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


ABSTRACT: 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.

SUBMITTER: Mills JD 

PROVIDER: S-EPMC5556011 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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

Mills James D JD   Iyer Anand M AM   van Scheppingen Jackelien J   Bongaarts Anika A   Anink Jasper J JJ   Janssen Bart B   Zimmer Till S TS   Spliet Wim G WG   van Rijen Peter C PC   Jansen Floor E FE   Feucht Martha M   Hainfellner Johannes A JA   Krsek Pavel P   Zamecnik Josef J   Kotulska Katarzyna K   Jozwiak Sergiusz S   Jansen Anna A   Lagae Lieven L   Curatolo Paolo P   Kwiatkowski David J DJ   Pasterkamp R Jeroen RJ   Senthilkumar Ketharini K   von Oerthel Lars L   Hoekman Marco F MF   Gorter Jan A JA   Crino Peter B PB   Mühlebner Angelika A   Scicluna Brendon P BP   Aronica Eleonora E  

Scientific reports 20170814 1


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 co  ...[more]

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