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Nat Commun. 2019 Feb 12;10(1):707. doi: 10.1038/s41467-018-07067-3.

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

Author information

1
Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA.
2
Division of Child Neurology, Rady Children's Hospital, San Diego, CA, 92123, USA.
3
Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA.
4
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA, 92123, USA.
5
Department of Clinical Chemistry, Metabolic Unit, Amsterdam UMC (University Medical Centers), Vrije Universiteit Amsterdam, 1081 HV, Amsterdam, The Netherlands.
6
Gastroenterology & Metabolism Amsterdam Neuroscience, 1081 HV, Amsterdam, The Netherlands.
7
Department of Clinical Genetics, National Research Centre, Cairo, 12311, Egypt.
8
Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, 92093, USA.
9
IAS HKUST-Scripps R&D Laboratory, Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
10
Pangu Biopharma, Edinburgh Tower, The Landmark, 15 Queen's Road Central, Hong Kong, China.
11
Departments of Neurology and Neurosurgery, Pediatrics and Human Genetics, McGill University, Montreal, H3A 0G4, Canada.
12
IRCCS Istituto Giannina Gaslini, Genova, 16147, Italy.
13
Division of Medical Genetics, Montreal Children's Hospital, McGill University Health Center, Montreal, H4A 3J1, Canada.
14
Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, H4A 3J1, Canada.
15
Department of Pediatrics, Alexandria University, Alexandria, 21526, Egypt.
16
Clinical and Metabolic Genetics, Department of Pediatrics, Hamad Medical Corporation, 3050, Doha, Qatar.
17
Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093, USA. jogleeson@ucsd.edu.
18
Division of Child Neurology, Rady Children's Hospital, San Diego, CA, 92123, USA. jogleeson@ucsd.edu.
19
Department of Pediatrics, University of California San Diego, La Jolla, CA, 92093, USA. jogleeson@ucsd.edu.
20
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA, 92123, USA. jogleeson@ucsd.edu.
21
Department of Neurosciences, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA, 92093, USA. jogleeson@ucsd.edu.

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.

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