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Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

DC Field Value Language
dc.contributor.author강훈철-
dc.contributor.author김형범-
dc.contributor.author김흥동-
dc.contributor.author이준수-
dc.contributor.author김동석-
dc.contributor.author김상우-
dc.contributor.author김세훈-
dc.date.accessioned2017-11-01T09:05:58Z-
dc.date.available2017-11-01T09:05:58Z-
dc.date.issued2017-
dc.identifier.issn0002-9297-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/154015-
dc.description.abstractFocal 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.statementOfResponsibilityrestriction-
dc.publisherUniversity of Chicago Press-
dc.relation.isPartOfAMERICAN JOURNAL OF HUMAN GENETICS-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAdolescent-
dc.subject.MESHAnimals-
dc.subject.MESHBrain/metabolism-
dc.subject.MESHCRISPR-Cas Systems-
dc.subject.MESHCell Line, Tumor-
dc.subject.MESHChild-
dc.subject.MESHClass I Phosphatidylinositol 3-Kinases-
dc.subject.MESHCloning, Molecular-
dc.subject.MESHDisease Models, Animal-
dc.subject.MESHEpilepsy/genetics*-
dc.subject.MESHFemale-
dc.subject.MESHHEK293 Cells-
dc.subject.MESHHumans-
dc.subject.MESHMale-
dc.subject.MESHMalformations of Cortical Development, Group I/genetics*-
dc.subject.MESHMice-
dc.subject.MESHMutation-
dc.subject.MESHNeurons-
dc.subject.MESHPhosphatidylinositol 3-Kinases/genetics-
dc.subject.MESHProto-Oncogene Proteins c-akt/genetics-
dc.subject.MESHSaliva/chemistry-
dc.subject.MESHSequence Analysis, DNA-
dc.subject.MESHSirolimus/pharmacology-
dc.subject.MESHTOR Serine-Threonine Kinases/genetics-
dc.subject.MESHTumor Suppressor Proteins/genetics*-
dc.titleSomatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia-
dc.typeArticle-
dc.publisher.locationUnited States-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Pediatrics-
dc.contributor.googleauthorJae Seok Lim-
dc.contributor.googleauthorRamu Gopalappa-
dc.contributor.googleauthorSe Hoon Kim-
dc.contributor.googleauthorSuresh Ramakrishna-
dc.contributor.googleauthorMinji Lee-
dc.contributor.googleauthorWoo-il Kim-
dc.contributor.googleauthorJunho Kim-
dc.contributor.googleauthorSang Min Park-
dc.contributor.googleauthorJunehawk Lee-
dc.contributor.googleauthorJung-Hwa Oh-
dc.contributor.googleauthorHeung Dong Kim-
dc.contributor.googleauthorChang-Hwan Park-
dc.contributor.googleauthorJoon Soo Lee-
dc.contributor.googleauthorSangwoo Kim-
dc.contributor.googleauthorDong Seok Kim-
dc.contributor.googleauthorJung Min Han-
dc.contributor.googleauthorHoon-Chul Kang-
dc.contributor.googleauthorHyongbum (Henry) Kim-
dc.contributor.googleauthorJeong Ho Lee-
dc.identifier.doi10.1016/j.ajhg.2017.01.030-
dc.contributor.localIdA01148-
dc.contributor.localIdA01208-
dc.contributor.localIdA03177-
dc.contributor.localIdA00402-
dc.contributor.localIdA00524-
dc.contributor.localIdA00610-
dc.contributor.localIdA00102-
dc.relation.journalcodeJ00086-
dc.identifier.eissn1537-6605-
dc.identifier.pmid28215400-
dc.identifier.urlhttp://www.sciencedirect.com/science/article/pii/S0002929717300319-
dc.subject.keywordCRISPR-Cas9 genome editing-
dc.subject.keywordTSC1-
dc.subject.keywordTSC2-
dc.subject.keywordbrain mosaicism-
dc.subject.keywordbrain somatic mutation-
dc.subject.keywordfocal cortical dysplasia-
dc.subject.keywordintractable epilepsy-
dc.contributor.alternativeNameKang, Hoon Chul-
dc.contributor.alternativeNameKim, Hyongbum-
dc.contributor.alternativeNameKim, Heung Dong-
dc.contributor.alternativeNameLee, Joon Soo-
dc.contributor.alternativeNameKim, Dong Seok-
dc.contributor.alternativeNameKim, Sang Woo-
dc.contributor.alternativeNameKim, Se Hoon-
dc.contributor.affiliatedAuthorKim, Hyongbum-
dc.contributor.affiliatedAuthorKim, Heung Dong-
dc.contributor.affiliatedAuthorLee, Joon Soo-
dc.contributor.affiliatedAuthorKim, Dong Seok-
dc.contributor.affiliatedAuthorKim, Sang Woo-
dc.contributor.affiliatedAuthorKim, Se Hoon-
dc.contributor.affiliatedAuthorKang, Hoon Chul-
dc.citation.titleAmerican Journal of Human Genetics-
dc.citation.volume100-
dc.citation.number3-
dc.citation.startPage454-
dc.citation.endPage472-
dc.identifier.bibliographicCitationAMERICAN JOURNAL OF HUMAN GENETICS, Vol.100(3) : 454-472, 2017-
dc.date.modified2017-11-01-
dc.identifier.rimsid44180-
dc.type.rimsART-
Appears in Collections:
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
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers

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