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Ann Neurol. 2004 Oct;56(4):478-87.

mTOR cascade activation distinguishes tubers from focal cortical dysplasia.

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PENN Epilepsy Center and Department of Neurology, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.


Balloon cells (BCs) in focal cortical dysplasia (FCD) and giant cells (GCs) in tubers of the tuberous sclerosis complex (TSC) share phenotypic similarities. TSC1 or TSC2 gene mutations in TSC lead to mTOR pathway activation and p70S6kinase (phospho-S6K) and ribosomal S6 (phospho-S6) protein phosphorylation. Phospho-S6K, phospho-S6, and phospho-S6K-activated proteins phospho-STAT3 and phospho-4EBP1 were detected immunohistochemically in GCs, whereas only phospho-S6 was observed in BCs. Expression of four candidate gene families (cell signaling, cell adhesion, growth factor/receptor, and transcription factor mRNAs) was assayed in single, microdissected phospho-S6-immunolabeled BCs and GCs as a strategy to define whether BCs and GCs exhibit differential transcriptional profiles. Among 60 genes, differential expression of 24 mRNAs distinguished BCs from GCs and only 4 genes showed similar expression profiles between BCs and GCs. Tuberin mRNA levels were reduced in GCs from TSC patients with TSC2 gene mutations but were unchanged in BCs. Phospho-S6K, -S6, -STAT3, and -4EBP1 expression in GCs reflects loss of hamartin-tuberin-mediated mTOR pathway inhibition. Phospho-S6 expression alone in BCs does not support mTOR cascade activation in FCD. Differential gene expression profiles in BCs and GCs supports the hypothesis that these cell types derive by distinct pathogenic mechanisms.

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