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Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations

Biallelic NARS2 mutations can cause various neurodegenerative diseases, leading to growth retardation, intractable epilepsy, and hearing loss in early infancy and further progressing to spastic paraplegia, neurodegeneration, and even death. NARS2 mutations are associated with mitochondrial dysfuncti...

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Autores principales: Hu, Wenjing, Fang, Hongjun, Peng, Yu, Li, Li, Guo, Danni, Tang, Jingwen, Yi, Jurong, Liu, Qingqing, Qin, Wei, Wu, Liwen, Ning, Zeshu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9811187/
https://www.ncbi.nlm.nih.gov/pubmed/36620461
http://dx.doi.org/10.3389/fnins.2022.1076183
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author Hu, Wenjing
Fang, Hongjun
Peng, Yu
Li, Li
Guo, Danni
Tang, Jingwen
Yi, Jurong
Liu, Qingqing
Qin, Wei
Wu, Liwen
Ning, Zeshu
author_facet Hu, Wenjing
Fang, Hongjun
Peng, Yu
Li, Li
Guo, Danni
Tang, Jingwen
Yi, Jurong
Liu, Qingqing
Qin, Wei
Wu, Liwen
Ning, Zeshu
author_sort Hu, Wenjing
collection PubMed
description Biallelic NARS2 mutations can cause various neurodegenerative diseases, leading to growth retardation, intractable epilepsy, and hearing loss in early infancy and further progressing to spastic paraplegia, neurodegeneration, and even death. NARS2 mutations are associated with mitochondrial dysfunction and cause combined oxidative phosphorylation deficiency 24 (COXPD24). Relatively few cases have been reported worldwide; therefore, the pathogenesis of COXPD24 is poorly understood. We studied two unrelated patients with COXPD24 with similar phenotypes who presented with intractable refractory epilepsia partialis continua, hearing loss, and growth retardation. One patient died from epilepsy. Three novel NARS2 variants (case 1: c.185T > C and c.251 + 2T > G; case 2: c.185T > C and c.509T > G) were detected with whole-exome sequencing. c.251 + 2T > G is located at the donor splicing site in the non-coding sequence of the gene. The minigene experiment further verified that c.251 + 2T > G caused variable splicing abnormalities and produced truncated proteins. Molecular dynamics studies showed that c.185T > C and c.509T > G reduced the binding free energy of the NARS2 protein dimer. The literature review revealed fewer than 30 NARS2 variants. These findings improved our understanding of the disease phenotype and the variation spectrum and revealed the potential pathogenic mechanism of non-coding sequence mutations in COXPD24.
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spelling pubmed-98111872023-01-05 Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations Hu, Wenjing Fang, Hongjun Peng, Yu Li, Li Guo, Danni Tang, Jingwen Yi, Jurong Liu, Qingqing Qin, Wei Wu, Liwen Ning, Zeshu Front Neurosci Neuroscience Biallelic NARS2 mutations can cause various neurodegenerative diseases, leading to growth retardation, intractable epilepsy, and hearing loss in early infancy and further progressing to spastic paraplegia, neurodegeneration, and even death. NARS2 mutations are associated with mitochondrial dysfunction and cause combined oxidative phosphorylation deficiency 24 (COXPD24). Relatively few cases have been reported worldwide; therefore, the pathogenesis of COXPD24 is poorly understood. We studied two unrelated patients with COXPD24 with similar phenotypes who presented with intractable refractory epilepsia partialis continua, hearing loss, and growth retardation. One patient died from epilepsy. Three novel NARS2 variants (case 1: c.185T > C and c.251 + 2T > G; case 2: c.185T > C and c.509T > G) were detected with whole-exome sequencing. c.251 + 2T > G is located at the donor splicing site in the non-coding sequence of the gene. The minigene experiment further verified that c.251 + 2T > G caused variable splicing abnormalities and produced truncated proteins. Molecular dynamics studies showed that c.185T > C and c.509T > G reduced the binding free energy of the NARS2 protein dimer. The literature review revealed fewer than 30 NARS2 variants. These findings improved our understanding of the disease phenotype and the variation spectrum and revealed the potential pathogenic mechanism of non-coding sequence mutations in COXPD24. Frontiers Media S.A. 2022-12-21 /pmc/articles/PMC9811187/ /pubmed/36620461 http://dx.doi.org/10.3389/fnins.2022.1076183 Text en Copyright © 2022 Hu, Fang, Peng, Li, Guo, Tang, Yi, Liu, Qin, Wu and Ning. 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 Neuroscience
Hu, Wenjing
Fang, Hongjun
Peng, Yu
Li, Li
Guo, Danni
Tang, Jingwen
Yi, Jurong
Liu, Qingqing
Qin, Wei
Wu, Liwen
Ning, Zeshu
Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations
title Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations
title_full Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations
title_fullStr Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations
title_full_unstemmed Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations
title_short Clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic NARS2 mutations
title_sort clinical and genetic analyses of premature mitochondrial encephalopathy with epilepsia partialis continua caused by novel biallelic nars2 mutations
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9811187/
https://www.ncbi.nlm.nih.gov/pubmed/36620461
http://dx.doi.org/10.3389/fnins.2022.1076183
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