title: Myelin uncompaction in Charcot-Marie-Tooth neuropathy type 1A with a point mutation of peripheral myelin protein-22.
abstract: BACKGROUND
  The peripheral myelin protein-22 (PMP22) gene has four transmembrane domains, two extracellular loops, and a short cytoplasmic tail. Its roles in the peripheral nervous system remain unclear. The most common cause of Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is a PMP22 gene duplication. Missense point mutations in the transmembrane domains are rare alternative causes that have undetermined pathogenetic mechanisms.
  
  
  OBJECTIVE
  To investigate the phenotype-to-genotype correlations in a pedigree with unusual CMT1A.
  
  
  METHODS
  We identified a pedigree with an autosomal dominant motor-sensory neuropathy and severely reduced nerve conduction velocities who did not have the PMP22 duplication. Specimens from sural nerve biopsies from two patients of different ages were evaluated morphometrically. By automated direct nucleotide sequencing we analyzed PMP22 and the gene of the major structural myelin protein zero (P0).
  
  
  RESULTS
  Nucleotide 159 of PMP22 showed an A-to-T heterozygous mutation, predicted to cause an aspartate-to-valine substitution at codon 37 in the first extracellular loop of the protein. The mutation co-segregated with the disease in the pedigree and was absent in 80 healthy controls. The histopathologic phenotype was a de-remyelinating neuropathy with onion bulb formations, characterized by prominent uncompaction of the myelin sheath in the majority of fibers and by frequent tomacula.
  
  
  CONCLUSIONS
  We have described a novel mutation in the first extracellular loop of PMP22 associated with an atypical CMT1A that overlaps pathologically with CMT1B caused by point mutations in the extracellular domain of P0.
authors.affiliation: Department of Neurological and Visual Sciences, University of Verona, Italy.
authors.forename: G M
authors.initials: GM
authors.lastname: Fabrizi
authors.forename: T
authors.initials: T
authors.lastname: Cavallaro
authors.forename: F
authors.initials: F
authors.lastname: Taioli
authors.forename: D
authors.initials: D
authors.lastname: Orrico
authors.forename: M
authors.initials: M
authors.lastname: Morbin
authors.forename: A
authors.initials: A
authors.lastname: Simonati
authors.forename: N
authors.initials: N
authors.lastname: Rizzuto
mesh_terms: D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009185:Myelin Proteins / Q000235:genetics*; D009186:Myelin Sheath / Q000648:ultrastructure; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*
chemical_list: D009185:Myelin Proteins; C073687:PMP22 protein, human