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Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy

DC Field Value Language
dc.contributor.author강훈철-
dc.contributor.author김동석-
dc.contributor.author김상우-
dc.contributor.author김세훈-
dc.contributor.author김정아-
dc.contributor.author김준호-
dc.contributor.author김흥동-
dc.contributor.author박은경-
dc.contributor.author강석구-
dc.date.accessioned2016-02-04T11:10:02Z-
dc.date.available2016-02-04T11:10:02Z-
dc.date.issued2015-
dc.identifier.issn1078-8956-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/139816-
dc.description.abstractFocal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.-
dc.description.statementOfResponsibilityopen-
dc.format.extent395~400-
dc.relation.isPartOfNATURE MEDICINE-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.subject.MESHAnimals-
dc.subject.MESHBrain/pathology*-
dc.subject.MESHExome/genetics-
dc.subject.MESHHumans-
dc.subject.MESHMalformations of Cortical Development/genetics*-
dc.subject.MESHMice-
dc.subject.MESHMutation/genetics*-
dc.subject.MESHSequence Analysis, DNA-
dc.subject.MESHTOR Serine-Threonine Kinases/genetics*-
dc.titleBrain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Pediatrics (소아과학)-
dc.contributor.googleauthorJae Seok Lim-
dc.contributor.googleauthorWoo-il Kim-
dc.contributor.googleauthorHoon-Chul Kang-
dc.contributor.googleauthorSe Hoon Kim-
dc.contributor.googleauthorAh Hyung Park-
dc.contributor.googleauthorEun Kyung Park-
dc.contributor.googleauthorYoung-Wook Cho-
dc.contributor.googleauthorSangwoo Kim-
dc.contributor.googleauthorHo Min Kim-
dc.contributor.googleauthorJeong A Kim-
dc.contributor.googleauthorJunho Kim-
dc.contributor.googleauthorHwanseok Rhee-
dc.contributor.googleauthorSeok-Gu Kang-
dc.contributor.googleauthorHeung Dong Kim-
dc.contributor.googleauthorDaesoo Kim-
dc.contributor.googleauthorDong-Seok Kim-
dc.contributor.googleauthorJeong Ho Lee-
dc.identifier.doi10.1038/nm.3824-
dc.admin.authorfalse-
dc.admin.mappingfalse-
dc.contributor.localIdA00102-
dc.contributor.localIdA00402-
dc.contributor.localIdA00610-
dc.contributor.localIdA00887-
dc.contributor.localIdA00960-
dc.contributor.localIdA01208-
dc.contributor.localIdA01607-
dc.contributor.localIdA00036-
dc.contributor.localIdA00524-
dc.relation.journalcodeJ02296-
dc.identifier.eissn1546-170X-
dc.identifier.pmid26779999-
dc.identifier.urlhttp://www.nature.com/nm/journal/v21/n4/full/nm.3824.html-
dc.subject.keywordFocal cortical dysplasia-
dc.subject.keywordMechanistic target of rapamycin-
dc.subject.keywordMouse model-
dc.subject.keywordSomatic mutation-
dc.contributor.alternativeNameKang, Hoon Chul-
dc.contributor.alternativeNameKim, Dong Seok-
dc.contributor.alternativeNameKim, Sang Woo-
dc.contributor.alternativeNameKim, Se Hoon-
dc.contributor.alternativeNameKim, Jeong A-
dc.contributor.alternativeNameKim, Jun Ho-
dc.contributor.alternativeNameKim, Heung Dong-
dc.contributor.alternativeNamePark, Eun Kyung-
dc.contributor.alternativeNameKang, Seok Gu-
dc.contributor.affiliatedAuthorKang, Hoon Chul-
dc.contributor.affiliatedAuthorKim, Dong Seok-
dc.contributor.affiliatedAuthorKim, Se Hoon-
dc.contributor.affiliatedAuthorKim, Jeong A-
dc.contributor.affiliatedAuthorKim, Jun Ho-
dc.contributor.affiliatedAuthorKim, Heung Dong-
dc.contributor.affiliatedAuthorPark, Eun Kyung-
dc.contributor.affiliatedAuthorKang, Seok Gu-
dc.contributor.affiliatedAuthorKim, Sang Woo-
dc.rights.accessRightsnot free-
dc.citation.volume21-
dc.citation.number4-
dc.citation.startPage395-
dc.citation.endPage400-
dc.identifier.bibliographicCitationNATURE MEDICINE, Vol.21(4) : 395-400, 2015-
dc.identifier.rimsid46579-
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

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