Aminoacyl-tRNA Synthetases: Variant Classification, Functional Assays, and Emerging Therapeutic Strategies.

M I Mendes, D E Smith, V Spek, A M Bosch, W E Corpeleijn, M Engelen, S A Fuchs, A Hadchouel, I U Heinemann, R H Houtkooper, E M M Hoytema van Konijnenburg, S Kemp, M Langeveld, C D M Karnebeek, A Pop, V M Siu, N I Wolf, G S Salomons

Journal: Journal of inherited metabolic disease 2026;49(3):e70184

PMID: 42028791

View on PubMed

Abstract

Aminoacyl-tRNA synthetases (aaRS) are essential enzymes that charge tRNAs with their corresponding amino acids, playing a critical role in protein synthesis. All 37 nuclear-encoded ARS genes, comprising both cytosolic (ARS1) and mitochondrial (ARS2) isoforms, have now been linked to human disease. Pathogenic variants in these genes cause a wide range of phenotypes, from dominant peripheral neuropathies to recessive multisystemic disorders. Despite the high number of ARS variants identified, functional validation remains difficult, with over 80% of missense variants classified as VUS in public databases. Additionally, the role of non-canonical aaRS functions in disease remains an area requiring further exploration. Our laboratory developed a high-throughput LC-MS/MS-based aminoacylation assay to measure aaRS activity in patient-derived fibroblasts, aiding in variant classification. This functional approach has contributed to the diagnosis of nearly 200 patients and has uncovered complex variant effects, including thermolabile and splicing-defective forms. Therapeutically, amino acid supplementation and dietary interventions have shown effect in select cases, while gene therapy is being explored for dominant ARS-related neuropathies. Amenability to targeted interventions further underlines the need for correct interpretation of genetic variants, which are increasingly recognized as genetic testing is progressively used in the diagnostic work-up and functional assays. Additionally, natural history studies are essential to improve diagnosis, understand disease mechanisms, and guide and evaluate personalized treatment. This review underscores the critical need for integrated genomic and functional approaches to advance variant interpretation and therapeutic development in the era of NGS.

Address: Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands.; Amsterdam Gastroenterology Endocrinology and Metabolism (AGEM), Amsterdam, the Netherlands.; Amsterdam Gastroenterology Endocrinology and Metabolism (AGEM), Amsterdam, the Netherlands.; Department of Pediatrics, Division of Metabolic Diseases, Amsterdam UMC Location University of Amsterdam, Emma Children's Hospital, Amsterdam, the Netherlands.; Amsterdam Gastroenterology Endocrinology and Metabolism (AGEM), Amsterdam, the Netherlands.; Department of Pediatrics, Division of Metabolic Diseases, Amsterdam UMC Location University of Amsterdam, Emma Children's Hospital, Amsterdam, the Netherlands.; Amsterdam Cardiovascular Sciences Institute, Amsterdam, the Netherlands.; Department of Child Neurology, Emma's Children's Hospital, Amsterdam UMC Location Vrije Universiteit, Amsterdam, the Netherlands.; Amsterdam Leukodystrophy Center, Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Amsterdam, the Netherlands.; Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands.; AP-HP, Hôpital Universitaire Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l'Enfant, INSERM U1151 INEM, Université Paris Cité, Paris, France.; Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, Canada.; Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands.; Amsterdam Gastroenterology Endocrinology and Metabolism (AGEM), Amsterdam, the Netherlands.; Emma Center for Personalized Medicine, Amsterdam UMC, Amsterdam, the Netherlands.; Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands.; Amsterdam Gastroenterology Endocrinology and Metabolism (AGEM), Amsterdam, the Netherlands.; Department of Pediatrics, Division of Metabolic Diseases, Amsterdam UMC Location University of Amsterdam, Emma Children's Hospital, Amsterdam, the Netherlands.; Department of Endocrinology and Metabolism, Amsterdam University Medical Center, Location University of Amsterdam, Amsterdam, the Netherlands.; Department of Pediatrics and Human Genetics, Emma Center for Personalized Medicine, Amsterdam Reproduction and Development, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands.; United for Metabolic Diseases, Amsterdam, the Netherlands.; Division of Medical Genetics, Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.; Child Health Research Institute, London, Ontario, Canada.; Laboratory Genetic Metabolic Diseases, Department of Laboratory Medicine, Amsterdam UMC Location University of Amsterdam, Amsterdam, the Netherlands.; Amsterdam Gastroenterology Endocrinology and Metabolism (AGEM), Amsterdam, the Netherlands.; Department of Pediatrics, Division of Metabolic Diseases, Amsterdam UMC Location University of Amsterdam, Emma Children's Hospital, Amsterdam, the Netherlands.

DOI: 10.1002/jimd.70184

MeSH Terms: Humans, Amino Acyl-tRNA Synthetases