Neurofibromatosis (NF) consists of two or more distinct autosomal dominant genetic disorders characterized by abnormalities involving multiple tissues derived from the neuronal crest and is associated with the development of several types of nervous system tumors. NF 1 and NF2 are caused by inactivation of tumor suppressor genes on chromosomes 17 and 22 respectively. The long-term objective is to determine how defects at the NF1 or NF2 loci lead to the formation of both familial and sporadic tumors. Recently, the NF2 gene was isolated and its product, called merlin, was shown to be a member of a family of cytoskeleton-associated proteins that includes moesin, ezrin, and radixin. Merlin thus represents a new class of tumor suppressor whose function may be mediated by interactions with the cytoskeletal network.
The first Aim i s to perform detailed analysis of mutations in the NF2 gene in schwannomas and ependymomas, tumors associated with NF2, and also in neurofibromas and neurofibrosarcomas, tumors associated with NF1. Tumors will be screened for mutations in the coding and non-coding regions of the NF2 gene by Southern blot analysis and single strand conformation polymorphism (SSCP) analysis of genomic DNA and NF2 cDNA. Potential mutations will be identified and characterized by direct DNA sequencing. The definition of mutations within the NF2 gene may pinpoint particular residues or domains of the protein that are critical for its normal function and, when disrupted, lead to tumor formation. Second, merlin production will be examined in selected tumors by immunoblot analysis, immunohistochemistry, and an in vitro protein synthesis assay to determine the effects of selected NF2 mutations on the protein. Third, the phenotypic effects of modulating the level of merlin expression will be examined in cultured rodent and human Schwann cells treated with antisense oligonucleotides or antisense NF2 mRNA, and also in culture schwannoma cells into which a full-length NF2 cDNA has been introduced. Finally, the molecular genetic findings will be correlated with the histology of the tumors and the clinical course of the patients from whence they came. These investigations should increase our understanding of how defects at the NF2 locus lead to the formation of both familial and sporadic nervous system tumors, and should lay the foundation for developing effective therapies for preventing the formation of tumors or slowing the growth of tumors associated with NF2.
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