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

TitleTRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies.
Publication TypeJournal Article
Year of Publication2015
AuthorsPowell, 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, Minczuk, M
JournalAm J Hum Genet
Date Published2015 Aug 06
KeywordsAmino Acid Sequence, Base Pairing, Base Sequence, Exome, Frameshift Mutation, Humans, Mitochondrial Diseases, Models, Molecular, Molecular Sequence Data, Pedigree, Polymerase Chain Reaction, RNA Processing, Post-Transcriptional, RNA, Transfer, Sequence Analysis, DNA, tRNA Methyltransferases

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.

Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2015.06.011
PubMed ID26189817
PubMed Central IDPMC4573257
Grant ListNIHR-HCS-D12-03-04 / / Department of Health / United Kingdom
GGP11011 / / Telethon / Italy
101876 / / Wellcome Trust / United Kingdom
096919/Z/11/Z / / Wellcome Trust / United Kingdom
101876/Z/13/Z / / Wellcome Trust / United Kingdom
GGP15041 / / Telethon / Italy
MC_UP_1501/2 / / Medical Research Council / United Kingdom
096919 / / Wellcome Trust / United Kingdom
G0601943 / / Medical Research Council / United Kingdom
MC_U105697135 / / Medical Research Council / United Kingdom