title: Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease.
abstract: OBJECTIVE
  On the basis of the hypothesis that copy number mutations of the genes encoding myelin compact proteins are responsible for myelin disorders in humans, we have explored the possibility of copy number mutations in patients with Charcot-Marie-Tooth disease (CMT) whose responsible genes remain undefined.
  
  
  METHODS
  A family with 6 affected members in 3 consecutive generations, presenting with motor and sensory demyelinating polyneuropathy, was investigated. Characteristic clinical features in this pedigree include Adie pupils and substantial intrafamilial variability in the age at onset, electrophysiological findings, and clinical severity. Nucleotide sequence analyses of PMP22, MPZ, or GJB1 and gene dosage study of PMP22 did not reveal causative mutations. Hence, we applied a custom-designed array for comparative genomic hybridization (CGH) analysis to conduct a comprehensive screening of copy number mutations involving any of the known causative genes for CMT other than PMP22.
  
  
  RESULTS
  The array CGH analyses revealed increased gene dosage involving the whole MPZ, and the flanking genes of SDHC and C1orf192. The gene dosage is estimated to be 5 copies. This mutation showed complete cosegregation with the disease phenotype in this pedigree.
  
  
  CONCLUSIONS
  The increased gene dosage of MPZ and increased expression level of MPZ mRNA emphasize the important role of the dosage of the MPZ protein in the functional integrity of peripheral nerve myelin in humans, and provide a new insight into the pathogenic mechanisms underlying CMT.
authors.affiliation: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Meiko Hashimoto
authors.initials: MH
authors.lastname: Maeda
authors.forename: Jun
authors.initials: J
authors.lastname: Mitsui
authors.forename: Bing-Wen
authors.initials: BW
authors.lastname: Soong
authors.forename: Yuji
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiura
authors.forename: Shin
authors.initials: S
authors.lastname: Hayashi
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Shirota
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Arai
authors.forename: Tomoko
authors.initials: T
authors.lastname: Okamoto
authors.forename: Sahoko
authors.initials: S
authors.lastname: Miyama
authors.forename: Jun
authors.initials: J
authors.lastname: Shimizu
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
authors.forename: Jun
authors.initials: J
authors.lastname: Goto
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D018993:Myelin P0 Protein / Q000235:genetics* / Q000502:physiology; D010375:Pedigree
chemical_list: C560547:MPZ protein, human; D018993:Myelin P0 Protein