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

Robert Kopajtich 1 Thomas Nicholls 2 Joanna Rorbach 2 Metodi d. Metodiev 3 Peter Freisinger 4 Hanna Mandel 5 Arnaud Vanlander 6 Daniele Ghezzi 7 Rosalba Carrozzo 8 Robert w. Taylor 9 Klaus Marquard 10 Kei Murayama 11 Thomas Wieland 12 Thomas Schwarzmayr 12 Johannes a. Mayr 13 Sarah f. Pearce 2 Christopher a. Powell 2 Ann Saada 14 Akira Ohtake 15 Federica Invernizzi 7 Eleonora Lamantea 7 Ewen w. Sommerville 9 Angela Pyle 9 Patrick f. Chinnery 9 Ellen Crushell 16 Yasushi Okazaki 17 Masakazu Kohda 17 Yoshihito Kishita 17 Yoshimi Tokuzawa 17 Zahra Assouline 18 Marlène Rio 18 François Feillet 19, 20 Bénédict Mousson de camaret 21 Dominique Chrétien 3 Arnold Munnich 3, 18 Björn Menten 22 Tom Sante 22 Joél Smet 6 Luc Régal 23 Abraham Lorber 5 Asaad Khoury 5 Massimo Zeviani 2, 7 Tim m. Strom 12 Thomas Meitinger 24, 25, 26 Enrico s. Bertini 8 Rudy Van coster 6 Thomas Klopstock 26, 27, 28 Agnès Rötig 3 Tobias b. Haack 12 Michal Minczuk 2 Holger Prokisch 12 
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.
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Robert Kopajtich, Thomas Nicholls, Joanna Rorbach, Metodi d. Metodiev, Peter Freisinger, et al.. Mutations in GTPBP3 Cause a Mitochondrial Translation Defect Associated with Hypertrophic Cardiomyopathy, Lactic Acidosis, and Encephalopathy. American Journal of Human Genetics, Elsevier (Cell Press), 2014, 95 (6), pp.708 - 720. ⟨10.1016/j.ajhg.2014.10.017⟩. ⟨hal-01692140⟩



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