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

Am J Hum Genet. 2015 Aug 6;97(2):319-28. doi: 10.1016/j.ajhg.2015.06.011.

Christopher A Powell ¹, Robert Kopajtich ², Aaron R D'Souza ¹, Joanna Rorbach ¹, Laura S Kremer ², Ralf A Husain ³, Cristina Dallabona ⁴, Claudia Donnini ⁴, Charlotte L Alston ⁵, Helen Griffin ⁶, Angela Pyle ⁶, Patrick F Chinnery ⁶, Tim M Strom ², Thomas Meitinger ⁷, Richard J Rodenburg ⁸, Gudrun Schottmann ⁹, Markus Schuelke ⁹, Nadine Romain ¹⁰, Ronald G Haller ¹⁰, Ileana Ferrero ⁴, Tobias B Haack ², Robert W Taylor ⁵, Holger Prokisch ¹¹, Michal Minczuk ¹²

Affiliations

1 Mitochondrial Biology Unit, Medical Research Council, CB2 0XY Cambridge, UK.
2 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
3 Department of Neuropediatrics, Jena University Hospital, 07740 Jena, Germany.
4 Department of Life Sciences, University of Parma, 43124 Parma, Italy.
5 Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
6 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, NE1 3BZ Newcastle upon Tyne, UK.
7 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany; Munich Heart Alliance, German Centre for Cardiovascular Research, 81675 Munich, Germany.
8 Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Centre, 6500HB Nijmegen, the Netherlands.
9 Department of Neuropediatrics and the NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
10 Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75231, USA; Neuromuscular Center, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, Dallas, TX 75231, USA.
11 Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany. Electronic address: prokisch@helmholtz-muenchen.de.
12 Mitochondrial Biology Unit, Medical Research Council, CB2 0XY Cambridge, UK. Electronic address: michal.minczuk@mrc-mbu.cam.ac.uk.

PMID: 26189817 DOI: 10.1016/j.ajhg.2015.06.011

Abstract

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.

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