The identification of a DALRD3 mutation that abolishes m3C formation in human patients with developmental delay and epileptic encephalopathy has uncovered a physiological link between the m3C modification and neurological function. This finding is intriguing because the majority of tRNA modification defects that are known to cause epileptic encephalopathies are due to alterations in mitochondrial function. For example, loss of the i6A59,60 or wobble taurine modification61–64 in mitochondrial tRNAs causes abnormal mitochondrial protein synthesis and defects in mitochondrial respiratory chain complexes that lead to developmental delay and epileptic encephalopathy. While there are no known mitochondrial tRNAs dependent upon DALRD3 for m3C formation, there could be a possible indirect impact of DALRD3-dependent tRNA modification on mitochondrial homeostasis since cytoplasmic tRNA modifications in the anticodon loop have been shown to impact mitochondrial metabolism43. The loss of arginine tRNA modification due to the DALRD3 mutation provides an avenue to explore additional biological pathways that are key to proper neurological function and perturbed in neurological disorders. Future experiments will investigate the role of DALRD3 and its associated tRNA modifications in protein translation to identify
