two novel mutations in an x-linked charcot-marie-tooth disease family

charcot-marie-tooth disease (cmt) is the most common form of inherited peripheral neuropathy. cmt is genetically and clinically heterogenous group of hereditary motor and sensory neuropathies characterized by areflexia, distal sensory loss and progressive weakness of the distal limb muscles. the x-linked cmt (cmtx) is the second most frequent form of charcot-marie-tooth disease. the dominant cmtx1 locus on chromosome xq13.1 accounts for about 90% of the x-linked cases and is usually associated with mutations in the gap junction protein β1 (gjb1) gene which encodes for connexin 32 (cx32), an integral transmembrane protein that involved in the transport of small molecules within schwann cells. gap junctions allow electrical communication between cells in the nervous system and gjb1 mutations affect the function of gap junctions in the myelin sheath. in x-linked charcot-marie-tooth disease electrophysiological and histopathological studies have suggested either a demyelinating or an axonal polyneuropathy. thirty two iranian families with a diagnosis of cmt disease, either axonal or demyelinating, were available for genetic analysis of gjb1. blood samples were obtained from the patients and members of their families. total genomic dna was extracted using standard procedure. the 1.5 mb cmt1a duplication on chromosome 17p11.2 was first excluded in patients with pcr-rflp. the gjb1 gene was then investigated with three markers linked to the chromosome x. then pcr amplification and direct sequencing of coding exon 2 and nerve-specific p2 promoter region performed for x-linked patients. in this study we describe a case of cmtx in a family caused by two novel point mutations in the gjb1 gene. a missense mutation (m194i) and a silent mutation (s225s) both in the coding exon 2 of the gjb1 gene. these mutations were not detected in normal subjects which support the hypothesis that they are responsible for the cmtx phenotype. the data in this study could also be used in prenatal diagnosis and carrier detection.