SEQUENCE HOMOLOGY SHARED BY NEUROFIBROMATOSIS TYPE-1 GENE AND IRA-1 AND IRA-2 NEGATIVE REGULATORS OF THE RAS CYCLIC-AMP PATHWAY

NEUROFIBROMATOSIS type-1 (NF-1) is one of the most frequently inherited genetic disorders affecting humans1. NF-1 primarily affects cells of neural crest origin and is characterized by patches of skin pigmentation (café-au-lait spots) and neurofibromas2. Cloning of the human NF-1 gene shows that it encodes an 11-13 kilobase transcript that is frequently disrupted in NF-1 patients3-5. The frequent disruption of the NF-1 gene in NF-1 patients combined with the autosomal dominant mode of inheritance of NF-1 strongly suggest that the NF-1 gene is a tumour-suppressor gene. We have now sequenced a portion of the murine NF-1 gene and show that the predicted amino-acid sequence is nearly the same as the corresponding region of the human NF-1 gene product. Northern blotting identified mouse NF-1 transcripts that are equivalent in size and complexity to those in human tissues, and Southern blotting shows that this region of the NF-1 gene is evolutionary well conserved. Finally, computer searches identified homology between the mouse NF-1 gene and IRA-1 and IRA-2, two genes identified in Saccharomyces cerevisiae that negatively regulate the RAS-cyclic AMP pathway. These findings provide important new insights into the possible function of the NF-1 gene. © 1990 Nature Publishing Group.