Charcot-Marie-Tooth Disease Type 1A – Association with a Spontaneous Point Mutation in the PMP22 Gene

B. B. Roa, C. A. Garcia, U. Suter, D. A. Kulpa, C. A. Wise, J. Mueller, A. A. Welcher, G. J. Snipes, E. M. Shooter, P. I. Patel, J. R. Lupski

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318 Scopus citations


Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. CMT type 1A is associated with a 1.5-megabase (Mb) 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., Charcot-Marie-Tooth disease (CMT)1,2 is the most common inherited peripheral neuropathy, with a frequency of 1 in 2500,3 and is one of the most prevalent autosomal dominant diseases4. It is a clinically heterogeneous disorder of the peripheral nerves characterized by slowly progressive atrophy of the distal muscles, predominantly those innervated by the peroneal nerve4,5. Progressive weakness of varying intensity and atrophy of the muscles of the feet, hands, and legs, leading to pes cavus deformity, clawhand, and stork-leg appearance, usually begin in the second or third decade of life4,5. Enlarged greater auricular nerves may be…

Original languageEnglish (US)
Pages (from-to)96-101
Number of pages6
JournalNew England Journal of Medicine
Issue number2
StatePublished - Jul 8 1993

ASJC Scopus subject areas

  • Medicine(all)


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