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김형범(약리학교실) Am J Hum Genet
등록일 : 2017-02-24 오후 7:01:00       조회 : 302
첨   부 :
공동제1저자 임재석(KAIST) Ramu Gopalappa(한양대/연세의대 약리학교실) 김세훈(연세의대 병리학교실)
공동교신저자 김형범(연세의대 약리학교실, BK21) 이정호(KAIST)
Am J Hum Genet. 2017 Feb 12. pii: S0002-9297(17)30031-9. doi: 10.1016/j.ajhg.2017.01.030. [Epub ahead of print]
Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia.
Lim JS1, Gopalappa R2, Kim SH3, Ramakrishna S4, Lee M5, Kim WI1, Kim J6, Park SM1, Lee J7, Oh JH8, Kim HD9, Park CH4, Lee JS9, Kim S6, Kim DS10, Han JM11, Kang HC9, Kim HH12, Lee JH13.

Author information
1Brain Korea 21 Plus Project, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science & Technology, Daejeon 34141, South Korea.
2Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, South Korea; Brain Korea 21 Plus Project for Medical Sciences, Graduate Program of Nano Science and Technology, Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, South Korea.
3Department of Pathology, Yonsei University College of Medicine, Seoul 03722, South Korea.
4Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, South Korea.
5Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, South Korea.
6Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea.
7Biomedical HPC Technology Research Center, Korea Institute of Science and Technology Information, Daejeon 34141, South Korea.
8Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, South Korea.
9Division of Pediatric Neurology, Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children''s Hospital, Epilepsy Research Institute, Yonsei University College of Medicine, Seoul 03722, South Korea.
10Pediatric Neurosurgery, Severance Children''s Hospital, Department of Neurosurgery, Yonsei University College of Medicine, Seoul 03722, South Korea.
11Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, South Korea; College of Pharmacy, Yonsei University, Seoul 03722, South Korea.
12Brain Korea 21 Plus Project for Medical Sciences, Graduate Program of Nano Science and Technology, Department of Pharmacology, Yonsei University College of Medicine, Seoul 03722, South Korea; Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea; Center for Nanomedicine, Institute for Basic Science, Yonsei University, Seoul 03722, South Korea. Electronic address: hkim1@yuhs.ac.
13Brain Korea 21 Plus Project, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science & Technology, Daejeon 34141, South Korea. Electronic address: jhlee4246@kaist.ac.kr.

Abstract
Focal cortical dysplasia (FCD) is a major cause of the sporadic form of intractable focal epilepsies that require surgical treatment. It has recently been reported that brain somatic mutations in MTOR account for 15%-25% of FCD type II (FCDII), characterized by cortical dyslamination and dysmorphic neurons. However, the genetic etiologies of FCDII-affected individuals who lack the MTOR mutation remain unclear. Here, we performed deep hybrid capture and amplicon sequencing (read depth of 100×-20,012×) of five important mTOR pathway genes-PIK3CA, PIK3R2, AKT3, TSC1, and TSC2-by using paired brain and saliva samples from 40 FCDII individuals negative for MTOR mutations. We found that 5 of 40 individuals (12.5%) had brain somatic mutations in TSC1 (c.64C>T [p.Arg22Trp] and c.610C>T [p.Arg204Cys]) and TSC2 (c.4639G>A [p.Val1547Ile]), and these results were reproducible on two different sequencing platforms. All identified mutations induced hyperactivation of the mTOR pathway by disrupting the formation or function of the TSC1-TSC2 complex. Furthermore, in utero CRISPR-Cas9-mediated genome editing of Tsc1 or Tsc2 induced the development of spontaneous behavioral seizures, as well as cytomegalic neurons and cortical dyslamination. These results show that brain somatic mutations in TSC1 and TSC2 cause FCD and that in utero application of the CRISPR-Cas9 system is useful for generating neurodevelopmental disease models of somatic mutations in the brain.
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