ArticleThe Journal of clinical investigation2019
Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal epilepsy.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 64 citations in OpenAlex.
- Disease insights from brain somatic mosaicism.Experimental & molecular medicine · 2026Review
- Early death and neuronal abnormalities inbioRxiv : the preprint server for biology · 2025Article
- The 4E-BPs as Translational Regulators in Neurological Disorders: Molecular Mechanisms and Therapeutic Potential.Molecular neurobiology · 2025Review
- Epilepsy and autophagy modulators: a therapeutic split.Autophagy · 2025Review
- Somatic mosaicism and interneuron involvement in mTORopathies.Trends in neurosciences · 2025Review
- Chloride deregulation and GABA depolarization in MTOR-related malformations of cortical development.Brain : a journal of neurology · 2025Article
- Erythropoietin for Seizures and Epilepsy: Neuroprotective Effects, Mechanisms, and Contradictory Risks.CNS & neurological disorders drug targets · 2025Review
- Compartment-specific small non-coding RNA changes and nucleolar defects in human mesial temporal lobe epilepsy.Acta neuropathologica · 2024Article
- Reducing Filamin A Restores Cortical Synaptic Connectivity and Early Social Communication Following Cellular Mosaicism in Autism Spectrum Disorder Pathways.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- The complex molecular epileptogenesis landscape of glioblastoma.Cell reports. Medicine · 2024Article
- mTORC2: The "Ace in the Hole" for a Broader Control of Epileptic Seizures?Neuroscience bulletin · 2024Article
- Anti-seizure gene therapy for focal cortical dysplasia.Brain : a journal of neurology · 2024Article
- mTOR Pathway Somatic Pathogenic Variants in Focal Malformations of Cortical Development: Novel Variants, Topographic Mapping, and Clinical Outcomes.Neurology. Genetics · 2023Article
- Targeted suppression of mTORC2 reduces seizures across models of epilepsy.Nature communications · 2023Article
- Enhanced Sestrin expression through Tanshinone 2A treatment improves PI3K-dependent inhibition of glioma growth.Cell death discovery · 2023Article
- Stem Cell-Based Organoid Models of Neurodevelopmental Disorders.Biological psychiatry · 2023Review
- Comprehensive multi-omic profiling of somatic mutations in malformations of cortical development.Nature genetics · 2023Article
- 4E-BP1 expression in embryonic postmitotic neurons mitigates mTORC1-induced cortical malformations and behavioral seizure severity but does not prevent epilepsy in mice.Frontiers in neuroscience · 2023Article
- Modeling genetic mosaicism of the mammalian target of rapamycin pathway in the cerebral cortex.Frontiers in mammal science · 2023Article
- Expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy.Brain : a journal of neurology · 2022Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Brain somatic mutations confer genomic diversity in the human brain and cause neurodevelopmental disorders. Recently, brain somatic activating mutations in MTOR have been identified as a major etiology of intractable epilepsy in patients with cortical malformations. However, the molecular genetic mechanism of how brain somatic mutations in MTOR cause intractable epilepsy has remained elusive. In this study, translational profiling of intractable epilepsy mouse models with brain somatic mutations and genome-edited cells revealed a novel translational dysregulation mechanism and mTOR activation-sensitive targets mediated by human MTOR mutations that lead to intractable epilepsy with cortical malformation. These mTOR targets were found to be regulated by novel mTOR-responsive 5'-UTR motifs, distinct from known mTOR inhibition-sensitive targets regulated by 5' terminal oligopyrimidine motifs. Novel mTOR target genes were validated in patient brain tissues, and the mTOR downstream effector eIF4E was identified as a new therapeutic target in intractable epilepsy via pharmacological or genetic inhibition. We show that metformin, an FDA-approved eIF4E inhibitor, suppresses intractable epilepsy. Altogether, the present study describes translational dysregulation resulting from brain somatic mutations in MTOR, as well as the pathogenesis and potential therapeutic targets of intractable epilepsy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.