PMID- 32216069
OWN - NLM
STAT- MEDLINE
DCOM- 20201016
LR  - 20201016
IS  - 1528-1167 (Electronic)
IS  - 0013-9580 (Linking)
VI  - 61
IP  - 4
DP  - 2020 Apr
TI  - Somatic variants in new candidate genes identified in focal cortical dysplasia 
      type II.
PG  - 667-678
LID - 10.1111/epi.16481 [doi]
AB  - 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.
CI  - Wiley Periodicals, Inc. (c) 2020 International League Against Epilepsy.
FAU - Zhang, Zhongbin
AU  - Zhang Z
AUID- ORCID: 0000-0003-3585-4359
AD  - Department of Pediatrics, Peking University First Hospital, Beijing, China.
FAU - Gao, Kai
AU  - Gao K
AUID- ORCID: 0000-0001-6427-2038
AD  - Department of Pediatrics, Peking University First Hospital, Beijing, China.
FAU - Liu, Qingzhu
AU  - Liu Q
AUID- ORCID: 0000-0002-9695-2246
AD  - Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.
FAU - Zhou, Jiapeng
AU  - Zhou J
AD  - College of Life Sciences, Hunan Normal University, Changsha, China.
FAU - Li, Xiyuan
AU  - Li X
AD  - Institute of Computing Technology, Chinese Academy of Science, Beijing, China.
FAU - Lang, Na
AU  - Lang N
AD  - College of Life Sciences, Hunan Normal University, Changsha, China.
FAU - Liu, Ming
AU  - Liu M
AD  - Department of Pediatrics, Peking University First Hospital, Beijing, China.
FAU - Wang, Tianshuang
AU  - Wang T
AUID- ORCID: 0000-0002-7397-9091
AD  - Department of Pediatrics, Peking University First Hospital, Beijing, China.
FAU - Zhang, Jie
AU  - Zhang J
AUID- ORCID: 0000-0002-4047-0897
AD  - Department of Pediatrics, Peking University First Hospital, Beijing, China.
FAU - Wang, Hui
AU  - Wang H
AD  - Department of Pathology, Peking University First Hospital, Beijing, China.
FAU - Dong, Ying
AU  - Dong Y
AD  - Department of Pathology, Peking University First Hospital, Beijing, China.
FAU - Ji, Taoyun
AU  - Ji T
AD  - Department of Pediatrics, Peking University First Hospital, Beijing, China.
AD  - Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.
FAU - Wang, Shuang
AU  - Wang S
AD  - Department of Pediatrics, Peking University First Hospital, Beijing, China.
AD  - Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.
FAU - Liu, Xiaoyan
AU  - Liu X
AD  - Department of Pediatrics, Peking University First Hospital, Beijing, China.
AD  - Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.
FAU - Jiang, Yuwu
AU  - Jiang Y
AUID- ORCID: 0000-0002-5179-9807
AD  - Department of Pediatrics, Peking University First Hospital, Beijing, China.
AD  - Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.
FAU - Cai, Lixin
AU  - Cai L
AUID- ORCID: 0000-0001-8231-6428
AD  - Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.
FAU - Wu, Ye
AU  - Wu Y
AUID- ORCID: 0000-0001-9644-9520
AD  - Department of Pediatrics, Peking University First Hospital, Beijing, China.
AD  - Pediatric Epilepsy Center, Peking University First Hospital, Beijing, China.
LA  - eng
SI  - GENBANK/NM_005544.2
SI  - GENBANK/NM_001290261.1
SI  - GENBANK/NM_016577.4
SI  - GENBANK/NM_004958.4
SI  - GENBANK/NM_000871.3
SI  - GENBANK/NM_000548.5
SI  - GENBANK/NM_005402.4
GR  - BMU2017JI002/The Fundamental Research Funds for the Central 
      Universities/International
GR  - BMU2018XY006/The Fundamental Research Funds for the Central 
      Universities/International
GR  - PKU2017LCX06/The Fundamental Research Funds for the Central 
      Universities/International
GR  - 2016YFC0901505/The National Key Research and Development Program of 
      China/International
GR  - 2016YFC1306201/The National Key Research and Development Program of 
      China/International
GR  - BZ0317/Beijing key laboratory of molecular diagnosis and study on pediatric 
      genetic diseases/International
GR  - 81971211, 81601131/National Natural Science Foundation of China/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200326
PL  - United States
TA  - Epilepsia
JT  - Epilepsia
JID - 2983306R
RN  - Focal cortical dysplasia of Taylor
SB  - IM
MH  - Child, Preschool
MH  - Epilepsy/*genetics
MH  - Female
MH  - Genetic Predisposition to Disease/*genetics
MH  - Humans
MH  - Infant
MH  - Male
MH  - Malformations of Cortical Development, Group I/*genetics
MH  - Mutation
OTO - NOTNLM
OT  - Ras pathway
OT  - focal cortical dysplasia type II
OT  - insulin pathway
OT  - mTOR
OT  - somatic variants
EDAT- 2020/03/28 06:00
MHDA- 2020/10/21 06:00
CRDT- 2020/03/28 06:00
PHST- 2019/08/09 00:00 [received]
PHST- 2020/02/25 00:00 [revised]
PHST- 2020/02/25 00:00 [accepted]
PHST- 2020/03/28 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2020/03/28 06:00 [entrez]
AID - 10.1111/epi.16481 [doi]
PST - ppublish
SO  - Epilepsia. 2020 Apr;61(4):667-678. doi: 10.1111/epi.16481. Epub 2020 Mar 26.