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Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia

Title
Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia
Author
Ramakrishna Suresh
Keywords
focal cortical dysplasia; intractable epilepsy; TSC1; TSC2; brain somatic mutation; CRISPR-Cas9 genome editing; brain mosaicism
Issue Date
2017-03
Publisher
CELL PRESS
Citation
AMERICAN JOURNAL OF HUMAN GENETICS, v. 100, no. 3, page. 454-472
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 x-20,012 x) 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.Va11547I1e]), 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 TSC1TSC2 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.
URI
https://www.cell.com/ajhg/fulltext/S0002-9297(17)30031-9https://repository.hanyang.ac.kr/handle/20.500.11754/113352
ISSN
0002-9297; 1537-6605
DOI
10.1016/j.ajhg.2017.01.030
Appears in Collections:
GRADUATE SCHOOL OF BIOMEDICAL SCIENCE AND ENGINEERING[S](의생명공학전문대학원) > ETC
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