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Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel...

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Autores principales: Siekierska, Aleksandra, Stamberger, Hannah, Deconinck, Tine, Oprescu, Stephanie N., Partoens, Michèle, Zhang, Yifan, Sourbron, Jo, Adriaenssens, Elias, Mullen, Patrick, Wiencek, Patrick, Hardies, Katia, Lee, Jeong-Soo, Giong, Hoi-Khoanh, Distelmaier, Felix, Elpeleg, Orly, Helbig, Katherine L., Hersh, Joseph, Isikay, Sedat, Jordan, Elizabeth, Karaca, Ender, Kecskes, Angela, Lupski, James R., Kovacs-Nagy, Reka, May, Patrick, Narayanan, Vinodh, Pendziwiat, Manuela, Ramsey, Keri, Rangasamy, Sampathkumar, Shinde, Deepali N., Spiegel, Ronen, Timmerman, Vincent, von Spiczak, Sarah, Helbig, Ingo, Weckhuysen, Sarah, Francklyn, Christopher, Antonellis, Anthony, de Witte, Peter, De Jonghe, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372652/
https://www.ncbi.nlm.nih.gov/pubmed/30755616
http://dx.doi.org/10.1038/s41467-018-07953-w
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author Siekierska, Aleksandra
Stamberger, Hannah
Deconinck, Tine
Oprescu, Stephanie N.
Partoens, Michèle
Zhang, Yifan
Sourbron, Jo
Adriaenssens, Elias
Mullen, Patrick
Wiencek, Patrick
Hardies, Katia
Lee, Jeong-Soo
Giong, Hoi-Khoanh
Distelmaier, Felix
Elpeleg, Orly
Helbig, Katherine L.
Hersh, Joseph
Isikay, Sedat
Jordan, Elizabeth
Karaca, Ender
Kecskes, Angela
Lupski, James R.
Kovacs-Nagy, Reka
May, Patrick
Narayanan, Vinodh
Pendziwiat, Manuela
Ramsey, Keri
Rangasamy, Sampathkumar
Shinde, Deepali N.
Spiegel, Ronen
Timmerman, Vincent
von Spiczak, Sarah
Helbig, Ingo
Weckhuysen, Sarah
Francklyn, Christopher
Antonellis, Anthony
de Witte, Peter
De Jonghe, Peter
author_facet Siekierska, Aleksandra
Stamberger, Hannah
Deconinck, Tine
Oprescu, Stephanie N.
Partoens, Michèle
Zhang, Yifan
Sourbron, Jo
Adriaenssens, Elias
Mullen, Patrick
Wiencek, Patrick
Hardies, Katia
Lee, Jeong-Soo
Giong, Hoi-Khoanh
Distelmaier, Felix
Elpeleg, Orly
Helbig, Katherine L.
Hersh, Joseph
Isikay, Sedat
Jordan, Elizabeth
Karaca, Ender
Kecskes, Angela
Lupski, James R.
Kovacs-Nagy, Reka
May, Patrick
Narayanan, Vinodh
Pendziwiat, Manuela
Ramsey, Keri
Rangasamy, Sampathkumar
Shinde, Deepali N.
Spiegel, Ronen
Timmerman, Vincent
von Spiczak, Sarah
Helbig, Ingo
Weckhuysen, Sarah
Francklyn, Christopher
Antonellis, Anthony
de Witte, Peter
De Jonghe, Peter
author_sort Siekierska, Aleksandra
collection PubMed
description Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.
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spelling pubmed-63726522019-02-14 Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish Siekierska, Aleksandra Stamberger, Hannah Deconinck, Tine Oprescu, Stephanie N. Partoens, Michèle Zhang, Yifan Sourbron, Jo Adriaenssens, Elias Mullen, Patrick Wiencek, Patrick Hardies, Katia Lee, Jeong-Soo Giong, Hoi-Khoanh Distelmaier, Felix Elpeleg, Orly Helbig, Katherine L. Hersh, Joseph Isikay, Sedat Jordan, Elizabeth Karaca, Ender Kecskes, Angela Lupski, James R. Kovacs-Nagy, Reka May, Patrick Narayanan, Vinodh Pendziwiat, Manuela Ramsey, Keri Rangasamy, Sampathkumar Shinde, Deepali N. Spiegel, Ronen Timmerman, Vincent von Spiczak, Sarah Helbig, Ingo Weckhuysen, Sarah Francklyn, Christopher Antonellis, Anthony de Witte, Peter De Jonghe, Peter Nat Commun Article Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies. Nature Publishing Group UK 2019-02-12 /pmc/articles/PMC6372652/ /pubmed/30755616 http://dx.doi.org/10.1038/s41467-018-07953-w 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
Siekierska, Aleksandra
Stamberger, Hannah
Deconinck, Tine
Oprescu, Stephanie N.
Partoens, Michèle
Zhang, Yifan
Sourbron, Jo
Adriaenssens, Elias
Mullen, Patrick
Wiencek, Patrick
Hardies, Katia
Lee, Jeong-Soo
Giong, Hoi-Khoanh
Distelmaier, Felix
Elpeleg, Orly
Helbig, Katherine L.
Hersh, Joseph
Isikay, Sedat
Jordan, Elizabeth
Karaca, Ender
Kecskes, Angela
Lupski, James R.
Kovacs-Nagy, Reka
May, Patrick
Narayanan, Vinodh
Pendziwiat, Manuela
Ramsey, Keri
Rangasamy, Sampathkumar
Shinde, Deepali N.
Spiegel, Ronen
Timmerman, Vincent
von Spiczak, Sarah
Helbig, Ingo
Weckhuysen, Sarah
Francklyn, Christopher
Antonellis, Anthony
de Witte, Peter
De Jonghe, Peter
Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
title Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
title_full Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
title_fullStr Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
title_full_unstemmed Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
title_short Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
title_sort biallelic vars variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372652/
https://www.ncbi.nlm.nih.gov/pubmed/30755616
http://dx.doi.org/10.1038/s41467-018-07953-w
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