Somatic variants in new candidate genes identified in focal cortical dysplasia type II

doi:10.1111/epi.16481

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	Somatic variants in new candidate genes identified in focal cortical dysplasia type II
	Zhang, Zhongbin 2; Gao, Kai 2; Liu, Qingzhu 3; Zhou, Jiapeng 4; Li, Xiyuan 5; Lang, Na 4; Liu, Ming 2; Wang, Tianshuang 2; Zhang, Jie 2; Wang, Hui 1
刊名	EPILEPSIA
	2020-03-26
页码	12
关键词	focal cortical dysplasia type II insulin pathway mTOR Ras pathway somatic variants
ISSN号	0013-9580
DOI	10.1111/epi.16481
英文摘要	Objective Focal cortical dysplasia type II (FCDII) is a malformation of cortex development commonly found in children with drug-resistant epilepsy. FCDII has been associated with somatic mutations in mammalian target of rapamycin (mTOR)-related pathway genes and an upregulation of mTOR. Somatic mutations were found in 10%-63% of FCDII samples; the frequency of the mutant allele was 0.93%-33.5%. This study aimed to find new candidate genes involved in FCDII. Methods We collected resected FCD lesions, perilesional brain tissues, and peripheral blood from 17 children with pathologically confirmed FCDII. We performed whole exome sequencing and followed a set of screening and analysis strategies to identify potentially deleterious somatic variants (PDSVs) in brain-expressed genes. We performed site-specific amplicon sequencing to validate the results. We also performed an in vitro functional study on an IRS1 variant. Results In six of 17 samples, we identified seven PDSVs in seven genes, including two frameshift variants and five missense variants. The frequencies of the variant allele were 1.29%-5.50%. The genes were MTOR, TSC2, IRS1, RAB6B, RALA, HTR6, and ZNF337. PDSVs in IRS1, RAB6B, ZNF337, RALA, and HTR6 had not been previously associated with FCD. In one lesion, two PDSVs were found in two genes. In a transfected cell line, we demonstrated that the c.1791dupG (identified in FCDII from Patient 1) led to a truncated IRS1 and significant mTOR hyperactivation compared to cells that carried wild-type IRS1. mTOR was also activated in FCDII tissue from Patient 1. Significance Seven PDSVs were identified in FCDII lesions in six of 17 children. Five variant genes had not been previously associated with cortical malformations. We demonstrated that the IRS1 variant led to mTOR hyperactivation in vitro. Although functional experiments are needed, the results provide evidence for novel candidate genes in the pathogenesis of FCDII.
资助项目	Fundamental Research Funds for the Central Universities[BMU2017JI002] ; Fundamental Research Funds for the Central Universities[BMU2018XY006] ; Fundamental Research Funds for the Central Universities[PKU2017LCX06] ; National Key Research and Development Program of China[2016YFC0901505] ; National Key Research and Development Program of China[2016YFC1306201] ; Beijing key laboratory of molecular diagnosis and study on pediatric genetic diseases[BZ0317] ; National Natural Science Foundation of China[81971211] ; National Natural Science Foundation of China[81601131]
WOS研究方向	Neurosciences & Neurology
语种	英语
出版者	WILEY
WOS记录号	WOS:000521624800001
内容类型	期刊论文
源URL	[http://119.78.100.204/handle/2XEOYT63/14017]
专题	中国科学院计算技术研究所期刊论文_英文
通讯作者	Jiang, Yuwu; Cai, Lixin; Wu, Ye
作者单位	1.Peking Univ, Hosp 1, Dept Pathol, Beijing, Peoples R China 2.Peking Univ, Hosp 1, Dept Pediat, Beijing, Peoples R China 3.Peking Univ, Hosp 1, Pediat Epilepsy Ctr, Beijing, Peoples R China 4.Hunan Normal Univ, Coll Life Sci, Changsha, Peoples R China 5.Chinese Acad Sci, Inst Comp Technol, Beijing, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Zhongbin,Gao, Kai,Liu, Qingzhu,et al. Somatic variants in new candidate genes identified in focal cortical dysplasia type II[J]. EPILEPSIA,2020:12.
APA	Zhang, Zhongbin.,Gao, Kai.,Liu, Qingzhu.,Zhou, Jiapeng.,Li, Xiyuan.,...&Wu, Ye.(2020).Somatic variants in new candidate genes identified in focal cortical dysplasia type II.EPILEPSIA,12.
MLA	Zhang, Zhongbin,et al."Somatic variants in new candidate genes identified in focal cortical dysplasia type II".EPILEPSIA (2020):12.