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Kopajtich, R. ; Nicholls, T.J.* ; Rorbach, J.* ; Metodiev, M.D.* ; Freisinger, P.* ; Mandel, H.* ; Vanlander, A.* ; Ghezzi, D.* ; Carrozzo, R.* ; Taylor, R.W.* ; Marquard, K.* ; Murayama, K.* ; Wieland, T. ; Schwarzmayr, T. ; Mayr, J.A.* ; Pearce, S.F.* ; Powell, C.A.* ; Saada, A.* ; Ohtake, A.* ; Invernizzi, F.* ; Lamantea, E.* ; Sommerville, E.W.* ; Pyle, A.* ; Chinnery, P.F.* ; 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, T.M. ; Meitinger, T. ; Bertini, E.S.* ; van Coster, R.* ; Klopstock, T.* ; Rotig, A.* ; Haack, T.B. ; Minczuk, M.* ; Prokisch, H.

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

Am. J. Hum. Genet. 59, 708-720 (2014)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
ISSN (print) / ISBN 0002-9297
e-ISSN 1537-6605
Zeitschrift American Journal of Human Genetics, The
Quellenangaben Band: 59, Heft: 6, Seiten: 708-720 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort New York, NY
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)