A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness

Charcot-Marie-Tooth disease (CMT) with deafness is clinically distinct among:the genetically heterogeneous group of CMT disorders. Molecular studies in a large family with-autosomal dominant CMT and deafness have not been reported. The present molecular study involves a family with progressive features of CMT and deafness, originally reported by Kousseff et al. Genetic analysis of 70 individuals (31 affected, 28 unaffected, and 11 spouses):revealed linkage to markers on chromosome 17p11.2-p12, with a maximum LOD score of 9.01 for marker D17S1357 at a recombination fraction of .03. Haplotype-analysis placed:the CMT-deafness locus between markers D17S839 and D17S122, a similar to 0.6-Mb interval. This critical region lies: within the CMT type 1A duplication region and excludes MYO15, a gene coding an unconventional myosin that causes a form of autosomal recessive deafness called DFNB3. Affected individuals from this family do not have the common 1.5- Mb duplication of CMT type 1A. Direct sequencing of the candidate peripheral myelin protein 22 (PMP22) gene detected a unique G-->C transversion in the heterozygous state in all affected individuals, at position 248 in coding exon, predicted to result in an Ala67Pro substitution in the second transmembrane domain of PMP22.