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.
Highlights
Mitochondrial respiratory chain disorders are among the most common early onset metabolic disorders with an estimated minimum prevalence of 1 in 5000 live births [1]
Attachment is catalysed by mitochondrial aminoacyl-transfer RNAs (tRNAs) synthetases that are encoded by nuclear genes and imported into mitochondria
We describe two unrelated patients presenting with fatal infantile cardiomyopathy, lactic acidosis and respiratory failure, with severe multiple oxidative phosphorylation (OXPHOS) deficiency and who both harboured an unreported AARS2 variant (c.1738C>T, p.Arg580Trp) in trans with a loss-of-function AARS2 variant, but not the recurrent p.Arg592Trp founder mutation
Summary
Mitochondrial respiratory chain disorders are among the most common early onset metabolic disorders with an estimated minimum prevalence of 1 in 5000 live births [1]. Disorders of mitochondrial mRNA translation or protein synthesis are especially important causes of multiple mitochondrial respiratory chain deficiency, which are linked to both mitochondrial DNA (mtDNA) and nuclear gene defects [2]. Following post-transcriptional modification, a critical step of mitochondrial protein synthesis is the aminoacylation or ‘charging’ of transfer RNAs (tRNAs) [3]. This step involves the recognition and conjugation of amino acids with their corresponding cognate mitochondrial transfer RNA (mt-tRNA), as dictated by the codon sequence. Attachment is catalysed by mitochondrial aminoacyl-tRNA synthetases (mt-aaRS) that are encoded by nuclear genes and imported into mitochondria. There are 17 mt-aaRS and two dual cytosolic-mitochondrial synthetases (GlyRS, LysRS), while mt-GluRS is required to efficiently misaminoacylate tRNAGln to form Glu-tRNAGln in mitochondria [4,5]
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