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조회 1863  인쇄하기 주소복사 트위터 공유 페이스북 공유 
Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Jae Seok Lim1, 13, Ramu Gopalappa2, 3, 13, Se Hoon Kim4, 13, Suresh Ramakrishna2, Minji Lee5, Woo-il Kim1, Junho Kim7, Sang Min Park1, Junehawk Lee8, Jung-Hwa Oh9, Heung Dong Kim10, Chang-Hwan Park2, Joon Soo Lee10, Sangwoo Kim7, Dong Seok Kim11, Jung Min Han5, 6, Hoon-Chul Kang10, 14, Hyongbum (Henry) Kim3, 7, 12, 14, Jeong Ho Lee1, 14

1
Brain Korea 21 Plus Project, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science & Technology, Daejeon 34141, South Korea
2 Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 04763, South Korea
3 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
4 Department of Pathology, Yonsei University College of Medicine, Seoul 03722, South Korea
5 Department of Integrated OMICS for Biomedical Science, Yonsei University, Seoul 03722, South Korea
6 College of Pharmacy, Yonsei University, Seoul 03722, South Korea
7 Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, South Korea
8 Biomedical HPC Technology Research Center, Korea Institute of Science and Technology Information, Daejeon 34141, South Korea
9 Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, South Korea
10 Division 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
11 Pediatric Neurosurgery, Severance Children’s Hospital, Department of Neurosurgery, Yonsei University College of Medicine, Seoul 03722, South Korea
12 Center for Nanomedicine, Institute for Basic Science, Yonsei University, Seoul 03722, South Korea
13 These authors contributed equally to this work
14 These authors contributed equally to this work

Corresponding author : Hyongbum (Henry) Kim, Jeong Ho Lee

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.

Keywords : focal cortical dysplasia; intractable epilepsy; TSC1; TSC2; brain somatic mutation; CRISPR-Cas9 genome editing; brain mosaicism

논문정보
- 형식: Research article
- 게재일: 2017년 02월 (BRIC 등록일 2017-02-17)
- 연구진: 국내연구진태극기
- 분야: Genetics
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정형록
발표: 정형록 (HHMI/Baylor College of M...)
일자: 2020년 7월 8일 (수) 오전 10시 (한국시간)
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광유전학의 과거, 현재와 미래[Neuron]
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발표: 김윤석 (Stanford University)
일자: 2020년 7월 30일 (목) 오후 02시 (한국시간)
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