A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci

被引:10
作者
Li, Youzhi [1 ]
Zhao, Xu [2 ]
Wang, Shanshan [1 ]
Xu, Ke [1 ]
Zhao, Xin [1 ]
Huang, Shanshan [1 ]
Zhu, Suiqiang [1 ]
机构
[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Neurol, Wuhan, Hubei, Peoples R China
[2] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Radiol, Wuhan, Hubei, Peoples R China
关键词
GATOR1; Nprl3; mTOR signaling pathway; whole-exome sequencing (WES); familial focal epilepsy with variable foci; MAMMALIAN TARGET; DEPDC5; MUTATIONS; GATOR1; COMPLEX; MTOR; CELLS;
D O I
10.3389/fgene.2021.766354
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Familial focal epilepsy with variable foci is an autosomal dominant disorder characterized by partial epilepsy with variable foci. In this study, we report a six-generation with segregation of the mutation present in four generations Chinese family presenting with focal epilepsy with variable foci. Whole exome sequencing confirms a novel pathogenic mutation in the NPRL3 gene (c316C>T; p. Q106*). PCR, Western blotting, and immunohistochemistry were conducted to analyze the gene transcription, protein expression, and subcellular localization of NPRL3 and related signaling molecules in peripheral blood cells from family members. As compared with healthy family members, both mRNA level and protein expression of NPRL3 are decreased in peripheral blood cells of the mutation carrier. In addition, the expression of downstream molecular Phospho-p70 S6 kinase (P-s6k) are increased consequently. Our findings expand the genotypic and phenotypic spectrum of the NPRL3-associated epilepsy and reveal the mechanisms of mTOR pathway signaling and GATOR1 pathogenesis in focal epilepsies, providing exciting potential for future diagnostic and therapeutic interventions. However, further in vitro and animal experiments are still needed to evaluate the role of NPRL3 loss-of-function mutation in epileptogensis.
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页数:8
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