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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&gt;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&gt;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.

Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy