Charcot-Marie-Tooth disease type 1A. Association with a spontaneous point mutation in the PMP22 gene

N Engl J Med. 1993 Jul 8;329(2):96-101. doi: 10.1056/NEJM199307083290205.


Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. CMT type 1A is associated with a 1.5-megabase DNA duplication in region p11.2-p12 of chromosome 17 in most patients. An increased dosage of a gene within the duplicated segment appears to cause the disease. The PMP22 gene, which encodes a myelin protein, has been mapped within the duplication and proposed as a candidate gene for CMT type 1A.

Methods: We analyzed DNA samples from a cohort of 32 unrelated patients with CMT type 1 who did not have the 1.5-Mb tandem duplication in 17p11.2-p12 for mutations within the PMP22 coding region. Molecular techniques included the polymerase chain reaction (PCR), heteroduplex analysis to detect point mutations, and direct nucleotide-sequence determination of amplified PCR products.

Results: A 10-year-old boy was identified with a point mutation in PMP22, which resulted in the substitution of cysteine for serine in a putative transmembrane domain of PMP22. Analysis of family members revealed that the PMP22 point mutation arose spontaneously and segregated with the CMT type 1 phenotype in an autosomal dominant pattern. The patients with the PMP22 point mutation had clinical and electrophysiologic phenotypes that were similar to those of patients with the 1.5-Mb duplication.

Conclusions: The PMP22 gene has a causative role in CMT type 1. Either a point mutation in PMP22 or a duplication of the region including the PMP22 gene can result in the disease phenotype.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Charcot-Marie-Tooth Disease / genetics*
  • Child
  • Chromosomes, Human, Pair 17
  • DNA, Antisense
  • Gene Amplification
  • Humans
  • Male
  • Molecular Sequence Data
  • Multigene Family
  • Nucleic Acid Heteroduplexes
  • Pedigree
  • Point Mutation*
  • Polymerase Chain Reaction
  • Sequence Homology, Amino Acid


  • DNA, Antisense
  • Nucleic Acid Heteroduplexes