Browse by author
Lookup NU author(s): Dr Joanna Rorbach, Professor Robert Taylor, Ewen Sommerville, Dr Angela Pyle, Professor Patrick Chinnery
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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 (tau m(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.
Author(s): Kopajtich 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, Invemizzi 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 BM, Chretien D, Munnich A, Menten B, Sante T, Smet J, Regal L, Lorber A, Khoury A, Zeviani M, Strom TM, Meitinger T, Bertini ES, Van Coster R, Klopstock T, Rotig A, Haack TB, Minczuk M, Prokisch H
Publication type: Article
Publication status: Published
Journal: American Journal of Human Genetics
Year: 2014
Volume: 95
Issue: 6
Pages: 708-720
Print publication date: 01/12/2014
Online publication date: 26/11/2014
Acceptance date: 29/10/2014
ISSN (print): 0002-9297
ISSN (electronic): 1537-6605
Publisher: Cell Press
URL: http://dx.doi.org/10.1016/j.ajhg.2014.10.017
DOI: 10.1016/j.ajhg.2014.10.017
Altmetrics provided by Altmetric