title: CMT1X phenotypes represent loss of GJB1 gene function.
abstract: OBJECTIVE
  To investigate possible genotype-phenotype correlations and to evaluate the natural history of patients with Charcot-Marie-Tooth disease type 1X (CMT1X).
  
  
  BACKGROUND
  CMT1X is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 (Cx32). The natural history of CMT1X is poorly understood, and it remains unknown whether particular mutations cause more severe neuropathies through abnormal gain-of-function mechanisms.
  
  
  METHODS
  We evaluated 73 male patients with CMT1X, who each have 1 of 28 different GJB1 mutations predicted to affect nearly all domains of Cx32. Disability was evaluated quantitatively by the CMT Neuropathy Score (CMTNS) as well as by the CMT Symptom Score (CMTSS) and the CMT Examination Score (CMTES), which are both based on the CMTNS. Patients were also evaluated by neurophysiology.
  
  
  RESULTS
  In all patients, disability increased with age, and the degree of disability was comparable with that observed in patients with a documented GJB1 deletion. Disability correlated with a loss of motor units as assessed by motor unit number estimates.
  
  
  CONCLUSIONS
  Taken together, these data suggest that most GJB1 mutations cause neuropathy by a loss of normal connexin 32 function. Therefore, treatment of male patients with Charcot-Marie-Tooth disease type 1X may prove amenable to gene replacement strategies.
authors.affiliation: Department of Neurology, Wayne State University, 421 E. Canfield, Detroit, MI 48201, USA. m.shy@wayne.edu
authors.forename: M E
authors.initials: ME
authors.lastname: Shy
authors.forename: C
authors.initials: C
authors.lastname: Siskind
authors.forename: E R
authors.initials: ER
authors.lastname: Swan
authors.forename: K M
authors.initials: KM
authors.lastname: Krajewski
authors.forename: T
authors.initials: T
authors.lastname: Doherty
authors.forename: D R
authors.initials: DR
authors.lastname: Fuerst
authors.forename: P J
authors.initials: PJ
authors.lastname: Ainsworth
authors.forename: R A
authors.initials: RA
authors.lastname: Lewis
authors.forename: S S
authors.initials: SS
authors.lastname: Scherer
authors.forename: A F
authors.initials: AF
authors.lastname: Hahn
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D002607:Charcot-Marie-Tooth Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D002648:Child; D017630:Connexins / Q000235:genetics*; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies; D000097002:Gap Junction beta-1 Protein
chemical_list: D017630:Connexins; D000097002:Gap Junction beta-1 Protein