT2 protein's subcellular localization.
  
  
  RESULTS
  We detected, low expression of truncated PRRT2 and was further rescued by applying the inhibitor of NMD pathway, suggesting that NMD plays an important role in the pathogenesis of PKD by haplo-insufficiency. Moreover, for the small portion of undegraded mutant PRRT2 that was translated into truncated proteins, their cellular localization changed from membrane to cytoplasm and nuclear, which might lead to a functional loss.
  
  
  CONCLUSIONS
  We suggest that the NMD of truncated mutation of PRRT2 and altered cellular localization of undegraded of PRRT2, might lead to PKD.
authors.affiliation: Department of Neurology and Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Neurology and Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Hui-Dong
authors.initials: HD
authors.lastname: Tang
authors.affiliation: Department of Neurology and Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Huang
authors.affiliation: Department of Neurology and Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Neurology and Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Liu
authors.affiliation: Department of Neurology and Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Neurology and Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China.
authors.forename: Jing-Yi
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Department of Neurology and Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China. Electronic address: caoli_csu@hotmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Neurology and Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, China. Electronic address: chen_sd@medmail.com.cn.
authors.forename: Sheng-Di
authors.initials: SD
authors.lastname: Chen
mesh_terms: D045744:Cell Line, Tumor; D002819:Chorea / Q000235:genetics*; D004252:DNA Mutational Analysis; D004421:Dystonia; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D016296:Mutagenesis / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology; D059365:Nonsense Mediated mRNA Decay / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C569370:PRRT2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering
keywords: Nonsense-mediated mRNA decay (NMD); Paroxysmal Kinesigenic Dyskinesia (PKD); Proline-rich transmembrane protein 2 (PRRT2); Regulator of nonsense transcripts 1(UPF1)