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TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies

Lookup NU author(s): Dr Joanna Rorbach, Dr Charlotte Alston, Dr Helen GriffinORCiD, Dr Angela Pyle, Professor Patrick Chinnery, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Deficiencies in respiratory-chain complexes lead to a variety of clinical phenotypes resulting from inadequate energy production by the mitochondrial oxidative phosphorylation system. Defective expression of mtDNA-encoded genes, caused by mutations in either the mitochondrial or nuclear genome, represents a rapidly growing group of human disorders. By whole-exome sequencing, we identified two unrelated individuals carrying compound heterozygous variants in TRMT5 (tRNA methyltransferase 5). TRMT5 encodes a mitochondrial protein with strong homology to members of the class I-like methyltransferase superfamily. Both affected individuals presented with lactic acidosis and evidence of multiple mitochondrial respiratory-chain-complex deficiencies in skeletal muscle, although the clinical presentation of the two affected subjects was remarkably different; one presented in childhood with failure to thrive and hypertrophic cardiomyopathy, and the other was an adult with a life-long history of exercise intolerance. Mutations in TRMT5 were associated with the hypomodification of a guanosine residue at position 37 (G37) of mitochondrial tRNA; this hypomodification was particularly prominent in skeletal muscle. Deficiency of the G37 modification was also detected in human cells subjected to TRMT5 RNAi. The pathogenicity of the detected variants was further confirmed in a heterologous yeast model and by the rescue of the molecular phenotype after re-expression of wild-type TRMT5 cDNA in cells derived from the affected individuals. Our study highlights the importance of post-transcriptional modification of mitochondrial tRNAs for faithful mitochondrial function.

Publication metadata

Author(s): Powell CA, Kopajtich R, D'Souza AR, Rorbach J, Kremer LS, Husain RA, Dallabona C, Donnini C, Alston CL, Griffin H, Pyle A, Chinnery PF, Strom TM, Meitinger T, Rodenburg RJ, Schottmann G, Schuelke M, Romain N, Haller RG, Ferrero I, Haack TB, Taylor RW, Prokisch H, Minczukl M

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2015

Volume: 97

Issue: 2

Pages: 319-328

Print publication date: 06/08/2015

Online publication date: 16/07/2015

Acceptance date: 16/06/2015

Date deposited: 02/10/2015

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2015.06.011


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Funder referenceFunder name
Lily Foundation
UK National Health Service Highly Specialised "Rare Mitochondrial Disorders of Adults and Children" Service
01GM1113CGerman Network or Mitochondrial Disorders
01GM0866German Network or Mitochondrial Disorders
01GM1207German Bundesministerium fur Bildung und Forschung through E-Rare project GENOMIT
096919/Z/11/ZWellcome Trust Strategic Award
FKZ 01ZX1405CJuniorverbund in der Systemmedizin "mitOmics"
G0601943Medical Research Council Centre for Neuromuscular Diseases
GGP11011Telethon Italy
MC_U105697135Medical Research Council UK
NIHR-HCS-D12-03-04National Institute for Health Research doctoral fellowship
Z56010015300German Center for Heart Research
Z76010017300German Center for Heart Research