NF1 (Neurofibromatosis Type 1) Greg Hogan Ribbon Representation of NF1-333 Scheffzek, et al. (The EMBO Journal Vol. 17,pp , 1998) Structural analysis of the GAP-related domain from neurofibromin and its implications Neurofibromatosis Type 1 a.k.a. - peripheral neurofibromatosis - von Recklinghausens disease prevalence ~ 1/3500 inherited in autosomal dominant fashion fully penetrant in adults NF1 has one of highest single locus mutation rates known in humans Common Signs of Neurofibromatosis Type 1 1.The NF1 Gene and Protein Product Neurofibromin 2.Nf1 Knockout Mice 3.Role of Neurofibromin in Cancer NF1 The NF1 Gene and Protein Product Neurofibromin NF1 gene identified by positional cloning in 1990 NF1 gene found to encode neurofibromin BLAST Fig. 1a, Dasgupta and Gutmann Human NF1 yeast Ira Lodish, Fig. 9-31 Proposed Binding of Ras to NF1 Scheffzek, et al. (The EMBO Journal Vol. 17,pp , 1998) Structural analysis of the GAP-related domain from neurofibromin and its implications Fig. 1b, Dasgupta and Gutmann Loss of Neurofibromin Fig. 2. Gutmann Mice Knockouts Nf1 -/- mutantsNf1 -/- mutants Die in utero between embryonic days 12.5 and 13.5 Death is result of cardiac vessel defect Also exhibit neural tube closure defects Mice Knockouts Nf1 +/- mutantsNf1 +/- mutants Are cancer prone (generally, die by month 15) Do not develop hallmark NF1 cancers (neurofibromas, astrocytomas) Develop leukemia and pheochromocytomas Exhibit cell-autonomous growth advantage Exhibit increased # of abnormal astrocytes Nf1 +/- astrocytes have increased RAS pathway activation Nf1 +/- cell phenotypes reversed by introduction of wild-type NF1-GAP domain or by directly inhibiting RAS or RAS pathway molecules Mice Knockouts Nf1 +/- ; p53 +/- mutantsNf1 +/- ; p53 +/- mutants Develop high-grade sarcomas with features of human MPNSTs (malignant peripheral nerve sheath tumors) Mice Knockouts Pathways to Tumor Development Fig. 2. b,c Dasgupta and Gutmann Pathways to Tumor Development Fig. 2. a Dasgupta and Gutmann Take Home Messages NF1 tumor suppressor encodes a protein product neurofibromin Neurofibromin functions as a negative regulator of RAS Neurofibromin loss can lead to the development of various type of tumors potential target for therapy Fig. 3.a Reed and Gutmann Mutations Deletions Insertions Subsitutions Possible gene conversion between non- homologous pseudogene and NF1 80% of new NF1 mutations are of paternal origin