Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

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Title
Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia
Author(s)
Lim J.S.; Gopalappa R.; Kim S.H.; Ramakrishna S.; Lee M.; Kim W.-I.; Kim J.; Park S.M.; Lee J.; Oh J.-H.; Kim H.D.; Park C.-H.; Lee J.S.; Kim S.; Kim D.S.; Han J.M.; Kang H.-C.; Hyongbum (Henry) Kim; Lee J.H.
Publication Date
2017-03
Journal
AMERICAN JOURNAL OF HUMAN GENETICS, v.100, no.3, pp.454 - 472
Publisher
CELL PRESS
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. © 2017 American Society of Human Genetic
URI
https://pr.ibs.re.kr/handle/8788114/4271
ISSN
0002-9297
Appears in Collections:
Center for Nanomedicine (나노의학 연구단) > Journal Papers
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