George Jackson Snipes
Baylor College of Medicine, Building: BCM-Ben Taub
Research Center
Room: BCMT-240
Phone: 713.798.1873
E~mail: gsnipes@bcm.tmc.edu
RESEARCH INTERESTS:
Our laboratory studies the molecular pathogenesis of inherited neuropathies. Mutations in number of genes have been identified that cause peripheral nerve disorders, collectively known a Charcot-Marie-Tooth CMT) disease, that specifically affect myelin formation in the PNS. We are studying these CMT genes to elucidate axon-glial interactions and other mechanisms that are required for myelin formation. We have developed a number of transgenic mice to functionally map important promoter elements in myelin structural protein genes. Ultimately, we will use these mice to develop assays for signal transduction pathways that directly control myelin gene expression. We also study the effects of "gain of function' missense mutations in the major CMT gene encoding for Peripheral Myelin protein 22 (PMP22). We have demonstrated that most of these mutations cause intracellular retention of the mutant PMP22 protein, in association with the endoplasmic reticulum quality control protein, calnexin. Studies are ongoing as to how ER retention of the mutant proteins cause demyelination. We use a multidisciplinary approach that extensively employs conventional and ES cell based mouse transgenesis to recreate a subset of these disorders and as assays for factors that affect myelin gene regulation. We then use a variety of cell, biochemical, and morphologic techniques, as appropriate, to understand the molecular mechanisms contributing to the formation and loss of myelin in these dysmyelinating/demyelinating disease models.
Selected Publications
Notterpek, L., Snipes, G.J. and E. M. Shooter (1999). In vitro studies support multiple roles for PMP22 in peripheral nerve myelination. Glia. 25:358-369.
Colby, J., Nicholson, R., Dickson, K. M., Orfali, W., Naef, R., Suter, U., and G. J. Snipes. (2000) PMP22 carrying the Trembler or Trembler-J mutation is intracellularly retained in myelinating Schwann cells. Neurobiol. of Disease,7:561-573.
Dickson, K., Bergeron, J.J.M., Shames, I, Colby, J., Nguyen, D.T., Chevet, E., Thomas, D.Y., and G. J. Snipes. (2002) Association of calnexin with mutant peripheral myelin protein-22 (PMP-22) ex vivo: A basis for "gain of function" ER diseases. Proc. Natl. Acad. Sci (USA) 99:9852-9857.
Shames, I., Fraser, A., , Colby, J., Orfali, W., and G. J. Snipes. (2003) Phenotypic differences between Peripheral Myelin Protein-22 (PMP-22) and Protein zero (P0) mutations associated with Charcot-Marie-Tooth and related diseases. J. Neuropathol. Exp. Neurol. 62:751-764.
Saifi, G. M., K. Szigeti, G. J. Snipes, C. A. Garica and J. R. Lupski. Cellular mechanisms, diagnosis and rational approaches to management and therapy for Charcot-Marie-Tooth and related neuropathies. J. Invest. Med. In press.