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Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal epilepsy
DC Field | Value | Language |
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dc.contributor.author | 강훈철 | - |
dc.contributor.author | 김동석 | - |
dc.contributor.author | 김세훈 | - |
dc.date.accessioned | 2019-12-18T01:18:18Z | - |
dc.date.available | 2019-12-18T01:18:18Z | - |
dc.date.issued | 2019 | - |
dc.identifier.issn | 0021-9738 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/173463 | - |
dc.description.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. | - |
dc.description.statementOfResponsibility | restriction | - |
dc.language | English | - |
dc.publisher | American Society for Clinical Investigation | - |
dc.relation.isPartOf | JOURNAL OF CLINICAL INVESTIGATION | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.title | Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal epilepsy | - |
dc.type | Article | - |
dc.contributor.college | College of Medicine (의과대학) | - |
dc.contributor.department | Dept. of Pediatrics (소아청소년과학교실) | - |
dc.contributor.googleauthor | Jang Keun Kim | - |
dc.contributor.googleauthor | Jun Cho | - |
dc.contributor.googleauthor | Se Hoon Kim | - |
dc.contributor.googleauthor | Hoon-Chul Kang | - |
dc.contributor.googleauthor | Dong-Seok Kim | - |
dc.contributor.googleauthor | V. Narry Kim | - |
dc.contributor.googleauthor | Jeong Ho Lee | - |
dc.identifier.doi | 10.1172/JCI127032 | - |
dc.contributor.localId | A00102 | - |
dc.contributor.localId | A00402 | - |
dc.contributor.localId | A00610 | - |
dc.relation.journalcode | J01322 | - |
dc.identifier.eissn | 1558-8238 | - |
dc.identifier.pmid | 31483294 | - |
dc.identifier.url | https://www.jci.org/articles/view/127032 | - |
dc.subject.keyword | Epilepsy | - |
dc.subject.keyword | Genetic variation | - |
dc.subject.keyword | Neuroscience | - |
dc.subject.keyword | Therapeutics | - |
dc.subject.keyword | Translation | - |
dc.contributor.alternativeName | Kang, Hoon Chul | - |
dc.contributor.affiliatedAuthor | 강훈철 | - |
dc.contributor.affiliatedAuthor | 김동석 | - |
dc.contributor.affiliatedAuthor | 김세훈 | - |
dc.citation.volume | 129 | - |
dc.citation.number | 10 | - |
dc.citation.startPage | 4207 | - |
dc.citation.endPage | 4223 | - |
dc.identifier.bibliographicCitation | JOURNAL OF CLINICAL INVESTIGATION, Vol.129(10) : 4207-4223, 2019 | - |
dc.identifier.rimsid | 63202 | - |
dc.type.rims | ART | - |
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