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Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

 Jae Seok Lim  ;  Ramu Gopalappa  ;  Se Hoon Kim  ;  Suresh Ramakrishna  ;  Minji Lee  ;  Woo-il Kim  ;  Junho Kim  ;  Sang Min Park  ;  Junehawk Lee  ;  Jung-Hwa Oh  ;  Heung Dong Kim  ;  Chang-Hwan Park  ;  Joon Soo Lee  ;  Sangwoo Kim  ;  Dong Seok Kim  ;  Jung Min Han  ;  Hoon-Chul Kang  ;  Hyongbum (Henry) Kim  ;  Jeong Ho Lee 
 American Journal of Human Genetics, Vol.100(3) : 454-472, 2017 
Journal Title
 American Journal of Human Genetics 
Issue Date
Adolescent ; Animals ; Brain/metabolism ; CRISPR-Cas Systems ; Cell Line, Tumor ; Child ; Class I Phosphatidylinositol 3-Kinases ; Cloning, Molecular ; Disease Models, Animal ; Epilepsy/genetics* ; Female ; HEK293 Cells ; Humans ; Male ; Malformations of Cortical Development, Group I/genetics* ; Mice ; Mutation ; Neurons ; Phosphatidylinositol 3-Kinases/genetics ; Proto-Oncogene Proteins c-akt/genetics ; Saliva/chemistry ; Sequence Analysis, DNA ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/genetics ; Tumor Suppressor Proteins/genetics*
CRISPR-Cas9 genome editing ; TSC1 ; TSC2 ; brain mosaicism ; brain somatic mutation ; focal cortical dysplasia ; intractable epilepsy
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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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
Yonsei Authors
강훈철(Kang, Hoon Chul) ORCID logo https://orcid.org/0000-0002-3659-8847
김동석(Kim, Dong Seok)
김상우(Kim, Sangwoo) ORCID logo https://orcid.org/0000-0001-5356-0827
김세훈(Kim, Se Hoon) ORCID logo https://orcid.org/0000-0001-7516-7372
김형범(Kim, Hyongbum) ORCID logo https://orcid.org/0000-0002-4693-738X
김흥동(Kim, Heung Dong) ORCID logo https://orcid.org/0000-0002-8031-7336
이준수(Lee, Joon Soo) ORCID logo https://orcid.org/0000-0001-9036-9343
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