Kim et al. 2019 (PRJNA532897)

General Details

Title Next Generation Sequencing Facilitates Quantitative Analysis of Wild Type and FMCD mice Translatomics
Organism
Number of Samples 9
Release Date 2019/04/15 00:00
Sequencing Types
Protocol Details

Study Links

Repository Details

SRA SRP192590
ENA SRP192590
GEO GSE129818
BioProject PRJNA532897

Publication

Title
Authors Kim JK,Cho J,Kim SH,Kang HC,Kim DS,Kim VN,Lee JH
Journal The Journal of clinical investigation
Publication Date 2019 Oct 1
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.
PMC PMC6763223
PMID 31483294
DOI
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)
SRR8899091 PRJNA532897 Mus musculus Cortical neuron sorted from brain Ribo-Seq
SRR8899092 PRJNA532897 Mus musculus Cortical neuron sorted from brain Ribo-Seq
SRR8899093 PRJNA532897 Mus musculus Cortical neuron sorted from brain Ribo-Seq
SRR8899094 PRJNA532897 Mus musculus Cortical neuron sorted from brain Ribo-Seq
SRR8899095 PRJNA532897 Mus musculus Cortical neuron sorted from brain Ribo-Seq
SRR8899096 PRJNA532897 Mus musculus Cortical neuron sorted from brain Ribo-Seq
SRR8899097 PRJNA532897 Mus musculus Cortical neuron sorted from brain Ribo-Seq
SRR8899089 PRJNA532897 Mus musculus Cortical neuron sorted from brain Ribo-Seq
SRR8899090 PRJNA532897 Mus musculus Cortical neuron sorted from brain Ribo-Seq
Run Accession Study Accession Scientific Name Cell Line Library Type Treatment GWIPS-viz Trips-Viz Reads BAM BigWig (F) BigWig (R)

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