Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment

J.D. Mills, A.M. Iyer, J. van Scheppingen, A. Bongaarts, J.J. Anink, B. Janssen, T.S. Zimmer, W.G. Spliet, P.C. van Rijen, F.E. Jansen, M. Feucht, J.A. Hainfellner, P. Krsek, J. Zamecnik, K. Kotulska, S. Jozwiak, A. Jansen, L. Lagae, P. Curatolo, D.J. KwiatkowskiR.J. Pasterkamp, K. Senthilkumar, L. von Oerthel, M.F. Hoekman, J.A. Gorter, P.B. Crino, A. Mühlebner, B.P. Scicluna, E. Aronica

Research output: Contribution to JournalArticleAcademicpeer-review


Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network. Overall we detected 438 differentially expressed genes and 991 differentially expressed small non-coding RNAs in cortical tubers compared to autopsy control brain tissue. We observed increased expression of genes associated with inflammatory, innate and adaptive immune responses. In contrast, we observed a down-regulation of genes associated with neurogenesis and glutamate receptor signaling. MicroRNAs represented the largest class of over-expressed small non-coding RNA species in tubers. In particular, our analysis revealed that the miR-34 family (including miR-34a, miR-34b and miR-34c) was significantly over-expressed. Functional studies demonstrated the ability of miR-34b to modulate neurite outgrowth in mouse primary hippocampal neuronal cultures. This study provides new insights into the TSC transcriptomic network along with the identification of potential new treatment targets.

Original languageEnglish
Article number8089
Pages (from-to)8089
Number of pages16
JournalScientific reports
Issue number1
Publication statusPublished - 14 Aug 2017


  • Adolescent
  • Adult
  • Animals
  • Cerebral Cortex/physiology
  • Child
  • Child, Preschool
  • Epilepsy/genetics
  • Female
  • Humans
  • Infant
  • Male
  • Mechanistic Target of Rapamycin Complex 1/genetics
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs/genetics
  • Middle Aged
  • Mutation/genetics
  • Neurons/physiology
  • Signal Transduction/genetics
  • Transcription, Genetic/genetics
  • Tuberous Sclerosis Complex 1 Protein/genetics
  • Tuberous Sclerosis Complex 2 Protein/genetics
  • Tuberous Sclerosis/genetics
  • Young Adult

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