Biallelic variants in VARS in a family with two siblings with intellectual disability and microcephaly: case report and review of the literature.

Two male siblings ages 15 and 10 yr old had similar features of intellectual disability, developmental delay, severe speech impairment, microcephaly, prematurity, and transient elevation of liver enzymes in infancy. Exome sequencing revealed one novel (c.65C>A; p.Ala22Asp) and one ultra-rare (c.3214T>C; p.Phe1072Leu) predicted damaging missense variant in trans in the gene encoding cytoplasmic valyl-tRNA synthetase (VARS). Biallelic variants in VARS have previously been associated with a neurodevelopmental disorder characterized by microcephaly, seizures, and cortical atrophy (NDMSCA; MIM #617802). Although our patients have no history of seizures or cortical atrophy, we suggest that the biallelic variants in VARS p.Ala22Asp and p.Phe1072Leu in this family are likely pathogenic and associated with NDMSCA, expanding the clinical phenotype of the condition.

Defective valyl-tRNA synthetase hampers the mitochondrial respiratory chain in Neurospora crassa.

Respiratory chain deficiency can result from alterations in mitochondrial and/or cytosolic protein synthesis due to the dual genetic origin of mitochondrial oxidative phosphorylation. In the present paper we report a point mutation (D750G) in the bifunctional VARS (valyl-tRNA synthetase) of the fungus Neurospora crassa, associated with a temperature-sensitive phenotype. Analysis of the mutant strain revealed decreased steady-state levels of VARS and a clear reduction in the rate of mitochondrial protein synthesis. We observed a robust induction of the mitochondrial alternative oxidase with a concomitant decrease in the canonical respiratory pathway, namely in cytochrome b and aa3 content. Furthermore, the mutant strain accumulates the peripheral arm of complex I and depicts decreased levels of complexes III and IV, consistent with severe impairment of the mitochondrial respiratory chain. The phenotypic alterations of the mutant strain are observed at the permissive growth temperature and exacerbated upon increase of the temperature. Surprisingly, glucose-6-phosphate dehydrogenase activities were similar in the wild-type and mutant strains, whereas mitochondrial activities for succinate dehydrogenase and alternative NADH dehydrogenases were increased in the mutant strain, suggesting that the VARSD-G mutation does not affect overall cytosolic protein synthesis. Expression of the wild-type vars gene rescues all of the mutant phenotypes, indicating that the VARSD-G mutation is a loss-of-function mutation that results in a combined respiratory chain deficiency.

A present-day aminoacyl-tRNA synthetase with ancestral editing properties.

Leucyl-, isoleucyl-, and valyl-tRNA synthetases form a subgroup of related aminoacyl-tRNA synthetases that attach similar amino acids to their cognate tRNAs. To prevent amino acid misincorporation during translation, these enzymes also hydrolyze mischarged tRNAs through a post-transfer editing mechanism. Here we show that LeuRS from the deep-branching bacterium Aquifex aeolicus edits the complete set of aminoacylated tRNAs generated by the three enzymes: Ile-tRNA(Ile), Val-tRNA(Ile), Val-tRNA(Val), Thr-tRNA(Val), and Ile-tRNA(Leu). This unusual enlarged editing property was studied in a model of a primitive editing system containing a composite minihelix carrying the triple leucine, isoleucine, and valine identity mimicking the primitive tRNA precursor. We found that the freestanding LeuRS editing domain can edit this precursor in contrast to IleRS and ValRS editing domains. These results suggest that A. aeolicus LeuRS carries editing properties that seem more primitive than those of IleRS and ValRS. They suggest that the A. aeolicus editing domain has preserved the ambiguous editing property from the ancestral common editing domain or, alternatively, that this plasticity results from a specific metabolic adaptation.