Neurofibromatosis type 1 (NF1) is a genetic disease caused by mutations in the NF1 gene. It has often been described as the most common genetic disease of man affecting approximately 1/3500. Familial cases are inherited as an autosomal dominant trait but sporadic cases account for approximately 50%. NF1 is fully penetrant but it is marked by substantial variation in expressivity. The NF1 gene encodes a large protein (neurofibromin) that enhances the GTPase activity of p2lras and mutations that affect the GTPase accelerating activity of neurofibromin have been detected in tumors both in and out of the context of NF1. The NF1 gene is often described as a tumor suppressor gene and it is believed that loss of both alleles is required for the formation of lesions (germ cell loss of one and somatic mutation in the other would explain the lesions in the familial cases). One of the remarkable features of the NF1 gene is that within one of its introns and on the strand opposite to the NF1 gene there are three smaller genes, one being a gene that encodes the oligodendrocytemyelin glycoprotein (OMgp). We propose that there is either a close connection between the functions of neurofibromin and OMgp or there is a coordination in the controls of expression of the genes that encode them or both. This hypothesis is based on preliminary work presented in the application and the view is that there is likely to be a reason for the placement of the OMgp gene within the NF1 gene. In this application we propose to: 1) use homologous recombination techniques to create null mutations in the OMgp gene in mice; 2) turn down expression of the NF1 and the OMgp genes in a limited number of cells in the mouse CNS using retrovirally transmitted antisense constructs, and 3). determine whether OMgp modulates the function of NF1 and whether there is a connection between the control of expression of the genes that encode them.
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| Habib, A A; Marton, L S; Allwardt, B et al. (1998) Expression of the oligodendrocyte-myelin glycoprotein by neurons in the mouse central nervous system. J Neurochem 70:1704-11 |
| Habib, A A; Gulcher, J R; Hognason, T et al. (1998) The OMgp gene, a second growth suppressor within the NF1 gene. Oncogene 16:1525-31 |
