title: Somatic mutations in the neurofibromatosis 1 gene in human tumors.
abstract: The neurofibromatosis 1 (NF1) gene product, neurofibromin, contains a GTPase-activating protein (GAP)-related domain, or NF1 GRD, that is able to down-regulate p21ras by stimulating its intrinsic GTPase. Since p21ras.GTP is a major regulator of growth and differentiation, mutant neurofibromins resulting from somatic mutations in the NF1 gene might interfere with ras signaling pathways and contribute to the development of tumors. We describe an amino acid substitution in the NF1 GRD, altering Lys-1423, that has occurred in three tumor types: colon adenocarcinoma, myelodysplastic syndrome, and anaplastic astrocytoma, and in one family with neurofibromatosis 1. The GAP activity of the mutant NF1 GRD is 200- to 400-fold lower than that of wild type, whereas binding affinity is unaffected. Thus, germline mutations in NF1 that cause neurofibromatosis 1 can also occur in somatic cells and contribute to the development of sporadic tumors, including tumors not associated with neurofibromatosis 1.
authors.affiliation: Department of Human Genetics, University of Utah School of Medicine, Salt Lake City 84112.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: G
authors.initials: G
authors.lastname: Bollag
authors.forename: R
authors.initials: R
authors.lastname: Clark
authors.forename: J
authors.initials: J
authors.lastname: Stevens
authors.forename: L
authors.initials: L
authors.lastname: Conroy
authors.forename: D
authors.initials: D
authors.lastname: Fults
authors.forename: K
authors.initials: K
authors.lastname: Ward
authors.forename: E
authors.initials: E
authors.lastname: Friedman
authors.forename: W
authors.initials: W
authors.lastname: Samowitz
authors.forename: M
authors.initials: M
authors.lastname: Robertson
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001254:Astrocytoma / Q000235:genetics; D001483:Base Sequence; D003110:Colonic Neoplasms / Q000235:genetics; D005260:Female; D020690:GTPase-Activating Proteins; D016514:Genes, Neurofibromatosis 1 / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000235:genetics*; D025542:Neurofibromin 1; D011506:Proteins / Q000032:analysis / Q000235:genetics*; D020703:ras GTPase-Activating Proteins
chemical_list: D020690:GTPase-Activating Proteins; D025542:Neurofibromin 1; D011506:Proteins; D020703:ras GTPase-Activating Proteins