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Brain somatic mutations in MTOR reveal translational dysregulations underlying intractable focal epilepsy

Authors
 Jang Keun Kim  ;  Jun Cho  ;  Se Hoon Kim  ;  Hoon-Chul Kang  ;  Dong-Seok Kim  ;  V. Narry Kim  ;  Jeong Ho Lee 
Citation
 JOURNAL OF CLINICAL INVESTIGATION, Vol.129(10) : 4207-4223, 2019 
Journal Title
 JOURNAL OF CLINICAL INVESTIGATION 
ISSN
 0021-9738 
Issue Date
2019
Keywords
Epilepsy ; Genetic variation ; Neuroscience ; Therapeutics ; Translation
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.
Full Text
https://www.jci.org/articles/view/127032
DOI
10.1172/JCI127032
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
Yonsei Authors
Kang, Hoon Chul(강훈철) ORCID logo https://orcid.org/0000-0002-3659-8847
Kim, Dong Seok(김동석)
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/173463
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