Connexin 32 (Cx32Y) is a gap junction protein found in the paranodal loops and Schmidt-Lantermann incisures of myelinating Schwann cells. Mutations in the gene encoding this gap junction protein lead to CMTX, an X linked form of Charcot-MarieTooth (CXMT) disease, a group of inherited peripheral neuropathies. The hypothesis underlying this work is that mutations in Cx32 found in patients with CMTX alter the functional properties of Cx32 so it can no longer provide a vital Schwann cell communication pathway. Based on recent observations at least one mutation may confer channel properties that could be toxic to cells in which the mutant protein is expressed. The experiments outlined in this proposal will examine alterations in functional expression and biophysical properties of Cx32 channels containing CMTX mutations. The effects of CMTX mutations on trafficking of gap junction proteins will also be examined. Findings will be correlated with both clinical data from the literature and with data provided by neurologists who care for patients with CXMT. A better understanding of the specific functional alterations in Cx32 associated with CMTX is needed before rational therapies for this disorder can be devised. In addition, a more complete understanding of the Cx32 dependent processes that are altered in this disease may provide clues to the specific roles of Cx32 in the normal Schwann cell. My sponsor, Dr. M.V.L. Bennett and co-sponsor, Dr. T.A. Bargiello, continue to provide strong support for the work outlined in this application and for my career development in general. The additional support that will be provided by a two-years continuation of my K08 grant will allow me to continue my transition to full independence and to submit my strongest application for an R01 grant within approximately 12-18 months.
| Abrams, Charles K; Freidin, Mona M; Verselis, Vytas K et al. (2006) Properties of human connexin 31, which is implicated in hereditary dermatological disease and deafness. Proc Natl Acad Sci U S A 103:5213-8 |
| Abrams, Charles K; Freidin, Mona; Bukauskas, Feliksas et al. (2003) Pathogenesis of X-linked Charcot-Marie-Tooth disease: differential effects of two mutations in connexin 32. J Neurosci 23:10548-58 |
| Abrams, C K; Bennett, M V L; Verselis, V K et al. (2002) Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease. Proc Natl Acad Sci U S A 99:3980-4 |
| Abrams, C K; Freidin, M M; Verselis, V K et al. (2001) Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease. Brain Res 900:9-25 |
