Genetic variation in the 3 ' untranslated region of the neurofibromatosis 1 gene: Application to unequal allelic expression

Neurofibromatosis type I (NF1) is a common genetic disorder caused by inact ivation of neurofibromin, a protein capable of modulating signal transducti on by activating Ras-GTPase activity. We have used cDNA cloning and Norther n blot analysis to confirm the NF1 gene produces alternatively polyadenylat ed mRNAs with 3' untranslated regions (3'UTR) that show striking evolutiona ry conservation. Scanning of the 3'UTRs for genetic variation revealed thre e common sequence polymorphisms (>30% heterozygosity), one less informative polymorphism (similar to 5% heterozygosity) and one rare variant (1/144 ch romosomes). These differences were used to examine relative levels of expre ssion of normal and mutant NF1 alleles in lymphoblast cell lines and in one case, autopsy tissue, from patients with NF1. Unequal allelic expression ( up to 4-fold) was observed in a subset of both sporadic and familial NF1 ca ses. Where linkage phase could be determined the allele segregating with th e disorder displayed a relative reduction in expression. However; the magni tude of this effect was variable suggesting the operation of additional, no n-genetic factors in determining the degree of relative expression of the m utant allele.