X-linked Charcot-Marie-Tooth (CMTX) disease is a hereditary motor and sensory neuropathy caused by mutations in the gap junction beta 1 gene (GJB1 codes for connexin 32). In this study we report six novel mutations p.Met1Arg, p.Leu9Phe, p.Ser17Tyr, p.Val63Phe, p.Val170Ile, and p.Leu212Phe in GJB1 and their phenotypic expression. These mutations affect both intracellular and extracellular parts of the GJB1 protein. The screened patients had previously excluded the duplication/deletion on 17p11.2 and the male-to-male transfer in the pedigree. Except p.Val170Ile, all reported mutations segregated with the CMT phenotype in the families and caused CMTX1 neuropathy. Mutations were not found in 200 control DNA samples. Additionally, we performed in silico analysis of the novel mutations with the program PANTHER. The PANTHER scored five mutations, all but p.Val170Ile, as likely deleterious and supported the pathogenicity of the found mutations. These results provided evidence that these five mutations are causative for CMTX1.

DNA Laboratory Department of Child Neurology Charles University 2nd Medical School and University Hospital Motol Prague Czech Republic

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Mosaicism for GJB1 mutation causes milder Charcot-Marie-Tooth X1 phenotype in a heterozygous man than in a manifesting heterozygous woman