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

• Published in: Nature communications Vol. 10; no. 1; pp. 707 - 10
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.02.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 38/88; 45/22; 45/23; 45/71; 45/77; 45/88; 631/208/2489/144; 631/208/366; 631/378/1689/2609; 692/617/375/178; 82/80; Age; Alleles; Amino acids; Aminoacyl-tRNA ligase; Anticodon; Atrophy; Child; Child, Preschool; Cortex; Disease Progression; Encephalopathy; Enzymatic activity; Epilepsy; Epilepsy - enzymology; Epilepsy - genetics; Epilepsy - pathology; Exome Sequencing; Female; Genes; Genetic Predisposition to Disease; Humanities and Social Sciences; Humans; Longitudinal Studies; Loss of Function Mutation; Male; Microcephaly - enzymology; Microcephaly - genetics; Microencephaly; Models, Molecular; multidisciplinary; Mutation; Neurodegeneration; Neurodevelopmental Disorders - enzymology; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - pathology; Pedigree; Protein Biosynthesis; Protein Interaction Domains and Motifs; Proteins; RNA, Transfer - genetics; Science; Science (multidisciplinary); Substantia alba; tRNA Val; Valine; Valine-tRNA Ligase - genetics; Whole Genome Sequencing
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07067-3

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. Valyl-tRNA synthetase (VARS) charges valyl-tRNA with the amino acid valine, required for translation. Here, the authors describe a progressive epileptic encephalopathy in individuals from five families carrying biallelic mutations in the VARS gene that leave the enzyme activity partially intact.