2. Academic Validation
  3. A brain somatic RHEB doublet mutation causes focal cortical dysplasia type II

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

  • Exp Mol Med. 2019 Jul 23;51(7):1-11. doi: 10.1038/s12276-019-0277-4.
Shanshan Zhao  # 1,  Zhenghui Li  # 2 3,  Muxian Zhang 1,  Lingliang Zhang 1,  Honghua Zheng 1,  Jinhuan Ning 1,  Yanyan Wang 1,  Fengpeng Wang 2 4,  Xiaobin Zhang 2 4,  Hexia Gan 2,  Yuanqing Wang 2,  Xian Zhang 1,  Hong Luo 1,  Guojun Bu 5,  Huaxi Xu 6,  Yi Yao 7 8 9,  Yun-Wu Zhang 10
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China.
  • 2 Neuromedicine Center, the 174th Hospital of Chinese People's Liberation Army, Affiliated Chenggong Hospital, Xiamen University, Xiamen, 361003, Fujian, China.
  • 3 Department of Neurosurgery, Kaifeng Central Hospital, Kaifeng, 475000, Henan, China.
  • 4 XiaMen Humanity Hospital, No.3777 XianYue Road, HuLi District, XiaMen, 361015, FuJian, China.
  • 5 Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
  • 6 Neuroscience Initiative, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, 92037, USA.
  • 7 Neuromedicine Center, the 174th Hospital of Chinese People's Liberation Army, Affiliated Chenggong Hospital, Xiamen University, Xiamen, 361003, Fujian, China. 13656008777@163.com.
  • 8 XiaMen Humanity Hospital, No.3777 XianYue Road, HuLi District, XiaMen, 361015, FuJian, China. 13656008777@163.com.
  • 9 Department of Pediatric Neurology, Shenzhen Children's Hospital, Shenzhen, 518026, Guangdong Province, China. 13656008777@163.com.
  • 10 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China. yunzhang@xmu.edu.cn.
  • # Contributed equally.
PMID: 31337748 DOI: 10.1038/s12276-019-0277-4
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.

Figures
Products