CELLULAR AND BIOPHYSICAL MECHANISMS OF CMTX

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Connexin 32 (Cx32), is a gap junction protein found in the paranodal loops and Schmidt-Lantermann incisures of myelinating Schwann cells. Mutations in the gene encoding the human gap junction protein lead to CMTX, the X-linked form of the clinical condition known as Charcot-Marie - Tooth disease, a group of inherited peripheral neuropathies. Some mutations in Cx32 appear to allow for appropriate membrane targeting and formation of functional channels, some may lead to altered cellular processing, and others prevent Cx32 synthesis entirely. Mutations in Cx32 may be important in determining the processing and biophysical behavior of the Cx32 ion-channel. I hypothesize that mutations in Cx32 found in patients with CMTX, lead to the loss of ability of Cx32 to provide a vital cellular communication pathway. Various mutations may lead to this loss-of-function by altering the biophysical properties of the pore, or by affecting cellular processing of the protein or its ability to organize into functional channels. To evaluate these possibilities: 1) I will determine the biophysical properties of the channels formed by connexins containing mutations corresponding to those found in patients with CMTX; channels will be expressed in Xenopus oocytes or transfected cells; and 2) I will observe the cellular trafficking of wild-type and mutant forms of Cx32 in real time, in living cells, using an EGFP-tagged form of the molecule. The work described in this proposal will provide the applicant with an opportunity to acquire the necessary intellectual and technical skills to be an independent investigator in translational neuroscience research.