A brain somatic RHEB doublet mutation causes focal cortical dysplasia type II

Shanshan Zhao, Zhenghui Li, Muxian Zhang, Lingliang Zhang, Honghua Zheng, Jinhuan Ning, Yanyan Wang, Fengpeng Wang, Xiaobin Zhang, Hexia Gan, Yuanqing Wang, Xian Zhang, Hong Luo, Guojun D Bu, Huaxi Xu, Yi Yao, Yun wu Zhang

Research output: Contribution to journalArticle

Abstract

Focal cortical dysplasia type II (FCDII) is a cerebral cortex malformation characterized by local cortical structure disorganization, neuronal dysmorphology, and refractory epilepsy. Brain somatic mutations in several genes involved in the PI3K/AKT/mTOR pathway are associated with FCDII, but they are only found in a proportion of patients with FCDII. The genetic causes underlying the development FCDII in other patients remain unclear. Here, we carried out whole exome sequencing and targeted sequencing in paired brain–blood DNA from patients with FCDII and identified a brain somatic doublet mutation c.(A104T, C105A) in the Ras homolog, mTORC1 binding (RHEB) gene, which led to the RHEB p.Y35L mutation in one patient with FCDII. This RHEB mutation carrier had a dramatic increase of ribosomal protein S6 phosphorylation, indicating mTOR activation in the region of the brain lesion. The RHEB p.Y35L mutant protein had increased GTPλS-binding activity compared with wild-type RHEB. Overexpression of the RHEB p.Y35L variant in cultured cells also resulted in elevated S6 phosphorylation compared to wild-type RHEB. Importantly, in utero electroporation of the RHEB p.Y35L variant in mice induced S6 phosphorylation, cytomegalic neurons, dysregulated neuron migration, abnormal electroencephalogram, and seizures, all of which are found in patients with FCDII. Rapamycin treatment rescued abnormal electroencephalograms and alleviated seizures in these mice. These results demonstrate that brain somatic mutations in RHEB are also responsible for the pathogenesis of FCDII, indicating that aberrant activation of mTOR signaling is a primary driver and potential drug target for FCDII.

Original languageEnglish (US)
Article number84
JournalExperimental and Molecular Medicine
Volume51
Issue number7
DOIs
StatePublished - Jul 1 2019

Fingerprint

Phosphorylation
Brain
Mutation
Electroencephalography
Neurons
Genes
Chemical activation
Ribosomal Protein S6
S 6
Mutant Proteins
Sirolimus
Phosphatidylinositol 3-Kinases
Refractory materials
Cells
Seizures
Exome
Focal cortical dysplasia of Taylor
DNA
Electroporation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Zhao, S., Li, Z., Zhang, M., Zhang, L., Zheng, H., Ning, J., ... Zhang, Y. W. (2019). A brain somatic RHEB doublet mutation causes focal cortical dysplasia type II. Experimental and Molecular Medicine, 51(7), [84]. https://doi.org/10.1038/s12276-019-0277-4

A brain somatic RHEB doublet mutation causes focal cortical dysplasia type II. / Zhao, Shanshan; Li, Zhenghui; Zhang, Muxian; Zhang, Lingliang; Zheng, Honghua; Ning, Jinhuan; Wang, Yanyan; Wang, Fengpeng; Zhang, Xiaobin; Gan, Hexia; Wang, Yuanqing; Zhang, Xian; Luo, Hong; Bu, Guojun D; Xu, Huaxi; Yao, Yi; Zhang, Yun wu.

In: Experimental and Molecular Medicine, Vol. 51, No. 7, 84, 01.07.2019.

Research output: Contribution to journalArticle

Zhao, S, Li, Z, Zhang, M, Zhang, L, Zheng, H, Ning, J, Wang, Y, Wang, F, Zhang, X, Gan, H, Wang, Y, Zhang, X, Luo, H, Bu, GD, Xu, H, Yao, Y & Zhang, YW 2019, 'A brain somatic RHEB doublet mutation causes focal cortical dysplasia type II', Experimental and Molecular Medicine, vol. 51, no. 7, 84. https://doi.org/10.1038/s12276-019-0277-4
Zhao, Shanshan ; Li, Zhenghui ; Zhang, Muxian ; Zhang, Lingliang ; Zheng, Honghua ; Ning, Jinhuan ; Wang, Yanyan ; Wang, Fengpeng ; Zhang, Xiaobin ; Gan, Hexia ; Wang, Yuanqing ; Zhang, Xian ; Luo, Hong ; Bu, Guojun D ; Xu, Huaxi ; Yao, Yi ; Zhang, Yun wu. / A brain somatic RHEB doublet mutation causes focal cortical dysplasia type II. In: Experimental and Molecular Medicine. 2019 ; Vol. 51, No. 7.
@article{8c6af2cda6be4e1c83c7b5328545ae25,
title = "A brain somatic RHEB doublet mutation causes focal cortical dysplasia type II",
abstract = "Focal cortical dysplasia type II (FCDII) is a cerebral cortex malformation characterized by local cortical structure disorganization, neuronal dysmorphology, and refractory epilepsy. Brain somatic mutations in several genes involved in the PI3K/AKT/mTOR pathway are associated with FCDII, but they are only found in a proportion of patients with FCDII. The genetic causes underlying the development FCDII in other patients remain unclear. Here, we carried out whole exome sequencing and targeted sequencing in paired brain–blood DNA from patients with FCDII and identified a brain somatic doublet mutation c.(A104T, C105A) in the Ras homolog, mTORC1 binding (RHEB) gene, which led to the RHEB p.Y35L mutation in one patient with FCDII. This RHEB mutation carrier had a dramatic increase of ribosomal protein S6 phosphorylation, indicating mTOR activation in the region of the brain lesion. The RHEB p.Y35L mutant protein had increased GTPλS-binding activity compared with wild-type RHEB. Overexpression of the RHEB p.Y35L variant in cultured cells also resulted in elevated S6 phosphorylation compared to wild-type RHEB. Importantly, in utero electroporation of the RHEB p.Y35L variant in mice induced S6 phosphorylation, cytomegalic neurons, dysregulated neuron migration, abnormal electroencephalogram, and seizures, all of which are found in patients with FCDII. Rapamycin treatment rescued abnormal electroencephalograms and alleviated seizures in these mice. These results demonstrate that brain somatic mutations in RHEB are also responsible for the pathogenesis of FCDII, indicating that aberrant activation of mTOR signaling is a primary driver and potential drug target for FCDII.",
author = "Shanshan Zhao and Zhenghui Li and Muxian Zhang and Lingliang Zhang and Honghua Zheng and Jinhuan Ning and Yanyan Wang and Fengpeng Wang and Xiaobin Zhang and Hexia Gan and Yuanqing Wang and Xian Zhang and Hong Luo and Bu, {Guojun D} and Huaxi Xu and Yi Yao and Zhang, {Yun wu}",
year = "2019",
month = "7",
day = "1",
doi = "10.1038/s12276-019-0277-4",
language = "English (US)",
volume = "51",
journal = "Experimental and Molecular Medicine",
issn = "1226-3613",
publisher = "Korean Society of Med. Biochemistry and Mol. Biology",
number = "7",

}

TY - JOUR

T1 - A brain somatic RHEB doublet mutation causes focal cortical dysplasia type II

AU - Zhao, Shanshan

AU - Li, Zhenghui

AU - Zhang, Muxian

AU - Zhang, Lingliang

AU - Zheng, Honghua

AU - Ning, Jinhuan

AU - Wang, Yanyan

AU - Wang, Fengpeng

AU - Zhang, Xiaobin

AU - Gan, Hexia

AU - Wang, Yuanqing

AU - Zhang, Xian

AU - Luo, Hong

AU - Bu, Guojun D

AU - Xu, Huaxi

AU - Yao, Yi

AU - Zhang, Yun wu

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Focal cortical dysplasia type II (FCDII) is a cerebral cortex malformation characterized by local cortical structure disorganization, neuronal dysmorphology, and refractory epilepsy. Brain somatic mutations in several genes involved in the PI3K/AKT/mTOR pathway are associated with FCDII, but they are only found in a proportion of patients with FCDII. The genetic causes underlying the development FCDII in other patients remain unclear. Here, we carried out whole exome sequencing and targeted sequencing in paired brain–blood DNA from patients with FCDII and identified a brain somatic doublet mutation c.(A104T, C105A) in the Ras homolog, mTORC1 binding (RHEB) gene, which led to the RHEB p.Y35L mutation in one patient with FCDII. This RHEB mutation carrier had a dramatic increase of ribosomal protein S6 phosphorylation, indicating mTOR activation in the region of the brain lesion. The RHEB p.Y35L mutant protein had increased GTPλS-binding activity compared with wild-type RHEB. Overexpression of the RHEB p.Y35L variant in cultured cells also resulted in elevated S6 phosphorylation compared to wild-type RHEB. Importantly, in utero electroporation of the RHEB p.Y35L variant in mice induced S6 phosphorylation, cytomegalic neurons, dysregulated neuron migration, abnormal electroencephalogram, and seizures, all of which are found in patients with FCDII. Rapamycin treatment rescued abnormal electroencephalograms and alleviated seizures in these mice. These results demonstrate that brain somatic mutations in RHEB are also responsible for the pathogenesis of FCDII, indicating that aberrant activation of mTOR signaling is a primary driver and potential drug target for FCDII.

AB - Focal cortical dysplasia type II (FCDII) is a cerebral cortex malformation characterized by local cortical structure disorganization, neuronal dysmorphology, and refractory epilepsy. Brain somatic mutations in several genes involved in the PI3K/AKT/mTOR pathway are associated with FCDII, but they are only found in a proportion of patients with FCDII. The genetic causes underlying the development FCDII in other patients remain unclear. Here, we carried out whole exome sequencing and targeted sequencing in paired brain–blood DNA from patients with FCDII and identified a brain somatic doublet mutation c.(A104T, C105A) in the Ras homolog, mTORC1 binding (RHEB) gene, which led to the RHEB p.Y35L mutation in one patient with FCDII. This RHEB mutation carrier had a dramatic increase of ribosomal protein S6 phosphorylation, indicating mTOR activation in the region of the brain lesion. The RHEB p.Y35L mutant protein had increased GTPλS-binding activity compared with wild-type RHEB. Overexpression of the RHEB p.Y35L variant in cultured cells also resulted in elevated S6 phosphorylation compared to wild-type RHEB. Importantly, in utero electroporation of the RHEB p.Y35L variant in mice induced S6 phosphorylation, cytomegalic neurons, dysregulated neuron migration, abnormal electroencephalogram, and seizures, all of which are found in patients with FCDII. Rapamycin treatment rescued abnormal electroencephalograms and alleviated seizures in these mice. These results demonstrate that brain somatic mutations in RHEB are also responsible for the pathogenesis of FCDII, indicating that aberrant activation of mTOR signaling is a primary driver and potential drug target for FCDII.

UR - http://www.scopus.com/inward/record.url?scp=85069724422&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069724422&partnerID=8YFLogxK

U2 - 10.1038/s12276-019-0277-4

DO - 10.1038/s12276-019-0277-4

M3 - Article

C2 - 31337748

AN - SCOPUS:85069724422

VL - 51

JO - Experimental and Molecular Medicine

JF - Experimental and Molecular Medicine

SN - 1226-3613

IS - 7

M1 - 84

ER -