title: Analysis of the GAP-related domain of the neurofibromatosis type 1 (NF1) gene in childhood brain tumors.
abstract: The neurofibromatosis type-1 (NF1) gene contains a 360-bp region with significant homology to the catalytic domain of mammalian GTPase-activating protein. This particular GAP-related domain of the NF1 gene (NF1-GRD) stimulates ras GTPase and inactivates ras protein p21ras. Therefore, it has been suggested that the NF1 gene represents another tumor-suppressor gene. In the search for molecular markers of possible diagnostic relevance, childhood brain-tumor specimens of different histologic diagnoses were tested for mutations of the so-called FLR-exon within the NF1-GRD. This part of the NF1-GRD has been shown to be most crucial for the GAP-like function. Using a highly sensitive PCR-SSCP technique, we tested 51 tumor specimens were tested, but found no mutations. We conclude that inactivation of this putative tumor-suppressor gene by mutations does not play a significant role in tumorigenesis of childhood brain tumors. Next, we compared the splice variants of the NF1-GRD in 33 brain tumors and 8 extraneural embryonal tumors. Primitive neuroectodermal tumors (PNET) (n = 10) and one intracranial teratoma were the only tumors that predominantly expressed a splice pattern that can be observed in the immature developing brain. In contrast to other embryonal neuronal tumors, this NF1-GRD splicing pattern could not be modified in a newly established medulloblastoma cell line by retinoic acid treatment. Since this particular splice variant suppresses p21ras more effectively than other NF1-GRD transcripts, its predominant expression may interfere with the physiological signal transduction of p21ras during differentiation of neurons. There may be a neurofibromin-induced and p21ras-mediated differentiation pathway of neuronal stem cells that is blocked in PNET. Such an arrest of a p21ras-dependent differentiation pathway may explain the persistence of primitive pluripotent neuronal cells in PNET.
authors.affiliation: Department of Pediatrics, University of Würzburg, Germany.
authors.forename: W G
authors.initials: WG
authors.lastname: Scheurlen
authors.forename: L
authors.initials: L
authors.lastname: Senf
mesh_terms: D017398:Alternative Splicing; D001254:Astrocytoma / Q000235:genetics*; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000235:genetics; D004806:Ependymoma / Q000235:genetics*; D005091:Exons; D016514:Genes, Neurofibromatosis 1; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics*; D008969:Molecular Sequence Data; D025542:Neurofibromin 1; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D017931:DNA Primers; D004273:DNA, Neoplasm; D025542:Neurofibromin 1; D011506:Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm