Cited 142 times in
Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia
DC Field | Value | Language |
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dc.contributor.author | 강훈철 | - |
dc.contributor.author | 김형범 | - |
dc.contributor.author | 김흥동 | - |
dc.contributor.author | 이준수 | - |
dc.contributor.author | 김동석 | - |
dc.contributor.author | 김상우 | - |
dc.contributor.author | 김세훈 | - |
dc.date.accessioned | 2017-11-01T09:05:58Z | - |
dc.date.available | 2017-11-01T09:05:58Z | - |
dc.date.issued | 2017 | - |
dc.identifier.issn | 0002-9297 | - |
dc.identifier.uri | https://ir.ymlib.yonsei.ac.kr/handle/22282913/154015 | - |
dc.description.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. | - |
dc.description.statementOfResponsibility | restriction | - |
dc.publisher | University of Chicago Press | - |
dc.relation.isPartOf | AMERICAN JOURNAL OF HUMAN GENETICS | - |
dc.rights | CC BY-NC-ND 2.0 KR | - |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/2.0/kr/ | - |
dc.subject.MESH | Adolescent | - |
dc.subject.MESH | Animals | - |
dc.subject.MESH | Brain/metabolism | - |
dc.subject.MESH | CRISPR-Cas Systems | - |
dc.subject.MESH | Cell Line, Tumor | - |
dc.subject.MESH | Child | - |
dc.subject.MESH | Class I Phosphatidylinositol 3-Kinases | - |
dc.subject.MESH | Cloning, Molecular | - |
dc.subject.MESH | Disease Models, Animal | - |
dc.subject.MESH | Epilepsy/genetics* | - |
dc.subject.MESH | Female | - |
dc.subject.MESH | HEK293 Cells | - |
dc.subject.MESH | Humans | - |
dc.subject.MESH | Male | - |
dc.subject.MESH | Malformations of Cortical Development, Group I/genetics* | - |
dc.subject.MESH | Mice | - |
dc.subject.MESH | Mutation | - |
dc.subject.MESH | Neurons | - |
dc.subject.MESH | Phosphatidylinositol 3-Kinases/genetics | - |
dc.subject.MESH | Proto-Oncogene Proteins c-akt/genetics | - |
dc.subject.MESH | Saliva/chemistry | - |
dc.subject.MESH | Sequence Analysis, DNA | - |
dc.subject.MESH | Sirolimus/pharmacology | - |
dc.subject.MESH | TOR Serine-Threonine Kinases/genetics | - |
dc.subject.MESH | Tumor Suppressor Proteins/genetics* | - |
dc.title | Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia | - |
dc.type | Article | - |
dc.publisher.location | United States | - |
dc.contributor.college | College of Medicine | - |
dc.contributor.department | Dept. of Pediatrics | - |
dc.contributor.googleauthor | Jae Seok Lim | - |
dc.contributor.googleauthor | Ramu Gopalappa | - |
dc.contributor.googleauthor | Se Hoon Kim | - |
dc.contributor.googleauthor | Suresh Ramakrishna | - |
dc.contributor.googleauthor | Minji Lee | - |
dc.contributor.googleauthor | Woo-il Kim | - |
dc.contributor.googleauthor | Junho Kim | - |
dc.contributor.googleauthor | Sang Min Park | - |
dc.contributor.googleauthor | Junehawk Lee | - |
dc.contributor.googleauthor | Jung-Hwa Oh | - |
dc.contributor.googleauthor | Heung Dong Kim | - |
dc.contributor.googleauthor | Chang-Hwan Park | - |
dc.contributor.googleauthor | Joon Soo Lee | - |
dc.contributor.googleauthor | Sangwoo Kim | - |
dc.contributor.googleauthor | Dong Seok Kim | - |
dc.contributor.googleauthor | Jung Min Han | - |
dc.contributor.googleauthor | Hoon-Chul Kang | - |
dc.contributor.googleauthor | Hyongbum (Henry) Kim | - |
dc.contributor.googleauthor | Jeong Ho Lee | - |
dc.identifier.doi | 10.1016/j.ajhg.2017.01.030 | - |
dc.contributor.localId | A01148 | - |
dc.contributor.localId | A01208 | - |
dc.contributor.localId | A03177 | - |
dc.contributor.localId | A00402 | - |
dc.contributor.localId | A00524 | - |
dc.contributor.localId | A00610 | - |
dc.contributor.localId | A00102 | - |
dc.relation.journalcode | J00086 | - |
dc.identifier.eissn | 1537-6605 | - |
dc.identifier.pmid | 28215400 | - |
dc.identifier.url | http://www.sciencedirect.com/science/article/pii/S0002929717300319 | - |
dc.subject.keyword | CRISPR-Cas9 genome editing | - |
dc.subject.keyword | TSC1 | - |
dc.subject.keyword | TSC2 | - |
dc.subject.keyword | brain mosaicism | - |
dc.subject.keyword | brain somatic mutation | - |
dc.subject.keyword | focal cortical dysplasia | - |
dc.subject.keyword | intractable epilepsy | - |
dc.contributor.alternativeName | Kang, Hoon Chul | - |
dc.contributor.alternativeName | Kim, Hyongbum | - |
dc.contributor.alternativeName | Kim, Heung Dong | - |
dc.contributor.alternativeName | Lee, Joon Soo | - |
dc.contributor.alternativeName | Kim, Dong Seok | - |
dc.contributor.alternativeName | Kim, Sang Woo | - |
dc.contributor.alternativeName | Kim, Se Hoon | - |
dc.contributor.affiliatedAuthor | Kim, Hyongbum | - |
dc.contributor.affiliatedAuthor | Kim, Heung Dong | - |
dc.contributor.affiliatedAuthor | Lee, Joon Soo | - |
dc.contributor.affiliatedAuthor | Kim, Dong Seok | - |
dc.contributor.affiliatedAuthor | Kim, Sang Woo | - |
dc.contributor.affiliatedAuthor | Kim, Se Hoon | - |
dc.contributor.affiliatedAuthor | Kang, Hoon Chul | - |
dc.citation.title | American Journal of Human Genetics | - |
dc.citation.volume | 100 | - |
dc.citation.number | 3 | - |
dc.citation.startPage | 454 | - |
dc.citation.endPage | 472 | - |
dc.identifier.bibliographicCitation | AMERICAN JOURNAL OF HUMAN GENETICS, Vol.100(3) : 454-472, 2017 | - |
dc.date.modified | 2017-11-01 | - |
dc.identifier.rimsid | 44180 | - |
dc.type.rims | ART | - |
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