Lee B. Jacoby, Ph.D.
Molecular Neurogenetics Unit
The long-term goal of our research is to better understand the genetic basis of nervous system tumors, particularly those associated with neurofibromatosis (NF), including neurofibromas and neurofibrosarcomas in NF1 and schwannomas, meningiomas and ependymomas in NF2. Both the NF1 and NF2 genes have been isolated and both appear to be tumor suppressor genes, whose loss of function is associated with tumor formation. Currently we are analyzing mutations in the NF2 gene in schwannomas and other NF-associated tumors. Most of these mutations cause frameshifts, creation of stop codons, or abnormal splicing and are predicted to inactivate the protein. Some, however, are missense mutations and these may pinpoint particular domains of the protein that are critical for its normal function and, when disrupted, lead to tumor formation. A second project involves examining the expression of the NF2 gene in rodent and human Schwann cells. The effects of antisense oligonucleotides or antisense NF2 mRNA on Schwann cell morphology, growth and ability to differentiate are being determined. Finally, in a third project, the clonal origin of neurofibromas is being determined by X-chromosome inactivation analysis using a trinucleotide repeat polymorphism in the human androgen receptor gene. These investigations should increase our understanding of the mechanisms by which tumors arise in NF and because solitary forms of these same tumors also commonly occur in people without NF, they should ultimately aid in understanding many nervous system tumors in the remaining population.