Novel mutations in the connexin 32 gene associated with X-linked Charcot-Marie tooth disease

Charcot-Marie tooth disease, a pathologically and genetically heterogeneous group of disorders that causes a progressive neuropathy, is characterized by weakness and atrophy, primarily in peroneal and distal leg muscles. It is defined pathologically by degeneration of the myelin (CMT1) or the axon (CMT2) of the peripheral nerves. Two major forms of CMT1 are recognized: CMT1A, which is linked to chromosome 17p, with the gene for peripheral myelin protein 22 (PMP22) being implicated (Matsunami et al., 1992; Patel et al., 1992; Timmerman et al., 1992; Valentijn et al., 1992a,b; Roa et al., 1993), and CMT1B, which is linked to chromosome 1p, where mutations in the gene for myelin protein zero (P sub(O)) account for the disease (Hayasaka et al., 1993a,b; Kulkens et al., 1993). The causative gene(s) for CMT2 has yet to be determined. An X-linked form of this disorder (CMTX) has recently been linked to mutations in the connexin 32 (Cx32) gene, which codes for a 283 amino acid gap junction protein found in myelinated peripheral nerve (Bergoffen et al., 1993). To date some 30 different mutations (from 35 families) in this gene have been identified as being responsible for CMTX (Bergoffen et al., 1993; Cherryson et al., 1994; Fairweather et al., 1994; Ionasescu et al., 1994; Orth et al., 1994; Bone LJ, pers. commun.). The majority of these predict nonconservative amino acid substitutions, whereas a minority result in the formation of either premature stop codons or cause frame shift mutations. Two deletion mutations have been reported, one involving the loss of a single leucine residue and the other an 18-base pair deletion from the Cx32 coding region.