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, Luan T. Tran, Tarek E. I. Omar, Tawfeg Ben-Omran, David Dimmock, Stephen F. Kingsmore, Gajja S. Salomons, Maha S. Zaki, Geneviève Bernard and Joseph G. Gleeson ()
Additional contact information
Jennifer Friedman: University of California San Diego
Desiree E. Smith: Metabolic Unit, Amsterdam UMC (University Medical Centers), Vrije Universiteit Amsterdam
Mahmoud Y. Issa: National Research Centre
Valentina Stanley: University of California San Diego
Rengang Wang: University of California San Diego
Marisa I. Mendes: Metabolic Unit, Amsterdam UMC (University Medical Centers), Vrije Universiteit Amsterdam
Meredith S. Wright: Rady Children’s Hospital
Kristen Wigby: University of California San Diego
Amber Hildreth: University of California San Diego
John R. Crawford: University of California San Diego
Alanna E. Koehler: Howard Hughes Medical Institute, University of California, San Diego
Shimul Chowdhury: Rady Children’s Hospital
Shareef Nahas: Rady Children’s Hospital
Liting Zhai: Hong Kong University of Science and Technology
Zhiwen Xu: Hong Kong University of Science and Technology
Wing-Sze Lo: Hong Kong University of Science and Technology
Kiely N. James: University of California San Diego
Damir Musaev: University of California San Diego
Andrea Accogli: Pediatrics and Human Genetics, McGill University
Kether Guerrero: Pediatrics and Human Genetics, McGill University
Luan T. Tran: Pediatrics and Human Genetics, McGill University
Tarek E. I. Omar: Alexandria University
Tawfeg Ben-Omran: Department of Pediatrics, Hamad Medical Corporation
David Dimmock: Rady Children’s Hospital
Stephen F. Kingsmore: Rady Children’s Hospital
Gajja S. Salomons: Metabolic Unit, Amsterdam UMC (University Medical Centers), Vrije Universiteit Amsterdam
Maha S. Zaki: National Research Centre
Geneviève Bernard: Pediatrics and Human Genetics, McGill University
Joseph G. Gleeson: University of California San Diego

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-018-07067-3

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