학술논문
Biallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy.
Document Type
article
Author
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 EI; Ben-Omran, Tawfeg; Dimmock, David; Kingsmore, Stephen F; Salomons, Gajja S; Zaki, Maha S; Bernard, Geneviève; Gleeson, Joseph G
Source
Nature communications. 10(1)
Subject
Language
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.