LOCALIZATION OF TUBEROUS SCLEROSIS-2 MESSENGER-RNA AND ITS PROTEIN PRODUCT TUBERIN IN NORMAL HUMAN BRAIN AND IN CEREBRAL-LESIONS OF PATIENTS WITH TUBEROUS SCLEROSIS

Tuberous sclerosis (TSC), an autosomal dominant disorder, is character ized by malformations, hamartomas and tumors in various organs includi ng the brain. TSC is genetically linked to two loci: TSC1 on chromosom e 9q34 and TSC2 on 16p13.3. TSC2 has been cloned, sequenced and encode s a protein (tuberin) which functions as a tumor suppressor. We have a nalyzed the distribution of TSC2 mRNA and tuberin in the brains of TSC patients and non-affected individuals using both autopsy and biopsy m aterial. High levels of transcript and protein expression were observe d in choroid plexus epithelium, ependymal cells, most brainstem and sp inal cord motor neurons, Purkinje cells and the external granule cell layer of the cerebellum in both TSC and control cases. Individual ball oon cells from TSC patients showed very faint expression while other g lia showed no expression of either transcript or tuberin. Neocortical and hippocampal neurons expressed high levels of TSC2 transcript, but only modest levels of tuberin. The internal granule cell layer of the cerebellum expressed abundant transcript but low levels of tuberin. Th ese observations suggest either that tuberin expression is controlled at the level of both transcription and translation or the antibody and in-situ hybridization recognize different splice variants of the TSC2 gene. In TSC patients, dysmorphic cytomegalic neurons expressed high levels of tuberin and transcript, particularly when in an 'ectopic' lo cation. individual cells within subependymal giant cell astrocytomas ( SEGAs) and hamartomas from TSC patients expressed moderate to high lev els of TSC2 transcript and tuberin. While the TSC2 transcript is widel y expressed primarily within neurons, tuberin is demonstrable primaril y within dysplastic/cytomegalic cells of the cortex and subependymal h amartomas/SEGAs. CNS expression of tuberin is unique in that primarily non-dividing cells express it in this location, whereas extra-CNS exp ression of tuberin is mainly found in actively proliferating cell type s such as epithelium.