RNA processing and clinical variability in neurofibromatosis type I (NF1).

Neurofibromatosis type 1 (NF1) is a common genetic disorder which predisposes affected individuals to a variety of clinical features including tumors of the central and peripheral nervous systems. The product of the NF1 gene, neurofibromin, is a tumor suppressor which most likely acts through the interaction of its GTPase activating protein (GAP) related domain (GRD) with RAS to regulate cellular growth. Two intriguing 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 somewhat unclear, but evidence suggests that aberrations in normal NF1 RNA processing may be involved. This evidence includes: (i) differences in the relative ratios of the type I and type II splice variants in NF1 tumors compared with nontumor tissues; (ii) unequal expression of mutant and normal NF1 alleles in cultured cells derived from NF1 patients; (iii) the existence of NF1 tumors which display NF1 mRNA editing levels that are greater than that seen in non-NF1 tumors; and (iv) tissue-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 tumorigenesis can be expanded to include the post-transcriptional mechanisms which regulate NF1 gene expression. Aberrations in these mechanisms may lead to the pathogenesis of NF1 and may play a role in the observed clinical variability.