VARS1 mutations associated with neurodevelopmental disorder are located on a short amino acid stretch of the anticodon-binding domain

• Published in: Turkish journal of biology Vol. 46; no. 6; pp. 458 - 464
• Main Authors: Hiz, Semra, Kiliç, Seval, Bademci, Güney, Karakulak, Tülay, Erdoğan, Aybike, Özden, Burcu, Eresen, Çiğdem, Erdal, Esra, Yiş, Uluç, Tekin, Mustafa, Karakülah, Gökhan, Karaca, Ezgi, Öztürk, Mehmet
• Format: Journal Article
• Language: English
• Published: Turkey Scientific and Technological Research Council of Turkey (TUBITAK) 01-01-2022
• Subjects: psychomotor retardation; structural modeling; protein stability; whole exome sequencing; VARS1; mutation modeling
• ISSN: 1300-0152; 1303-6092; 1300-0152
• DOI: 10.55730/1300-0152.2631

Majority of 37 human aminoacyl tRNA synthetases have been incriminated in diverse, mostly recessive, genetic diseases. In accordance with this, we uncovered a novel homozygous valyl-tRNA synthetase 1 (
) gene variant, leading to p.T1068M mutation. As in the previously reported
mutations, the affected individual harboring p.T1068M was experiencing a neurodevelopmental disorder with intractable seizures, psychomotor retardation, and microcephaly. To link this phenotypic outcome with the observed genotype, we structurally modeled human
and interpreted p.T1068M within the spatial distribution of previously reported
variants. As a result, we uncovered that p.T1068M is clustered with three other pathogenic mutations in a 15 amino acid long stretch of the VARS1 anticodon-binding domain. While forming a helix-turn-helix motif within the anticodon-binding domain, this stretch harbors one-fourth of the reported
mutations. Here, we propose that these clustered mutations can destabilize the interactions between the anticodon-binding and the tRNA synthetase domains and thus hindering the optimal enzymatic activity of
. We expect that the depiction of this mutation cluster will pave the way for the development of drugs, capable of alleviating the functional impact of these mutations.