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

Sommerville, EW; Zhou, X-L; Oláhová, M; Jenkins, J; Euro, L; Konovalova, S; Hilander, T; Pyle, A; He, L; Habeebu, S; et al. Sommerville, EW; Zhou, X-L; Oláhová, 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 (2019) Instability of the mitochondrial alanyl-tRNA synthetase underlies fatal infantile-onset cardiomyopathy. Hum Mol Genet, 28 (2). pp. 258-268. ISSN 1460-2083 https://doi.org/10.1093/hmg/ddy294
SGUL Authors: Hilander, Taru

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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 (COX)-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.

Item Type: Article
Additional Information: © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: 06 Biological Sciences, 11 Medical And Health Sciences, Genetics & Heredity
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Hum Mol Genet
ISSN: 1460-2083
Language: eng
Dates:
DateEvent
15 January 2019Published
4 October 2018Published Online
7 August 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
203105/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
G0800674Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
31670801National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
91440204National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
16QA140440Shanghai Rising-Star ProgramUNSPECIFIED
Y119S41291Chinese Academy of Scienceshttp://dx.doi.org/10.13039/501100002367
PubMed ID: 30285085
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/110264
Publisher's version: https://doi.org/10.1093/hmg/ddy294

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