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공공누리This item is licensed Korea Open Government License

dc.contributor.author
임재석
dc.contributor.author
이정호
dc.contributor.author
이준학
dc.date.accessioned
2019-08-28T07:42:11Z
dc.date.available
2019-08-28T07:42:11Z
dc.date.issued
2017-03-02
dc.identifier.issn
0002-9297
dc.identifier.uri
https://repository.kisti.re.kr/handle/10580/14707
dc.identifier.uri
http://www.ndsl.kr/ndsl/search/detail/article/articleSearchResultDetail.do?cn=NART77440407
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.language
eng
dc.relation.ispartofseries
AMERICAN JOURNAL OF HUMAN GENETICS
dc.title
Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia
dc.citation.endPage
472
dc.citation.number
3
dc.citation.startPage
454
dc.citation.volume
100
dc.subject.keyword
focal cortical dysplasia
dc.subject.keyword
intractable epilepsy
dc.subject.keyword
TSC1
dc.subject.keyword
TSC2
dc.subject.keyword
brain somatic mutation
dc.subject.keyword
CRISPR-Cas9 genome editing
dc.subject.keyword
brain mosaicism
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7. KISTI 연구성과 > 학술지 발표논문
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