RNA PROCESSING AND CLINICAL VARIABILITY IN NEUROFIBROMATOSIS TYPE-I (NF1)

Neurofibromatosis type 1 (NF1) is a common genetic disorder which pred isposes affected individuals to a variety of clinical features includi ng tumors of the central and peripheral nervous systems. The product o f the NF1 gene, neurofibromin, is a tumor suppressor which most likely acts through the interaction of its GTPase activating protein (GAP) r elated domain (GRD) with RAS to regulate cellular growth. Two intrigui ng features of NF1 are the wide range of potentially affected tissues and the great variation in expressivity of disease traits across those affected. To date, the underlying source of this variation remains so mewhat unclear, but evidence suggests that aberrations in normal NF1 R NA processing may be involved. This evidence includes: (i) differences in the relative ratios of the type I and type II splice variants in N F1 tumors compared with nontumor tissues; (ii) unequal expression of m utant and normal NF1 alleles in cultured cells derived from NF1 patien ts; (iii) the existence of NF1 tumors which display NF1 mRNA editing l evels that are greater than that seen in non-NF1 tumors; and (iv) tiss ue-specific and developmental stage-specific expression of particular alternative NF1 transcripts. These findings suggest that the classical 2-hit model for tumor suppressor inactivation used to explain NF1 tum origenesis can be expanded to include the post-transcriptional mechani sms which regulate NF1 gene expression. Aberrations in these mechanism s may lead to the pathogenesis of NF1 and may play a role in the obser ved clinical variability.