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Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic...

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Autores principales: Friedman, Jennifer, Smith, Desiree E., Issa, Mahmoud Y., Stanley, Valentina, Wang, Rengang, Mendes, Marisa I., Wright, Meredith S., Wigby, Kristen, Hildreth, Amber, Crawford, John R., Koehler, Alanna E., Chowdhury, Shimul, Nahas, Shareef, Zhai, Liting, Xu, Zhiwen, Lo, Wing-Sze, James, Kiely N., Musaev, Damir, Accogli, Andrea, Guerrero, Kether, Tran, Luan T., Omar, Tarek E. I., Ben-Omran, Tawfeg, Dimmock, David, Kingsmore, Stephen F., Salomons, Gajja S., Zaki, Maha S., Bernard, Geneviève, Gleeson, Joseph G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372641/
https://www.ncbi.nlm.nih.gov/pubmed/30755602
http://dx.doi.org/10.1038/s41467-018-07067-3
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author Friedman, Jennifer
Smith, Desiree E.
Issa, Mahmoud Y.
Stanley, Valentina
Wang, Rengang
Mendes, Marisa I.
Wright, Meredith S.
Wigby, Kristen
Hildreth, Amber
Crawford, John R.
Koehler, Alanna E.
Chowdhury, Shimul
Nahas, Shareef
Zhai, Liting
Xu, Zhiwen
Lo, Wing-Sze
James, Kiely N.
Musaev, Damir
Accogli, Andrea
Guerrero, Kether
Tran, Luan T.
Omar, Tarek E. I.
Ben-Omran, Tawfeg
Dimmock, David
Kingsmore, Stephen F.
Salomons, Gajja S.
Zaki, Maha S.
Bernard, Geneviève
Gleeson, Joseph G.
author_facet Friedman, Jennifer
Smith, Desiree E.
Issa, Mahmoud Y.
Stanley, Valentina
Wang, Rengang
Mendes, Marisa I.
Wright, Meredith S.
Wigby, Kristen
Hildreth, Amber
Crawford, John R.
Koehler, Alanna E.
Chowdhury, Shimul
Nahas, Shareef
Zhai, Liting
Xu, Zhiwen
Lo, Wing-Sze
James, Kiely N.
Musaev, Damir
Accogli, Andrea
Guerrero, Kether
Tran, Luan T.
Omar, Tarek E. I.
Ben-Omran, Tawfeg
Dimmock, David
Kingsmore, Stephen F.
Salomons, Gajja S.
Zaki, Maha S.
Bernard, Geneviève
Gleeson, Joseph G.
author_sort Friedman, Jennifer
collection PubMed
description Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.
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spelling pubmed-63726412019-02-14 Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy Friedman, Jennifer Smith, Desiree E. Issa, Mahmoud Y. Stanley, Valentina Wang, Rengang Mendes, Marisa I. Wright, Meredith S. Wigby, Kristen Hildreth, Amber Crawford, John R. Koehler, Alanna E. Chowdhury, Shimul Nahas, Shareef Zhai, Liting Xu, Zhiwen Lo, Wing-Sze James, Kiely N. Musaev, Damir Accogli, Andrea Guerrero, Kether Tran, Luan T. Omar, Tarek E. I. Ben-Omran, Tawfeg Dimmock, David Kingsmore, Stephen F. Salomons, Gajja S. Zaki, Maha S. Bernard, Geneviève Gleeson, Joseph G. Nat Commun Article Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes. Nature Publishing Group UK 2019-02-12 /pmc/articles/PMC6372641/ /pubmed/30755602 http://dx.doi.org/10.1038/s41467-018-07067-3 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Friedman, Jennifer
Smith, Desiree E.
Issa, Mahmoud Y.
Stanley, Valentina
Wang, Rengang
Mendes, Marisa I.
Wright, Meredith S.
Wigby, Kristen
Hildreth, Amber
Crawford, John R.
Koehler, Alanna E.
Chowdhury, Shimul
Nahas, Shareef
Zhai, Liting
Xu, Zhiwen
Lo, Wing-Sze
James, Kiely N.
Musaev, Damir
Accogli, Andrea
Guerrero, Kether
Tran, Luan T.
Omar, Tarek E. I.
Ben-Omran, Tawfeg
Dimmock, David
Kingsmore, Stephen F.
Salomons, Gajja S.
Zaki, Maha S.
Bernard, Geneviève
Gleeson, Joseph G.
Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
title Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
title_full Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
title_fullStr Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
title_full_unstemmed Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
title_short Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
title_sort biallelic mutations in valyl-trna synthetase gene vars are associated with a progressive neurodevelopmental epileptic encephalopathy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372641/
https://www.ncbi.nlm.nih.gov/pubmed/30755602
http://dx.doi.org/10.1038/s41467-018-07067-3
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