Gary R. Skuse, Ph.D.

Tel or Fax: (585) 223-3114

Molecular Pathogenesis of Neurofibromatosis Type I.Our research efforts are directed toward understanding the genetic and epigenetic mechanisms responsible for the pathogenesis of and tumor formation in von Recklinghausen neurofibromatosis, also known as neurofibromatosis type 1 or NF1. NF1 is the most common hereditary disease predisposing to tumors, affecting approximately 1 in 3000 births, with both sexes and all races affected equally. The NF1 gene encodes a tumor suppressor. In addition to benign and malignant tumors, NF1 individuals also display a broad range of symptoms which include learning disabilities, skeletal abnormalities, Lisch nodules of the iris, and cafe au lait spots of the skin. We are studying two epigenetic events which modulate NF1 expression. The first line of investigation is founded on the observation that the single NF1 gene gives rise to multiple alternate transcripts, two of which differ by the alternate splicing of a single exon. Previous work has demonstrated that one of the two transcripts (type I) is predominantly expressed in tumors or undifferentiated cells while the type II transcript predominates in nontumor or differentiated cells. Our laboratory is extending those studies in an analysis of the NF1 transcripts expressed as cultured cells are induced to differentiate. Cells are being treated with various inducers of differentiation in vitro and changes in the levels of transcript isoform expression are being studied. The roles of transcription and translation elongation in those alternative splicing events are being investigated. We have observed the expression of a third transcript, type III, in rat cells treated with inhibitors of protein synthesis. The type III transcript includes a 41bp exon which introduces a frameshift resulting in the creation of a stop codon in the 5' end of the only functional region of the NF1 mRNA identified to date, the NF1 GAP related domain (GRD).

We are also investigating a second epigenetic event, namely RNA editing. A unique site for RNA editing has been identified in the NF1 mRNA which lies upstream of the NF1 GRD. We have demonstrated that RNA editing occurs at this site resulting in the introduction of a stop codon which has the potential to lead to functional inactivation of the NF1 tumor suppressor either by encoding a truncated protein or reducing transcript stability. NF1 mRNA editing occurs to varying extents in all cell types studied, but occurs at higher levels in NF1 tumors compared to nontumor tissue, with higher levels of editing in malignant compared to benign tumors. It is interesting to note that a premature stop codon is introduced, albeit by different mechanisms, in rat and human cells. This observation lends further support to the notion that introduction of a stop codon represents another mechanism, besides genetic mutation, which may inactivate the NF1 tumor suppressor. We are currently working to identify cellular factors which regulate NF1 mRNA editing.


Ludlow JW, Skuse GR "Tumor Suppressors: Involvement in Human Diseases, Viral Protein Interactions, and Growth Regulation". The R.G. Landes Company, Georgetown, TX (1994).

Metheny, L. J., Cappione, A.J. and Skuse, G.R. Genetic and epigenetic mechanisms in the pathogenesis of neurofibromatosis type I. J. Neuropathol. Exp. Neurol. 1995; 54:753-760.

Skuse, G.R., Cappione, A.J., Sowden, M., Metheny, L.J. and Smith, H.C. The Neurofibromatosis type I messenger RNA undergoes base-modification RNA editing. Nucl. Acids Res. 1996; 24:478-486.

Skuse, G.R. Identification of an insertion and accompanying deletion in exon 31 of the neurofibromatosis type 1 gene. Human Mutation 1996; 8: in press.

Metheny, L.J. and Skuse, G.R. NF1 mRNA isoform expression in PC12 cells: Modulation by extrinsic factors. Exp. Cell Res. 1996; 228: 44-49.

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