title: Clinical and biophysical characterization of 19GJB1mutations.
abstract: Charcot-Marie-Tooth disease type X1 (CMTX1), which is caused by mutations in the gap junction (GJ) protein beta-1 gene (GJB1), is the second most common form of Charcot-Marie-Tooth disease (CMT).GJB1encodes the GJ beta-1 protein (GJB1), which forms GJs within the myelin sheaths of peripheral nerves. The process by which GJB1 mutants cause neuropathy has not been fully elucidated. This study evaluated the biophysical characteristics of GJB1 mutants and their correlations with the clinical features of CMTX1 patients.
  
  
  
  All patients with a validatedGJB1mutation were assessed using the Charcot-Marie-Tooth disease neuropathy score version 2 (CMTNS). The impacts of the mutations on the biophysical functions of GJB1 were characterized by assessing intracellular localization, expression patterns, and GJ Ca2+permeability.
  
  
  
  NineteenGJB1mutations were identified in 24 patients with a clinical diagnosis of CMT. Six are novel mutations: p.L6S, p.I20F, p.I101Rfs*8, p.F153L, p.R215P, and p.D278V. Diverse pathological effects of the mutations were demonstrated, including reduced GJB1 expression, intracellular mislocalization, and altered GJ functions.GJB1mutations that caused a complete loss of GJ Ca2+permeability appeared to be associated with an earlier disease onset, whereas those resulting in preservation of GJ permeability and with predominant cell membrane expression tended to have a later onset and a milder phenotype.
  
  
  
  This study demonstrated that the degree of loss of GJ function caused by theGJB1mutations might contribute to the onset and severity of neuropathic symptoms in CMTX1.
authors.affiliation: Department of Neurology Taipei Veterans General Hospital Taipei 11217 Taiwan; Department of Neurology National Yang-Ming University School of Medicine Taipei 11221 Taiwan; Brain Research Center National Yang-Ming University Taipei 11221 Taiwan.
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.affiliation: Microscopy Service Laboratory Basic Research Division Department of Medical Research and Education Taipei Veterans General Hospital Taipei 11217 Taiwan; Institute of Biophotonics School of Medical Technology & Engineering; Biophotonics and Molecular Imaging Research Center (BMIRC) National Yang-Ming University Taipei 11212 Taiwan.
authors.forename: De-Ming
authors.initials: DM
authors.lastname: Yang
authors.affiliation: Department of Neurology Taipei Veterans General Hospital Taipei 11217 Taiwan; Department of Neurology National Yang-Ming University School of Medicine Taipei 11221 Taiwan.
authors.forename: Yi-Chu
authors.initials: YC
authors.lastname: Liao
authors.affiliation: Microscopy Service Laboratory Basic Research Division Department of Medical Research and Education Taipei Veterans General Hospital Taipei 11217 Taiwan; Institute of Biophotonics School of Medical Technology & Engineering; Biophotonics and Molecular Imaging Research Center (BMIRC) National Yang-Ming University Taipei 11212 Taiwan.
authors.forename: Tai-Yu
authors.initials: TY
authors.lastname: Chiu
authors.affiliation: Department of Neurology Chang Gung Memorial Hospital at Linkou Medical Center and Chang Gung University College of Medicine Taoyuan 33302 Taiwan.
authors.forename: Hung-Chou
authors.initials: HC
authors.lastname: Kuo
authors.affiliation: Department of Psychiatry Cathay General Hospital Taipei 10687 Taiwan; School of Medicine Fu-Jen Catholic University Taipei 24205 Taiwan.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Su
authors.affiliation: Institute of Clinical Medicine National Yang-Ming University Taipei 11221 Taiwan; Neuroscience Laboratory Department of Neurology China Medical University Hospital Taichung 40447 Taiwan; School of Medicine College of Medicine China Medical University Taichung 40402 Taiwan.
authors.forename: Yuh-Cherng
authors.initials: YC
authors.lastname: Guo
authors.affiliation: Department of Neurology Taipei Veterans General Hospital Taipei 11217 Taiwan; Department of Neurology National Yang-Ming University School of Medicine Taipei 11221 Taiwan; Brain Research Center National Yang-Ming University Taipei 11221 Taiwan.
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
authors.affiliation: Department of Neurology Taipei Veterans General Hospital Taipei 11217 Taiwan; Department of Neurology National Yang-Ming University School of Medicine Taipei 11221 Taiwan.
authors.forename: Kon-Ping
authors.initials: KP
authors.lastname: Lin
authors.affiliation: Department of Neurology Taipei Veterans General Hospital Taipei 11217 Taiwan; Department of Neurology National Yang-Ming University School of Medicine Taipei 11221 Taiwan.
authors.forename: Yo-Tsen
authors.initials: YT
authors.lastname: Liu
authors.affiliation: Department of Neurology Taipei Veterans General Hospital Taipei 11217 Taiwan; Department of Neurology National Yang-Ming University School of Medicine Taipei 11221 Taiwan; Brain Research Center National Yang-Ming University Taipei 11221 Taiwan.
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Lee