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Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia.

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.

journal_name

Am J Hum Genet

journal_title

American journal of human genetics

authors

Lim JS,Gopalappa R,Kim SH,Ramakrishna S,Lee M,Kim WI,Kim J,Park SM,Lee J,Oh JH,Kim HD,Park CH,Lee JS,Kim S,Kim DS,Han JM,Kang HC,Kim HH,Lee JH

doi

10.1016/j.ajhg.2017.01.030

subject

Has Abstract

pub_date

2017-03-02 00:00:00

pages

454-472

issue

3

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(17)30031-9

journal_volume

100

pub_type

杂志文章

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