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Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy

Lookup NU author(s): Dr Joanna Rorbach, Professor Robert Taylor, Ewen Sommerville, Dr Angela Pyle, Professor Patrick Chinnery


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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 (tau m(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.

Publication metadata

Author(s): Kopajtich R, Nicholls TJ, Rorbach J, Metodiev MD, Freisinger P, Mandel H, Vanlander A, Ghezzi D, Carrozzo R, Taylor RW, Marquard K, Murayama K, Wieland T, Schwarzmayr T, Mayr JA, Pearce SF, Powell CA, Saada A, Ohtake A, Invemizzi F, Lamantea E, Sommerville EW, Pyle A, Chinnery PF, Crushell E, Okazaki Y, Kohda M, Kishita Y, Tokuzawa Y, Assouline Z, Rio M, Feillet F, de Camaret BM, Chretien D, Munnich A, Menten B, Sante T, Smet J, Regal L, Lorber A, Khoury A, Zeviani M, Strom TM, Meitinger T, Bertini ES, Van Coster R, Klopstock T, Rotig A, Haack TB, Minczuk M, Prokisch H

Publication type: Article

Publication status: Published

Journal: American Journal of Human Genetics

Year: 2014

Volume: 95

Issue: 6

Pages: 708-720

Print publication date: 01/12/2014

Online publication date: 26/11/2014

Acceptance date: 29/10/2014

ISSN (print): 0002-9297

ISSN (electronic): 1537-6605

Publisher: Cell Press


DOI: 10.1016/j.ajhg.2014.10.017


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Funder referenceFunder name
Association Francaise contre les Myopathies (AFM)
Pierfranco and Luisa Mariani Foundation
Research Program of Innovative Cell Biology by Innovative Technology (Cell Innovation)
Italian Association of Mitochondrial Disease Patients and Families (Mitocon)
Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics
Ministry of Health, Labour and Welfare of Japan
Promotion and Mutual Aid Corporation for Private Schools of Japan from MEXT
01GM1113AGerman Network for Mitochondrial Disorders
01GM1207German Bundesministerium fur Bildung und Forschung (BMBF) through E-Rare project GENOMIT
096919/Z/11/ZWellcome Trust
2011-RARE-005-03German Bundesministerium fur Bildung und Forschung (BMBF) through E-Rare project GENOMIT
EXC 1010Deutsche Forschungsgemeinschaft
FWF I 920-B13German Bundesministerium fur Bildung und Forschung (BMBF) through E-Rare project GENOMIT
G.0200.10Fund for Scientific Research Belgium (FWO)
GPP10005Fondazione Telethon
GR2010-2316392Italian Ministry of Health
G0601943MRC Centre for Neuromuscular Diseases
J41J11000420001German Bundesministerium fur Bildung und Forschung (BMBF) through E-Rare project GENOMIT
GGP11011Fondazione Telethon
mito-NET 01GM1113CGerman Network for Mitochondrial Disorders
N261123European Commission
MC_U105697135Medical Research Council, UK
Z56010015300German Center for Heart Research
Z76010017300German Center for Heart Research