Von Recklinghausen neurofibromatosis (NF1), a major autosomal dominant disorder in man, affects 1 in 3,500 and displays a remarkably high mutation rate of approximately 1 in 10,000. NF1 symptoms are extremely variable, including cafe-au-lait spots, neurofibromas, Lisch nodules, learning disabilities and a predisposition to malignant tumors. They result from inactivating mutations in the gene encoding neurofibromin, a large protein with a GAP-like domain (GRD) implicated in Ras-mediated signal transduction. Precisely which pathways are modulated or how defects in neurofibromin produce the NF1 phenotypes remain uncertain, as is the basis of the high rate of sporadic NF1 cases. Striking sequence conservation outside the ORE) implies participation of neurofibromin in critical, as yet undefined functions. Our continuing investigation of NF1 will involve screening familial and sporadic cases for mutations and relating these to both patient phenotype and protein function. Cultured human Schwann cells will be used to test the hypothesis that NF1 neurofibromas result from somatic inactivation of the remaining wild-type allele and to examine the nature of such mutations. In each case, we will particularly focus on identifying missense or other alterations that target non-GRD) domains. We will test the effects of these mutations on biological and biochemical properties of neurofibromin to distinguish those functions that are unaltered from those critical to NF1's target tissues. The underlying premise is that properties of neurofibromin not affected by NF1 mutations must not be central to NF1 pathogenesis. Finally, by identifying interacting proteins, defining neurofibromin domains to which they bind, and ascertaining the effects of NF1 mutations on the interaction, we will implicate particular functions and/or pathways in the pathogenesis of the disorder. NF1 is an important disorder because of the large number of persons that it afflicts, and because of the window that it provides on the complexities of signal transduction in mammalian cells. There is currently no effective treatment for NF1. Many of its victims have a diminished quality of life because of its disfiguring consequences, and in some cases, their lives are cut short by malignant tumors. In our studies, we will take advantage of the variety of mutational deficits that nature has generated in this gene to tease out which of its functions are relevant to the disease and to define the structural and biochemical correlates to these functions. The results should yield a much better understanding of the mechanisms of mutation in NF1, and of the role that neurofibromin plays in various signal transduction pathways. Hopefully, this knowledge will provide specific clues to the development of successful treatments for the victims of NF1, and broader hints concerning the manipulation of signal transduction for influencing the course of any number of other disorders, particularly various forms of cancer.
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