ArticleHuman molecular genetics2019
Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 26 citations in OpenAlex.
- White matter disorders at the intersection of transcription, RNA processing and translation.Nature reviews. Neurology · 2026Review
- Advances in Research onGenes · 2026Review
- Aminoacyl-tRNA Synthetases: Variant Classification, Functional Assays, and Emerging Therapeutic Strategies.Journal of inherited metabolic disease · 2026Review
- PCBP1 regulates alternative splicing of AARS2 in congenital cardiomyopathy.Nature cardiovascular research · 2026Article
- How RNA splicing decisions shape and break the developing heart.Nature cardiovascular research · 2026Article
- Dysfunctional Electron Transport Chain Assembly in COXPD8.Journal of cardiovascular development and disease · 2025Article
- Translational Control in Cardiac Pathophysiology and Therapeutic Development: When mRNA Meets the Heart.International journal of molecular sciences · 2025Review
- Serine mistranslation induces the integrated stress response through the P stalk.The Journal of biological chemistry · 2025Article
- Mitochondrial aminoacyl-tRNA synthetases trigger unique compensatory mechanisms in neurons.Human molecular genetics · 2024Article
- RNA granule-clustered mitochondrial aminoacyl-tRNA synthetases form multiple complexes with the potential to fine-tune tRNA aminoacylation.Nucleic acids research · 2022Article
- The Primary Microglial Leukodystrophies: A Review.International journal of molecular sciences · 2022Review
- Four pedigrees with aminoacyl-tRNA synthetase abnormalities.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2022Article
- The regulatory roles of aminoacyl-tRNA synthetase in cardiovascular disease.Molecular therapy. Nucleic acids · 2021Review
- Mitochondrial Aminoacyl-tRNA Synthetase and Disease: The Yeast Contribution for Functional Analysis of Novel Variants.International journal of molecular sciences · 2021Review
- Article
- Mitochondrial Protein Translation: Emerging Roles and Clinical Significance in Disease.Frontiers in cell and developmental biology · 2021Review
- Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases.International journal of molecular sciences · 2020Review
- Mitochondrial aminoacyl-tRNA synthetase disorders: an emerging group of developmental disorders of myelination.Journal of neurodevelopmental disorders · 2019Review
- Mitochondrial Dysfunction in Primary Ovarian Insufficiency.Endocrinology · 2019Review
- Siblings with lethal primary pulmonary hypoplasia and compound heterozygous variants in theCold Spring Harbor molecular case studies · 2019Article
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Authors and funding
20 authors at 9 institutions in 4 countries.
Funding
Abstract
Recessively inherited variants in AARS2 (NM_020745.2) encoding mitochondrial alanyl-tRNA synthetase (mt-AlaRS) were first described in patients presenting with fatal infantile cardiomyopathy and multiple oxidative phosphorylation defects. To date, all described patients with AARS2-related fatal infantile cardiomyopathy are united by either a homozygous or compound heterozygous c.1774C>T (p.Arg592Trp) missense founder mutation that is absent in patients with other AARS2-related phenotypes. We describe the clinical, biochemical and molecular investigations of two unrelated boys presenting with fatal infantile cardiomyopathy, lactic acidosis and respiratory failure. Oxidative histochemistry showed cytochrome c oxidase-deficient fibres in skeletal and cardiac muscle. Biochemical studies showed markedly decreased activities of mitochondrial respiratory chain complexes I and IV with a mild decrease of complex III activity in skeletal and cardiac muscle. Using next-generation sequencing, we identified a c.1738C>T (p.Arg580Trp) AARS2 variant shared by both patients that was in trans with a loss-of-function heterozygous AARS2 variant; a c.1008dupT (p.Asp337*) nonsense variant or an intragenic deletion encompassing AARS2 exons 5-7. Interestingly, our patients did not harbour the p.Arg592Trp AARS2 founder mutation. In silico modelling of the p.Arg580Trp substitution suggested a deleterious impact on protein stability and folding. We confirmed markedly decreased mt-AlaRS protein levels in patient fibroblasts, skeletal and cardiac muscle, although mitochondrial protein synthesis defects were confined to skeletal and cardiac muscle. In vitro data showed that the p.Arg580Trp variant had a minimal effect on activation, aminoacylation or misaminoacylation activities relative to wild-type mt-AlaRS, demonstrating that instability of mt-AlaRS is the biological mechanism underlying the fatal cardiomyopathy phenotype in our patients.
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