title: Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy.
abstract: Respiratory chain deficiencies exhibit a wide variety of clinical phenotypes resulting from defective mitochondrial energy production through oxidative phosphorylation. These defects can be caused by either mutations in the mtDNA or mutations in nuclear genes coding for mitochondrial proteins. The underlying pathomechanisms can affect numerous pathways involved in mitochondrial physiology. By whole-exome and candidate gene sequencing, we identified 11 individuals from 9 families carrying compound heterozygous or homozygous mutations in GTPBP3, encoding the mitochondrial GTP-binding protein 3. Affected individuals from eight out of nine families presented with combined respiratory chain complex deficiencies in skeletal muscle. Mutations in GTPBP3 are associated with a severe mitochondrial translation defect, consistent with the predicted function of the protein in catalyzing the formation of 5-taurinomethyluridine (τm(5)U) in the anticodon wobble position of five mitochondrial tRNAs. All case subjects presented with lactic acidosis and nine developed hypertrophic cardiomyopathy. In contrast to individuals with mutations in MTO1, the protein product of which is predicted to participate in the generation of the same modification, most individuals with GTPBP3 mutations developed neurological symptoms and MRI involvement of thalamus, putamen, and brainstem resembling Leigh syndrome. Our study of a mitochondrial translation disorder points toward the importance of posttranscriptional modification of mitochondrial tRNAs for proper mitochondrial function.
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Kopajtich
authors.affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nicholls
authors.affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Joanna
authors.initials: J
authors.lastname: Rorbach
authors.affiliation: INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Metodi D
authors.initials: MD
authors.lastname: Metodiev
authors.affiliation: Department of Pediatrics, Klinikum Reutlingen, 72764 Reutlingen, Germany.
authors.forename: Peter
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authors.lastname: Freisinger
authors.affiliation: Metabolic Unit, Children's Hospital, Ramban Health Care Campus, 31096 Haifa, Israel.
authors.forename: Hanna
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authors.lastname: Mandel
authors.affiliation: Department of Pediatric Neurology and Metabolism, University Hospital Ghent, 9000 Ghent, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Vanlander
authors.affiliation: Unit of Molecular Neurogenetics, Fondazione IRCCS (Istituto di Ricovero e Cura a CarattereScientifico) Istituto Neurologico "Carlo Besta," 20126 Milan, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ghezzi
authors.affiliation: Unità di Malattie Neuromuscolari e Neurodegenerative, Laboratorio di Medicina Molecolare, Dipartimento di Neuroscienze, IRCCS Ospedale Pediatrico Bambino Gesù, 00165 Roma, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Carrozzo
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.affiliation: Department of Neuropediatrics, Klinikum Stuttgart, 70176 Stuttgart, Germany.
authors.forename: Klaus
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authors.affiliation: Department of Metabolism, Chiba Children's Hospital, Chiba 266-0007, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Murayama
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: Thomas
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authors.lastname: Wieland
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: Thomas
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authors.affiliation: Department of Pediatrics, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria.
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authors.initials: JA
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authors.affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Sarah F
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authors.affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Christopher A
authors.initials: CA
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authors.affiliation: Monique and Jacques Roboh Department of Genetic Research and the Department of Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, 91120 Jerusalem, Israel.
authors.forename: Ann
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authors.affiliation: Department of Pediatrics, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan.
authors.forename: Akira
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authors.affiliation: Unit of Molecular Neurogenetics, Fondazione IRCCS (Istituto di Ricovero e Cura a CarattereScientifico) Istituto Neurologico "Carlo Besta," 20126 Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Invernizzi
authors.affiliation: Unit of Molecular Neurogenetics, Fondazione IRCCS (Istituto di Ricovero e Cura a CarattereScientifico) Istituto Neurologico "Carlo Besta," 20126 Milan, Italy.
authors.forename: Eleonora
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authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
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authors.initials: EW
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authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Patrick F
authors.initials: PF
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authors.affiliation: Metabolic Paediatrician, National Centre for Inherited Metabolic Disorders, Temple Street Children's University Hospital, Dublin 1, Ireland.
authors.forename: Ellen
authors.initials: E
authors.lastname: Crushell
authors.affiliation: Department of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan; Department of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Department of Translational Research, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan.
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authors.affiliation: Department of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan.
authors.forename: Yoshihito
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authors.lastname: Kishita
authors.affiliation: Department of Functional Genomics & Systems Medicine, Research Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan.
authors.forename: Yoshimi
authors.initials: Y
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authors.affiliation: Departments of Pediatrics and Genetics, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Zahra
authors.initials: Z
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authors.affiliation: Departments of Pediatrics and Genetics, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Marlène
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authors.affiliation: Service de médecine infantile, Hôpitald'Enfants de Brabois, CHU de Nancy, 54511 Vandoeuvre-les Nancy, France.
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authors.initials: F
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authors.affiliation: Service des Maladies Héréditaires du Métabolisme, CHU de Lyon, 69677 Bron, France.
authors.forename: Bénédict
authors.initials: B
authors.lastname: Mousson de Camaret
authors.affiliation: INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Chretien
authors.affiliation: INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France; Departments of Pediatrics and Genetics, Hôpital Necker-Enfants Malades, 75015 Paris, France.
authors.forename: Arnold
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authors.affiliation: Center for Medical Genetics, Ghent University, Ghent University Hospital, 9000 Ghent, Belgium.
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authors.affiliation: Center for Medical Genetics, Ghent University, Ghent University Hospital, 9000 Ghent, Belgium.
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authors.affiliation: Department of Pediatric Cardiology, Ramban Medical Center, 31096 Haifa, Israel.
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authors.affiliation: Department of Pediatric Cardiology, Ramban Medical Center, 31096 Haifa, Israel.
authors.forename: Asaad
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authors.affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK; Unit of Molecular Neurogenetics, Fondazione IRCCS (Istituto di Ricovero e Cura a CarattereScientifico) Istituto Neurologico "Carlo Besta," 20126 Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Zeviani
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
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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; DZHK (German Centre for Cardiovascular Research), partner site Munich, 81675 Munich, Germany; Munich Heart Alliance, 80802 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
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authors.affiliation: Department of Pediatric Neurology and Metabolism, University Hospital Ghent, 9000 Ghent, Belgium.
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authors.affiliation: Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany; German Research Center for Neurodegenerative Diseases (DZNE), 80336 Munich, Germany; Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians-University, 80336 Munich, Germany.
authors.forename: Thomas
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authors.affiliation: INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
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authors.forename: Tobias B
authors.initials: TB
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authors.affiliation: MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK. Electronic address: michal.minczuk@mrc-mbu.cam.ac.uk.
authors.forename: Michal
authors.initials: M
authors.lastname: Minczuk
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
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mesh_terms: D000140:Acidosis, Lactic / Q000235:genetics* / Q000503:physiopathology; D000595:Amino Acid Sequence; D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics* / Q000503:physiopathology; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000503:physiopathology; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D005260:Female; D005347:Fibroblasts; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D012343:RNA, Transfer; D019204:GTP-Binding Proteins; C498989:GTPBP3 protein, human