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

Jennifer Friedman, Desiree E. Smith, Mahmoud Y. Issa, Valentina Stanley, Rengang Wang, Marisa I. Mendes, Meredith S. Wright, Kristen Wigby, Amber Hildreth, John R. Crawford, Alanna E. Koehler, Shimul Chowdhury, Shareef Nahas, Liting Zhai, Zhiwen Xu, Wing-Sze Lo, Kiely N. James, Damir Musaev, Andrea Accogli, Kether Guerrero & 9 others Luan T. Tran, Tarek E. I. Omar, Tawfeg Ben-Omran, David Dimmock, Stephen F. Kingsmore, Gajja S. Salomons, Maha S. Zaki, Geneviève Bernard, Joseph G. Gleeson

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
Article number707
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019

Cite this

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. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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title = "Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy",
abstract = "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.",
author = "Jennifer Friedman and Smith, {Desiree E.} and Issa, {Mahmoud Y.} and Valentina Stanley and Rengang Wang and Mendes, {Marisa I.} and Wright, {Meredith S.} and Kristen Wigby and Amber Hildreth and Crawford, {John R.} and Koehler, {Alanna E.} and Shimul Chowdhury and Shareef Nahas and Liting Zhai and Zhiwen Xu and Wing-Sze Lo and James, {Kiely N.} and Damir Musaev and Andrea Accogli and Kether Guerrero and Tran, {Luan T.} and Omar, {Tarek E. I.} and Tawfeg Ben-Omran and David Dimmock and Kingsmore, {Stephen F.} and Salomons, {Gajja S.} and Zaki, {Maha S.} and Genevi{\`e}ve Bernard and Gleeson, {Joseph G.}",
year = "2019",
doi = "10.1038/s41467-018-07067-3",
language = "English",
volume = "10",
journal = "Nature Communications",
issn = "2041-1723",
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Friedman, J, Smith, DE, Issa, MY, Stanley, V, Wang, R, Mendes, MI, Wright, MS, Wigby, K, Hildreth, A, Crawford, JR, Koehler, AE, Chowdhury, S, Nahas, S, Zhai, L, Xu, Z, Lo, W-S, James, KN, Musaev, D, Accogli, A, Guerrero, K, Tran, LT, Omar, TEI, Ben-Omran, T, Dimmock, D, Kingsmore, SF, Salomons, GS, Zaki, MS, Bernard, G & Gleeson, JG 2019, 'Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy' Nature Communications, vol. 10, no. 1, 707. https://doi.org/10.1038/s41467-018-07067-3

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.

In: Nature Communications, Vol. 10, No. 1, 707, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy

AU - Friedman, Jennifer

AU - Smith, Desiree E.

AU - Issa, Mahmoud Y.

AU - Stanley, Valentina

AU - Wang, Rengang

AU - Mendes, Marisa I.

AU - Wright, Meredith S.

AU - Wigby, Kristen

AU - Hildreth, Amber

AU - Crawford, John R.

AU - Koehler, Alanna E.

AU - Chowdhury, Shimul

AU - Nahas, Shareef

AU - Zhai, Liting

AU - Xu, Zhiwen

AU - Lo, Wing-Sze

AU - James, Kiely N.

AU - Musaev, Damir

AU - Accogli, Andrea

AU - Guerrero, Kether

AU - Tran, Luan T.

AU - Omar, Tarek E. I.

AU - Ben-Omran, Tawfeg

AU - Dimmock, David

AU - Kingsmore, Stephen F.

AU - Salomons, Gajja S.

AU - Zaki, Maha S.

AU - Bernard, Geneviève

AU - Gleeson, Joseph G.

PY - 2019

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N2 - 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.

AB - 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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