Neurofibromatosis type 1 is a common hereditary disorder characterized by the presence of multiple neurofibromas and café-au-lait spots, and is frequently associated with intellectual handicaps and brain tumours. The gene responsible for neurofibromatosis (the NF1 gene) codes for a protein of 2818 amino acids, termed neurofibromin, which has a domain related to mammalian ras GTPase-activating protein. 2. The NF1 gene gives rise to multiple transcripts generated by alternative splicing, that encode neurofibromin and its isoforms. These include type I mRNA coding for neurofibromin, type II mRNA coding for neurofibromin containing the insertion of 21 amino acids in the GTPase-activating protein-related related domain and mRNA coding for an N-terminal isoform lacking the GTPase-activating protein-related domain (N-isoform). 3. In the present study, the relative levels of mRNAs encoding type I, type II and N-isoform were determined by S1-nuclease mapping analysis in human brain tissue and in primary brain tumours obtained from patients with tumours unrelated to neurofibromatosis type 1. 4. These three mRNAs were expressed in all ten brain tumours and in every region of the brain examined, with the highest levels found in the cerebellum. Type I mRNA was the predominant form in the human brain except for the pons, whereas type II mRNA was predominantly expressed in eight out of ten primary brain tumours. 5. In contrast, N-isoform mRNA was similarly expressed in normal brain tissue and brain tumours. 6. These findings suggest that neurofibromin and its isoforms have important physiological roles in the human brain and that the altered expression of type I and type II mRNAs in brain tumours may be related to the tumorigenesis.
