Browse by author
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.
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
URL: https://doi.org/10.1093/hmg/ddy294
DOI: 10.1093/hmg/ddy294
PubMed id: 30285085
Altmetrics provided by Altmetric
