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 amon g:the genetically heterogeneous group of CMT disorders. Molecular studies i n a large family with-autosomal dominant CMT and deafness have not been rep orted. The present molecular study involves a family with progressive featu res of CMT and deafness, originally reported by Kousseff et al. Genetic ana lysis of 70 individuals (31 affected, 28 unaffected, and 11 spouses):reveal ed linkage to markers on chromosome 17p11.2-p12, with a maximum LOD score o f 9.01 for marker D17S1357 at a recombination fraction of .03. Haplotype-an alysis 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. Aff ected individuals from this family do not have the common 1.5- Mb duplicati on of CMT type 1A. Direct sequencing of the candidate peripheral myelin pro tein 22 (PMP22) gene detected a unique G-->C transversion in the heterozygo us state in all affected individuals, at position 248 in coding exon, predi cted to result in an Ala67Pro substitution in the second transmembrane doma in of PMP22.