Aminoacyl-tRNA Synthetases in Human Genetic Diseases

Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that charge transfer RNAs with their cognate amino acids, ensuring the fidelity of protein synthesis in both cytosolic and mitochondrial compartments. Pathogenic variants in aaRS genes underlie a spectrum of human genetic diseases, ranging from peripheral neuropathies and cardiomyopathies to neurodevelopmental syndromes and mitochondrial encephalopathies. These disorders may result from loss-of-function mutations that impair aminoacylation and mitochondrial translation or from gain-of-function alleles that confer novel toxic interactions, as seen in several forms of Charcot–Marie–Tooth disease. Beyond their canonical role in translation, some aaRSs exert non-canonical functions—such as cytoskeletal regulation—that contribute to tissue-specific vulnerability. The clinical presentation is highly heterogeneous, reflecting the interplay between aaRS activity, organ-specific energy demands and specialised cellular processes. Advances in genomic technologies, coupled with functional assays in cellular and animal models, have refined diagnostic criteria and opened avenues for targeted therapies, including modulation of mitochondrial quality control, neurotrophic support and small-molecule stabilisers of mutant synthetases.

Research from Nature Portfolio

Recent studies have uncovered a novel non-canonical role of tyrosyl-tRNA synthetase (TyrRS) in organising the actin cytoskeleton. Disease-causing mutations in TyrRS enhance its actin-bundling activity, leading to disorganisation of F-actin structures in neuronal cells and models of peripheral neuropathy. Modulation of actin dynamics in vivo ameliorated electrophysiological and morphological defects, highlighting a toxic gain-of-function mechanism independent of aminoacylation. Another foundational investigation in Drosophila revealed that dominant mutations in glycyl-tRNA synthetase (GlyRS) and TyrRS slow global protein synthesis in motor and sensory neurons, triggering neuropathic phenotypes. This translational slowdown was not rescued by overexpression of wild-type enzymes, implicating a shared toxic mechanism among aaRS-linked neuropathies. Genetic or pharmacological reduction of translation alone recapitulated disease hallmarks, establishing perturbation of proteostasis as a causal driver in Charcot–Marie–Tooth pathogenesis.

Aminoacyl-tRNA Synthetases in Human Genetic Diseases publication trend

The graph below shows the total number of articles in aminoacyl-trna synthetases in human genetic diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Aminoacyl-tRNA synthetase: Enzyme that attaches a specific amino acid to its corresponding tRNA, ensuring accurate translation of the genetic code.

Aminoacylation: The biochemical reaction catalysed by aaRSs in which an amino acid is covalently linked to a tRNA molecule.

Gain-of-function mutation: Genetic alteration that confers a novel or enhanced activity on the encoded protein, potentially leading to toxic effects.

Charcot–Marie–Tooth disease (CMT): A group of inherited peripheral neuropathies characterised by progressive motor and sensory deficits due to axonal or demyelinating pathology.

Mitochondrial quality control: Cellular processes, including mitophagy and chaperone-mediated pathways, that maintain mitochondrial integrity and function.

Brain-derived neurotrophic factor (BDNF): A neurotrophin that supports neuronal survival, differentiation and axonal transport, and is explored as a therapeutic agent in neurodegenerative conditions.

References

1. FARS2 Deficiency Causes Cardiomyopathy by Disrupting Mitochondrial Homeostasis and the Mitochondrial Quality Control System. Circulation (2024).
2. Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling. Nature Communications (2023).
3. Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy. Neurobiology of Disease (2024).
4. Clinical, neuroradiological, and molecular characterization of mitochondrial threonyl-tRNA-synthetase (TARS2)-related disorder. Genetics in Medicine (2023).
5. Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases. Nature Communications (2015).