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

Lookup NU author(s): Dr Ewen Sommerville, Dr Monika Olahova, Dr Angela Pyle, Dr Langping He, Professor Bobby McFarlandORCiD, Professor Grainne Gorman, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Sommerville EW, Zhou X-L, Olahova M, Jenkins J, Euro L, Konovalova S, Hilander T, Pyle A, He L, Habeebu S, Saunders C, Kelsey A, Morris AAM, McFarland R, Suomalainen A, Gorman GS, Wang E-D, Thiffault I, Tyynismaa H, Taylor RW

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2019

Volume: 28

Issue: 2

Pages: 258-268

Print publication date: 15/01/2019

Online publication date: 04/10/2018

Acceptance date: 07/08/2018

Date deposited: 15/01/2019

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddy294

PubMed id: 30285085


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust