期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 95, 期 6, 页码 708-720出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2014.10.017
关键词
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资金
- Deutsche Forschungsgemeinschaft [EXC 1010]
- German Bundesministerium fur Bildung und Forschung (BMBF) through E-Rare project GENOMIT [01GM1207, 2011-RARE-005-03, J41J11000420001, FWF I 920-B13]
- German Network for Mitochondrial Disorders [mito-NET 01GM1113C, 01GM1113A]
- German Center for Heart Research [Z76010017300, Z56010015300]
- European Commission [N261123]
- Medical Research Council, UK [MC_U105697135]
- Wellcome Trust [096919/Z/11/Z]
- MRC Centre for Neuromuscular Diseases [G0601943]
- UK NHS
- Fund for Scientific Research Belgium (FWO) [G.0200.10]
- Fondazione Telethon [GGP11011, GPP10005]
- Italian Ministry of Health [GR2010-2316392]
- CARIPLO [2011/0526]
- Pierfranco and Luisa Mariani Foundation
- Italian Association of Mitochondrial Disease Patients and Families (Mitocon)
- Research Program of Innovative Cell Biology by Innovative Technology (Cell Innovation)
- Promotion and Mutual Aid Corporation for Private Schools of Japan from MEXT
- Ministry of Health, Labour and Welfare of Japan
- Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics
- Association Francaise contre les Myopathies (AFM)
- AFM [16615]
- MRC [MC_U105697135, G0601943, MC_UP_1002/1] Funding Source: UKRI
- Austrian Science Fund (FWF) [I 920] Funding Source: researchfish
- Medical Research Council [MC_UP_1002/1, MC_U105697135, G0601943, 1594369] Funding Source: researchfish
- Wellcome Trust [101876/B/13/Z] Funding Source: researchfish
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.
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