Document Type

Article

Publication Date

1-15-2019

Identifier

DOI: 10.1093/hmg/ddy294; PMCID: PMC6321959

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.

Journal Title

Human molecular genetics

Volume

28

Issue

2

First Page

258

Last Page

268

MeSH Keywords

Alanine-tRNA Ligase; Cardiomyopathies; Diseases in Twins; Enzyme Stability; Fibroblasts; Genes, Recessive; Humans; Infant; Lactic Acid; Male; Mitochondria; Mitochondrial Proteins; Muscle, Skeletal; Myocardium; Pedigree; Respiratory Insufficiency

Keywords

Alanine-tRNA Ligase; Cardiomyopathies; Diseases in Twins; Enzyme Stability; Fibroblasts; Genes, Recessive; Humans; Infant; Lactic Acid; Male; Mitochondria; Mitochondrial Proteins; Muscle, Skeletal; Myocardium; Pedigree; Respiratory Insufficiency

Comments

Grant support

This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Publisher's Link: https://academic.oup.com/hmg/article/28/2/258/5114638

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