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

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....

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Autores principales: Li, Youzhi, Zhao, Xu, Wang, Shanshan, Xu, Ke, Zhao, Xin, Huang, Shanshan, Zhu, Suiqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633433/
https://www.ncbi.nlm.nih.gov/pubmed/34868250
http://dx.doi.org/10.3389/fgene.2021.766354
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author Li, Youzhi
Zhao, Xu
Wang, Shanshan
Xu, Ke
Zhao, Xin
Huang, Shanshan
Zhu, Suiqiang
author_facet Li, Youzhi
Zhao, Xu
Wang, Shanshan
Xu, Ke
Zhao, Xin
Huang, Shanshan
Zhu, Suiqiang
author_sort Li, Youzhi
collection PubMed
description 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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spelling pubmed-86334332021-12-02 A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci Li, Youzhi Zhao, Xu Wang, Shanshan Xu, Ke Zhao, Xin Huang, Shanshan Zhu, Suiqiang Front Genet Genetics 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. Frontiers Media S.A. 2021-11-12 /pmc/articles/PMC8633433/ /pubmed/34868250 http://dx.doi.org/10.3389/fgene.2021.766354 Text en Copyright © 2021 Li, Zhao, Wang, Xu, Zhao, Huang and Zhu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Li, Youzhi
Zhao, Xu
Wang, Shanshan
Xu, Ke
Zhao, Xin
Huang, Shanshan
Zhu, Suiqiang
A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci
title A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci
title_full A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci
title_fullStr A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci
title_full_unstemmed A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci
title_short A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci
title_sort novel loss-of-function mutation in the nprl3 gene identified in chinese familial focal epilepsy with variable foci
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633433/
https://www.ncbi.nlm.nih.gov/pubmed/34868250
http://dx.doi.org/10.3389/fgene.2021.766354
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