title: TRMT5 Mutations Cause a Defect in Post-transcriptional Modification of Mitochondrial tRNA Associated with Multiple Respiratory-Chain Deficiencies.
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.
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, CB2 0XY Cambridge, UK.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Powell
authors.affiliation: 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.
authors.forename: Robert
authors.initials: R
authors.lastname: Kopajtich
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, CB2 0XY Cambridge, UK.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: D'Souza
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, CB2 0XY Cambridge, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Rorbach
authors.affiliation: 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.
authors.forename: Laura S
authors.initials: LS
authors.lastname: Kremer
authors.affiliation: Department of Neuropediatrics, Jena University Hospital, 07740 Jena, Germany.
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Husain
authors.affiliation: Department of Life Sciences, University of Parma, 43124 Parma, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Dallabona
authors.affiliation: Department of Life Sciences, University of Parma, 43124 Parma, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Donnini
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Alston
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, NE1 3BZ Newcastle upon Tyne, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, NE1 3BZ Newcastle upon Tyne, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, NE1 3BZ Newcastle upon Tyne, UK.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: 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.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: 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.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.affiliation: Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Centre, 6500HB Nijmegen, the Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Department of Neuropediatrics and the NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schottmann
authors.affiliation: Department of Neuropediatrics and the NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schuelke
authors.affiliation: 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.
authors.forename: Nadine
authors.initials: N
authors.lastname: Romain
authors.affiliation: 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.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Haller
authors.affiliation: Department of Life Sciences, University of Parma, 43124 Parma, Italy.
authors.forename: Ileana
authors.initials: I
authors.lastname: Ferrero
authors.affiliation: 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.
authors.forename: Tobias B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, NE2 4HH Newcastle upon Tyne, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: 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.
authors.forename: Holger
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Mitochondrial Biology Unit, Medical Research Council, CB2 0XY Cambridge, UK. Electronic address: michal.minczuk@mrc-mbu.cam.ac.uk.
authors.forename: Michal
authors.initials: M
authors.lastname: Minczuk
mesh_terms: D000595:Amino Acid Sequence; D020029:Base Pairing; D001483:Base Sequence; D059472:Exome / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D012343:RNA, Transfer / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012359:tRNA Methyltransferases / Q000737:chemistry / Q000235:genetics*
chemical_list: D012343:RNA, Transfer; D012359:tRNA Methyltransferases; C489294:TRMT5 protein, human