TY  - JOUR
AU  - Kopajtich, Robert
AU  - Nicholls, Thomas J
AU  - Rorbach, Joanna
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
AU  - Haack, Tobias B
AU  - Minczuk, Michal
AU  - Prokisch, Holger
TI  - Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy.
JO  - The American journal of human genetics
VL  - 95
IS  - 6
SN  - 0002-9297
CY  - New York, NY
PB  - Elsevier
M1  - DZNE-2020-04014
SP  - 708-720
PY  - 2014
AB  - 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.
KW  - Acidosis, Lactic: genetics
KW  - Acidosis, Lactic: physiopathology
KW  - Amino Acid Sequence
KW  - Brain: pathology
KW  - Brain Diseases: genetics
KW  - Brain Diseases: physiopathology
KW  - Cardiomyopathy, Hypertrophic: genetics
KW  - Cardiomyopathy, Hypertrophic: physiopathology
KW  - Cell Line
KW  - Child
KW  - Child, Preschool
KW  - Consanguinity
KW  - Female
KW  - Fibroblasts
KW  - GTP-Binding Proteins: genetics
KW  - GTP-Binding Proteins: metabolism
KW  - Humans
KW  - Infant
KW  - Infant, Newborn
KW  - Male
KW  - Molecular Sequence Data
KW  - Mutation
KW  - Pedigree
KW  - Protein Biosynthesis
KW  - Protein Processing, Post-Translational
KW  - RNA Interference
KW  - RNA, Transfer: genetics
KW  - RNA, Transfer: metabolism
KW  - Sequence Alignment
KW  - RNA, Transfer (NLM Chemicals)
KW  - GTP-Binding Proteins (NLM Chemicals)
KW  - GTPBP3 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25434004
C2  - pmc:PMC4259976
DO  - DOI:10.1016/j.ajhg.2014.10.017
UR  - https://pub.dzne.de/record/137692
ER  -