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

Robert Kopajtich, 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 InvernizziEleonora Lamantea, Ewen W. Sommerville, Angela Pyle, Patrick F. Chinnery, Ellen Crushell, Yasushi Okazaki, Masakazu Kohda, Yoshihito Kishita, Yoshimi Tokuzawa, Zahra Assouline, Marlène Rio, François 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, Holger Prokisch

Research output: Contribution to journalArticle

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 (τm5U) 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.

Original languageEnglish
Pages (from-to)708-720
Number of pages13
JournalAmerican Journal of Human Genetics
Volume95
Issue number6
DOIs
Publication statusPublished - Dec 4 2014

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Lactic Acidosis
Hypertrophic Cardiomyopathy
Brain Diseases
Mutation
Mitochondrial Proteins
Electron Transport
Transfer RNA
Leigh Disease
Exome
Anticodon
Mitochondrial Diseases
Putamen
Oxidative Phosphorylation
Thalamus
Mitochondrial DNA
GTP-Binding Proteins
Genes
Brain Stem
Skeletal Muscle
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. / Kopajtich, Robert; Nicholls, Thomas J.; Rorbach, Joanna; Metodiev, Metodi D.; Freisinger, Peter; Mandel, Hanna; Vanlander, Arnaud; Ghezzi, Daniele; Carrozzo, Rosalba; Taylor, Robert W.; Marquard, Klaus; Murayama, Kei; Wieland, Thomas; Schwarzmayr, Thomas; Mayr, Johannes A.; Pearce, Sarah F.; Powell, Christopher A.; Saada, Ann; Ohtake, Akira; Invernizzi, Federica; Lamantea, Eleonora; Sommerville, Ewen W.; Pyle, Angela; Chinnery, Patrick F.; Crushell, Ellen; Okazaki, Yasushi; Kohda, Masakazu; Kishita, Yoshihito; Tokuzawa, Yoshimi; Assouline, Zahra; Rio, Marlène; Feillet, François; Mousson De Camaret, Bénédict; Chretien, Dominique; Munnich, Arnold; Menten, Björn; Sante, Tom; Smet, Joél; Régal, Luc; Lorber, Abraham; Khoury, Asaad; Zeviani, Massimo; Strom, Tim M.; Meitinger, Thomas; Bertini, Enrico S.; Van Coster, Rudy; Klopstock, Thomas; Rötig, Agnès; Haack, Tobias B.; Minczuk, Michal; Prokisch, Holger.

In: American Journal of Human Genetics, Vol. 95, No. 6, 04.12.2014, p. 708-720.

Research output: Contribution to journalArticle

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, Invernizzi, 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, Mousson De Camaret, B, Chretien, D, Munnich, A, Menten, B, Sante, T, Smet, J, Régal, L, Lorber, A, Khoury, A, Zeviani, M, Strom, TM, Meitinger, T, Bertini, ES, Van Coster, R, Klopstock, T, Rötig, A, Haack, TB, Minczuk, M & Prokisch, H 2014, '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. https://doi.org/10.1016/j.ajhg.2014.10.017
Kopajtich, Robert ; Nicholls, Thomas J. ; Rorbach, Joanna ; Metodiev, Metodi D. ; Freisinger, Peter ; Mandel, Hanna ; Vanlander, Arnaud ; Ghezzi, Daniele ; Carrozzo, Rosalba ; Taylor, Robert W. ; Marquard, Klaus ; Murayama, Kei ; Wieland, Thomas ; Schwarzmayr, Thomas ; Mayr, Johannes A. ; Pearce, Sarah F. ; Powell, Christopher A. ; Saada, Ann ; Ohtake, Akira ; Invernizzi, Federica ; Lamantea, Eleonora ; Sommerville, Ewen W. ; Pyle, Angela ; Chinnery, Patrick F. ; Crushell, Ellen ; Okazaki, Yasushi ; Kohda, Masakazu ; Kishita, Yoshihito ; Tokuzawa, Yoshimi ; Assouline, Zahra ; Rio, Marlène ; Feillet, François ; Mousson De Camaret, Bénédict ; Chretien, Dominique ; Munnich, Arnold ; Menten, Björn ; Sante, Tom ; Smet, Joél ; Régal, Luc ; Lorber, Abraham ; Khoury, Asaad ; Zeviani, Massimo ; Strom, Tim M. ; Meitinger, Thomas ; Bertini, Enrico S. ; Van Coster, Rudy ; Klopstock, Thomas ; Rötig, Agnès ; Haack, Tobias B. ; Minczuk, Michal ; Prokisch, Holger. / Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. In: American Journal of Human Genetics. 2014 ; Vol. 95, No. 6. pp. 708-720.
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AU - Kopajtich, Robert

AU - Nicholls, Thomas J.

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AU - Metodiev, Metodi D.

AU - Freisinger, Peter

AU - Mandel, Hanna

AU - Vanlander, Arnaud

AU - Ghezzi, Daniele

AU - Carrozzo, Rosalba

AU - Taylor, Robert W.

AU - Marquard, Klaus

AU - Murayama, Kei

AU - Wieland, Thomas

AU - Schwarzmayr, Thomas

AU - Mayr, Johannes A.

AU - Pearce, Sarah F.

AU - Powell, Christopher A.

AU - Saada, Ann

AU - Ohtake, Akira

AU - Invernizzi, Federica

AU - Lamantea, Eleonora

AU - Sommerville, Ewen W.

AU - Pyle, Angela

AU - Chinnery, Patrick F.

AU - Crushell, Ellen

AU - Okazaki, Yasushi

AU - Kohda, Masakazu

AU - Kishita, Yoshihito

AU - Tokuzawa, Yoshimi

AU - Assouline, Zahra

AU - Rio, Marlène

AU - Feillet, François

AU - Mousson De Camaret, Bénédict

AU - Chretien, Dominique

AU - Munnich, Arnold

AU - Menten, Björn

AU - Sante, Tom

AU - Smet, Joél

AU - Régal, Luc

AU - Lorber, Abraham

AU - Khoury, Asaad

AU - Zeviani, Massimo

AU - Strom, Tim M.

AU - Meitinger, Thomas

AU - Bertini, Enrico S.

AU - Van Coster, Rudy

AU - Klopstock, Thomas

AU - Rötig, Agnès

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AU - Minczuk, Michal

AU - Prokisch, Holger

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