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

TitleMutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy.
Publication TypeJournal Article
Year of Publication2014
AuthorsKopajtich, 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, de Camaret, BMousson, 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
JournalAm J Hum Genet
Date Published2014 Dec 04
KeywordsAcidosis, Lactic, Amino Acid Sequence, Brain, Brain Diseases, Cardiomyopathy, Hypertrophic, Cell Line, Child, Child, Preschool, Consanguinity, Female, Fibroblasts, GTP-Binding Proteins, Humans, Infant, Infant, Newborn, Male, Molecular Sequence Data, Mutation, Pedigree, Protein Biosynthesis, Protein Processing, Post-Translational, RNA Interference, RNA, Transfer, Sequence Alignment

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.

Alternate JournalAm. J. Hum. Genet.
Citation Key10.1016/j.ajhg.2014.10.017
PubMed ID25434004
PubMed Central IDPMC4259976
Grant ListGGP11011 / / Telethon / Italy
101876 / / Wellcome Trust / United Kingdom
MC_UP_1002/1 / / Medical Research Council / United Kingdom
096919/Z/11/Z / / Wellcome Trust / United Kingdom
MC_U105697135 / / Medical Research Council / United Kingdom
GPP10005 / / Telethon / Italy
G0601943 / / Medical Research Council / United Kingdom