Advanced search
1 file | 1.07 MB

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

Author
Organization
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

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 1.07 MB

Citation

Please use this url to cite or link to this publication:

Chicago
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.
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.
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.
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.
@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, Marl{\`e}ne and Feillet, Francois and Mousson de Camaret, B{\'e}n{\'e}dict and Chretien, Dominique and Munnich, Arnold and Menten, Bj{\"o}rn and Sante, Tom and Smet, Jo{\'e}l and R{\'e}gal, 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 R{\"o}tig, Agn{\`e}s and Haack, Tobias B and Minczuk, Michal and Prokisch, Holger},
  issn         = {0002-9297},
  journal      = {AMERICAN JOURNAL OF HUMAN GENETICS},
  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},
}

Altmetric
View in Altmetric
Web of Science
Times cited: