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

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

B B Roa  1 , 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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Free article

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

B B Roa et al. N Engl J Med. .
Free article

Abstract

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.

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