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@ARTICLE{Kopajtich:137692,
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
Invernizzi, 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, Marlène and Feillet, François and Mousson
de Camaret, Bénédict and Chretien, Dominique and Munnich,
Arnold and Menten, Björn and Sante, Tom and Smet, Joél and
Régal, 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 Rötig, Agnès and Haack, Tobias B and Minczuk, Michal
and Prokisch, Holger},
title = {{M}utations in {GTPBP}3 cause a mitochondrial translation
defect associated with hypertrophic cardiomyopathy, lactic
acidosis, and encephalopathy.},
journal = {The American journal of human genetics},
volume = {95},
number = {6},
issn = {0002-9297},
address = {New York, NY},
publisher = {Elsevier},
reportid = {DZNE-2020-04014},
pages = {708-720},
year = {2014},
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.},
keywords = {Acidosis, Lactic: genetics / Acidosis, Lactic:
physiopathology / Amino Acid Sequence / Brain: pathology /
Brain Diseases: genetics / Brain Diseases: physiopathology /
Cardiomyopathy, Hypertrophic: genetics / Cardiomyopathy,
Hypertrophic: physiopathology / Cell Line / Child / Child,
Preschool / Consanguinity / Female / Fibroblasts /
GTP-Binding Proteins: genetics / GTP-Binding Proteins:
metabolism / Humans / Infant / Infant, Newborn / Male /
Molecular Sequence Data / Mutation / Pedigree / Protein
Biosynthesis / Protein Processing, Post-Translational / RNA
Interference / RNA, Transfer: genetics / RNA, Transfer:
metabolism / Sequence Alignment / RNA, Transfer (NLM
Chemicals) / GTP-Binding Proteins (NLM Chemicals) / GTPBP3
protein, human (NLM Chemicals)},
cin = {AG Levin},
ddc = {570},
cid = {I:(DE-2719)1111016},
pnm = {344 - Clinical and Health Care Research (POF3-344)},
pid = {G:(DE-HGF)POF3-344},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:25434004},
pmc = {pmc:PMC4259976},
doi = {10.1016/j.ajhg.2014.10.017},
url = {https://pub.dzne.de/record/137692},
}