CHARCOT-MARIE-TOOTH DISEASE TYPE-1A - ASSOCIATION WITH A SPONTANEOUS POINT MUTATION IN THE PMP22 GENE

Background. Charcot-Marie-Tooth disease (CMT) is the most common inher ited peripheral neuropathy. CMT type 1A is associated with a 1.5-megab ase (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 p rotein, has been mapped within the duplication and proposed as a candi date gene for CMT type 1A. Methods. We analyzed DNA samples from a coh ort 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 co ding region. Molecular techniques included the polymerase chain reacti on (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 tra nsmembrane domain of PMP22. Analysis of family members revealed that t he PMP22 point mutation arose spontaneously and segregated with the CM T type 1 phenotype in an autosomal dominant pattern. The patients with the PMP22 point mutation had clinical and electrophysiologic phenotyp es 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. Eithe r a point mutation in PMP22 or a duplication of the region including t he PMP22 gene can result in the disease phenotype.