V is for valine – VARS mutations in epileptic encephalopathy

Transfer RNAs. A critical step in translating a cDNA into proteins involves transfer RNAs (tRNAs) that deliver a specific amino acid to the ribosome based on a specific codon in the messenger RNA. Thereby, tRNAs establish the physical link between the mRNA and the amino acid sequence of the growing protein, an essential cellular function. In order for tRNAs to be loaded with the appropriate amino acids, the organism has developed enzymes specific for the individual amino acids that are referred to as tRNA ligases or, more precisely, aminoacyl tRNA synthetases (aaRS). Despite the ubiquitous role of aaRS in the cell, pathogenic variants in genes coding for specific aaRS result primarily in neurological phenotypes, ranging from peripheral neuropathy to early-onset epileptic encephalopathies. In two recent back-to-back publications, bi-allelic pathogenic variants in VARS are described as a novel cause for epileptic encephalopathy, adding VARS to the list of aaRS genes linked to human disease and solving an almost decade-old mystery. Continue reading