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Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy

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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 (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.
Keywords
TRANSFER-RNA MODIFICATION, AFFECTED PATIENT FIBROBLASTS, RESPIRATORY-CHAIN, OXIDATIVE DEFECTS, GALACTOSE MEDIUM, SCREENING-TEST, CELLS, DEFICIENCIES, ANTICODON, MYOPATHY

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MLA
Kopajtich, Robert, Thomas J Nicholls, Joanna Rorbach, et al. “Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy.” AMERICAN JOURNAL OF HUMAN GENETICS 95.6 (2014): 708–720. Print.
APA
Kopajtich, R., Nicholls, T. J., Rorbach, J., Metodiev, M. D., Freisinger, P., Mandel, H., Vanlander, A., et al. (2014). Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. AMERICAN JOURNAL OF HUMAN GENETICS, 95(6), 708–720.
Chicago author-date
Kopajtich, Robert, Thomas J Nicholls, Joanna Rorbach, Metodi D Metodiev, Peter Freisinger, Hanna Mandel, Arnaud Vanlander, et al. 2014. “Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy.” American Journal of Human Genetics 95 (6): 708–720.
Chicago author-date (all authors)
Kopajtich, Robert, Thomas J Nicholls, Joanna Rorbach, Metodi D Metodiev, Peter Freisinger, Hanna Mandel, Arnaud Vanlander, Daniele Ghezzi, Rosalba Carrozzo, Robert W Taylor, Klaus Marquard, Kei Murayama, Thomas Wieland, Thomas Schwarzmayr, Johannes A Mayr, Sarah F Pearce, Christopher A Powell, Ann Saada, Akira Ohtake, Federica Invemizzi, Eleonora Lamantea, Ewen W Sommerville, Angela Pyle, Patrick F Chinnery, Ellen Crushell, Yasushi Okazaki, Masakazu Kohda, Yoshihito Kishita, Yoshimi Tokuzawa, Zahra Assouline, Marlène Rio, Francois Feillet, Bénédict Mousson de Camaret, Dominique Chretien, Arnold Munnich, Björn Menten, Tom Sante, Joél Smet, Luc Régal, Abraham Lorber, Asaad Khoury, Massimo Zeviani, Tim M Strom, Thomas Meitinger, Enrico S Bertini, Rudy Van Coster, Thomas Klopstock, Agnès Rötig, Tobias B Haack, Michal Minczuk, and Holger Prokisch. 2014. “Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy.” American Journal of Human Genetics 95 (6): 708–720.
Vancouver
1.
Kopajtich R, Nicholls TJ, Rorbach J, Metodiev MD, Freisinger P, Mandel H, et al. Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. AMERICAN JOURNAL OF HUMAN GENETICS. 2014;95(6):708–20.
IEEE
[1]
R. Kopajtich et al., “Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy,” AMERICAN JOURNAL OF HUMAN GENETICS, vol. 95, no. 6, pp. 708–720, 2014.
@article{5839319,
  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 (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.},
  author       = {Kopajtich, Robert and Nicholls, Thomas J and Rorbach, Joanna and Metodiev, Metodi D and Freisinger, Peter and Mandel, Hanna and Vanlander, Arnaud and Ghezzi, Daniele and Carrozzo, Rosalba and Taylor, Robert W and Marquard, Klaus and Murayama, Kei and Wieland, Thomas and Schwarzmayr, Thomas and Mayr, Johannes A and Pearce, Sarah F and Powell, Christopher A and Saada, Ann and Ohtake, Akira and Invemizzi, Federica and Lamantea, Eleonora and Sommerville, Ewen W and Pyle, Angela and Chinnery, Patrick F and Crushell, Ellen and Okazaki, Yasushi and Kohda, Masakazu and Kishita, Yoshihito and Tokuzawa, Yoshimi and Assouline, Zahra and Rio, Marlène and Feillet, Francois and Mousson de Camaret, Bénédict and Chretien, Dominique and Munnich, Arnold and Menten, Björn and Sante, Tom and Smet, Joél and Régal, Luc and Lorber, Abraham and Khoury, Asaad and Zeviani, Massimo and Strom, Tim M and Meitinger, Thomas and Bertini, Enrico S and Van Coster, Rudy and Klopstock, Thomas and Rötig, Agnès and Haack, Tobias B and Minczuk, Michal and Prokisch, Holger},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  keywords     = {TRANSFER-RNA MODIFICATION,AFFECTED PATIENT FIBROBLASTS,RESPIRATORY-CHAIN,OXIDATIVE DEFECTS,GALACTOSE MEDIUM,SCREENING-TEST,CELLS,DEFICIENCIES,ANTICODON,MYOPATHY},
  language     = {eng},
  number       = {6},
  pages        = {708--720},
  title        = {Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy},
  url          = {http://dx.doi.org/10.1016/j.ajhg.2014.10.017},
  volume       = {95},
  year         = {2014},
}

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