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).
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