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Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment
JD. Mills, AM. Iyer, J. van Scheppingen, A. Bongaarts, JJ. Anink, B. Janssen, TS. Zimmer, WG. Spliet, PC. van Rijen, FE. Jansen, M. Feucht, JA. Hainfellner, P. Krsek, J. Zamecnik, K. Kotulska, S. Jozwiak, A. Jansen, L. Lagae, P. Curatolo, DJ....
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
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- MeSH
- Child MeSH
- Adult MeSH
- Epilepsy genetics MeSH
- Transcription, Genetic genetics MeSH
- Tuberous Sclerosis Complex 1 Protein genetics MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- MicroRNAs genetics MeSH
- Adolescent MeSH
- Young Adult MeSH
- Cerebral Cortex physiology MeSH
- Mechanistic Target of Rapamycin Complex 1 genetics MeSH
- Mutation genetics MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Neurons physiology MeSH
- Child, Preschool MeSH
- Signal Transduction genetics MeSH
- Tuberous Sclerosis Complex 2 Protein genetics MeSH
- Tuberous Sclerosis genetics MeSH
- Animals MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Infant MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Mice MeSH
- Child, Preschool MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
Department of Heemstede The Netherlands
Department of Medicine Brigham and Women's Hospital Boston Massachusetts USA
Department of Neurology University of Maryland School of Medicine Baltimore MD USA
Department of Pathology Academic Medical Center University of Amsterdam Amsterdam The Netherlands
Department of Pathology University Medical Center Utrecht Utrecht The Netherlands
Department of Pediatrics Medical University Vienna Vienna Austria
GenomeScan BV Leiden The Netherlands
Institute of Neurology Medical University Vienna Vienna Austria
References provided by Crossref.org
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