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

Jae Seok Lim, Woo Il Kim, Hoon Chul Kang, Se Hoon Kim, Ah Hyung Park, Eun Kyung Park, Young Wook Cho, Sangwoo Kim, Ho Min Kim, Jeong A. Kim, Junho Kim, Hwanseok Rhee, Seok Gu Kang, Heung Dong Kim, Daesoo Kim, Dong Seok Kim, Jeong Ho Lee

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

Focal 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.

Original languageEnglish
Pages (from-to)395-400
Number of pages6
JournalNature Medicine
Volume21
Issue number4
DOIs
Publication statusPublished - 2015 Apr 1

Fingerprint

Sirolimus
Brain
Mutation
Neurons
Epilepsy
Exome
High-Throughput Nucleotide Sequencing
Electroporation
Missense Mutation
Cerebral Cortex
Refractory materials
Seizures
Blood
Phosphotransferases
Genes
Focal cortical dysplasia of Taylor
Drug Resistant Epilepsy
Tissue
Polymerase Chain Reaction
DNA

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Lim, Jae Seok ; Kim, Woo Il ; Kang, Hoon Chul ; Kim, Se Hoon ; Park, Ah Hyung ; Park, Eun Kyung ; Cho, Young Wook ; Kim, Sangwoo ; Kim, Ho Min ; Kim, Jeong A. ; Kim, Junho ; Rhee, Hwanseok ; Kang, Seok Gu ; Kim, Heung Dong ; Kim, Daesoo ; Kim, Dong Seok ; Lee, Jeong Ho. / Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. In: Nature Medicine. 2015 ; Vol. 21, No. 4. pp. 395-400.
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abstract = "Focal 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.",
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Lim, JS, Kim, WI, Kang, HC, Kim, SH, Park, AH, Park, EK, Cho, YW, Kim, S, Kim, HM, Kim, JA, Kim, J, Rhee, H, Kang, SG, Kim, HD, Kim, D, Kim, DS & Lee, JH 2015, 'Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy', Nature Medicine, vol. 21, no. 4, pp. 395-400. https://doi.org/10.1038/nm.3824

Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. / Lim, Jae Seok; Kim, Woo Il; Kang, Hoon Chul; Kim, Se Hoon; Park, Ah Hyung; Park, Eun Kyung; Cho, Young Wook; Kim, Sangwoo; Kim, Ho Min; Kim, Jeong A.; Kim, Junho; Rhee, Hwanseok; Kang, Seok Gu; Kim, Heung Dong; Kim, Daesoo; Kim, Dong Seok; Lee, Jeong Ho.

In: Nature Medicine, Vol. 21, No. 4, 01.04.2015, p. 395-400.

Research output: Contribution to journalArticle

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AU - Park, Eun Kyung

AU - Cho, Young Wook

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AU - Kim, Ho Min

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AU - Kang, Seok Gu

AU - Kim, Heung Dong

AU - Kim, Daesoo

AU - Kim, Dong Seok

AU - Lee, Jeong Ho

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