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Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy

Authors
 Jae Seok Lim  ;  Woo-il Kim  ;  Hoon-Chul Kang  ;  Se Hoon Kim  ;  Ah Hyung Park  ;  Eun Kyung Park  ;  Young-Wook Cho  ;  Sangwoo Kim  ;  Ho Min Kim  ;  Jeong A Kim  ;  Junho Kim  ;  Hwanseok Rhee  ;  Seok-Gu Kang  ;  Heung Dong Kim  ;  Daesoo Kim  ;  Dong-Seok Kim  ;  Jeong Ho Lee 
Citation
 Nature Medicine, Vol.21(4) : 395-400, 2015 
Journal Title
 Nature Medicine 
ISSN
 1078-8956 
Issue Date
2015
Abstract
Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.
Full Text
http://www.nature.com/nm/journal/v21/n4/full/nm.3824.html
DOI
10.1038/nm.3824
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 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, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Kang, Hoon Chul(강훈철) ORCID logo https://orcid.org/0000-0002-3659-8847
Kim, Dong Seok(김동석)
Kim, Sangwoo(김상우) ORCID logo https://orcid.org/0000-0001-5356-0827
Kim, Se Hoon(김세훈) ORCID logo https://orcid.org/0000-0001-7516-7372
Kim, Jeong A(김정아)
Kim, Jun Ho(김준호)
Kim, Heung Dong(김흥동) ORCID logo https://orcid.org/0000-0002-8031-7336
Park, Eun Kyung(박은경)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/139816
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