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VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain

Majority of 37 human aminoacyl tRNA synthetases have been incriminated in diverse, mostly recessive, genetic diseases. In accordance with this, we uncovered a novel homozygous valyl-tRNA synthetase 1 (VARS1) gene variant, leading to p.T1068M mutation. As in the previously reported VARS1 mutations, t...

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Autores principales: HIZ, Semra, KILIÇ, Seval, BADEMCİ, Güney, KARAKULAK, Tülay, ERDOĞAN, Aybike, ÖZDEN, Burcu, ERESEN, Çiğdem, ERDAL, Esra, YİŞ, Uluç, TEKİN, Mustafa, KARAKÜLAH, Gökhan, KARACA, Ezgi, ÖZTÜRK, Mehmet
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Scientific and Technological Research Council of Turkey (TUBITAK) 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10388123/
https://www.ncbi.nlm.nih.gov/pubmed/37529793
http://dx.doi.org/10.55730/1300-0152.2631
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author HIZ, Semra
KILIÇ, Seval
BADEMCİ, Güney
KARAKULAK, Tülay
ERDOĞAN, Aybike
ÖZDEN, Burcu
ERESEN, Çiğdem
ERDAL, Esra
YİŞ, Uluç
TEKİN, Mustafa
KARAKÜLAH, Gökhan
KARACA, Ezgi
ÖZTÜRK, Mehmet
author_facet HIZ, Semra
KILIÇ, Seval
BADEMCİ, Güney
KARAKULAK, Tülay
ERDOĞAN, Aybike
ÖZDEN, Burcu
ERESEN, Çiğdem
ERDAL, Esra
YİŞ, Uluç
TEKİN, Mustafa
KARAKÜLAH, Gökhan
KARACA, Ezgi
ÖZTÜRK, Mehmet
author_sort HIZ, Semra
collection PubMed
description Majority of 37 human aminoacyl tRNA synthetases have been incriminated in diverse, mostly recessive, genetic diseases. In accordance with this, we uncovered a novel homozygous valyl-tRNA synthetase 1 (VARS1) gene variant, leading to p.T1068M mutation. As in the previously reported VARS1 mutations, the affected individual harboring p.T1068M was experiencing a neurodevelopmental disorder with intractable seizures, psychomotor retardation, and microcephaly. To link this phenotypic outcome with the observed genotype, we structurally modeled human VARS1 and interpreted p.T1068M within the spatial distribution of previously reported VARS1 variants. As a result, we uncovered that p.T1068M is clustered with three other pathogenic mutations in a 15 amino acid long stretch of the VARS1 anticodon-binding domain. While forming a helix-turn-helix motif within the anticodon-binding domain, this stretch harbors one-fourth of the reported VARS1 mutations. Here, we propose that these clustered mutations can destabilize the interactions between the anticodon-binding and the tRNA synthetase domains and thus hindering the optimal enzymatic activity of VARS1. We expect that the depiction of this mutation cluster will pave the way for the development of drugs, capable of alleviating the functional impact of these mutations.
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spelling pubmed-103881232023-08-01 VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain HIZ, Semra KILIÇ, Seval BADEMCİ, Güney KARAKULAK, Tülay ERDOĞAN, Aybike ÖZDEN, Burcu ERESEN, Çiğdem ERDAL, Esra YİŞ, Uluç TEKİN, Mustafa KARAKÜLAH, Gökhan KARACA, Ezgi ÖZTÜRK, Mehmet Turk J Biol Research Article Majority of 37 human aminoacyl tRNA synthetases have been incriminated in diverse, mostly recessive, genetic diseases. In accordance with this, we uncovered a novel homozygous valyl-tRNA synthetase 1 (VARS1) gene variant, leading to p.T1068M mutation. As in the previously reported VARS1 mutations, the affected individual harboring p.T1068M was experiencing a neurodevelopmental disorder with intractable seizures, psychomotor retardation, and microcephaly. To link this phenotypic outcome with the observed genotype, we structurally modeled human VARS1 and interpreted p.T1068M within the spatial distribution of previously reported VARS1 variants. As a result, we uncovered that p.T1068M is clustered with three other pathogenic mutations in a 15 amino acid long stretch of the VARS1 anticodon-binding domain. While forming a helix-turn-helix motif within the anticodon-binding domain, this stretch harbors one-fourth of the reported VARS1 mutations. Here, we propose that these clustered mutations can destabilize the interactions between the anticodon-binding and the tRNA synthetase domains and thus hindering the optimal enzymatic activity of VARS1. We expect that the depiction of this mutation cluster will pave the way for the development of drugs, capable of alleviating the functional impact of these mutations. Scientific and Technological Research Council of Turkey (TUBITAK) 2022-12-05 /pmc/articles/PMC10388123/ /pubmed/37529793 http://dx.doi.org/10.55730/1300-0152.2631 Text en © TÜBİTAK https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License.
spellingShingle Research Article
HIZ, Semra
KILIÇ, Seval
BADEMCİ, Güney
KARAKULAK, Tülay
ERDOĞAN, Aybike
ÖZDEN, Burcu
ERESEN, Çiğdem
ERDAL, Esra
YİŞ, Uluç
TEKİN, Mustafa
KARAKÜLAH, Gökhan
KARACA, Ezgi
ÖZTÜRK, Mehmet
VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain
title VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain
title_full VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain
title_fullStr VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain
title_full_unstemmed VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain
title_short VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain
title_sort vars1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10388123/
https://www.ncbi.nlm.nih.gov/pubmed/37529793
http://dx.doi.org/10.55730/1300-0152.2631
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