A potential role for NF1 mRNA editing in the pathogenesis of NF1 tumors.
Neurofibromatosis type I (NF1) is a common disorder that predisposes to neoplasia in tissues derived from the embryonic neural crest. The NF1 gene encodes a tumor suppressor that most likely acts through the interaction of its GTPase-activating protein (GAP)-related domain (GRD) with the product of the ras protooncogene. We have previously identified a site in the NF1 mRNA, within the first half of the NF1 GRD, which undergoes base-modification editing. Editing at that site changes a C to a U, thereby introducing an in-frame stop codon. NF1 RNA editing has been detected in all cell types studied, to date. In order to investigate the role played by editing in NF1 tumorigenesis, we analyzed RNA from 19 NF1 and 4 non-NF1 tumors. We observed varying levels of NF1 mRNA editing in different tumors, with a higher range of editing levels in more malignant tumors (e.g., neurofibrosarcomas) compared to benign tumors (cutaneous neurofibromas). Plexiform neurofibromas have an intermediate range of levels of NF1 mRNA editing. We also compared tumor and nontumor tissues from several NF1 individuals, to determine the extent of variability present in the constitutional levels of NF1 mRNA editing and to determine whether higher levels are present in tumors. The constitutional levels of NF1 mRNA editing varied slightly but were consistent with the levels observed in non-NF1 individuals. In every case, there was a greater level of NF1 mRNA editing in the tumor than in the nontumor tissue from the same patient. These results suggest that inappropriately high levels of NF1 mRNA editing does play a role in NF1 tumorigenesis and that editing may result in the functional equivalent of biallelic inactivation of the NF1 tumor suppressor.
Cappione
A J
AJ
Department of Medicine, Division of Genetics, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
French
B L
BL
Skuse
G R
GR
D001254:Astrocytoma / Q000235:genetics; D003001:Cloning, Molecular; D018388:Codon, Terminator; D018076:DNA, Complementary; D016514:Genes, Neurofibromatosis 1; D005910:Glioma / Q000235:genetics; D006801:Humans; D009455:Neurofibroma / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000235:genetics*; D018319:Neurofibrosarcoma / Q000235:genetics; D010673:Pheochromocytoma / Q000235:genetics; D017393:RNA Editing; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA
D018388:Codon, Terminator; D018076:DNA, Complementary; D012333:RNA, Messenger; D012334:RNA, Neoplasm