Functional consequences of mitochondrial tRNA Trp and tRNA Arg mutations causing combined OXPHOS defects.
until further notice
Number of pages
SourceEuropean Journal of Human Genetics, 18, 3, (2010), pp. 324-329
01 maart 2010
Article / Letter to editor
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Paediatrics - OUD tm 2017
Laboratory of Genetic, Endocrine and Metabolic Diseases
European Journal of Human Genetics
SubjectBio-Molecular Chemistry; IGMD 8: Mitochondrial medicine; NCMLS 4: Energy and redox metabolism
Combined oxidative phosphorylation (OXPHOS) system deficiencies are a group of mitochondrial disorders that are associated with a range of clinical phenotypes and genetic defects. They occur in approximately 30% of all OXPHOS disorders and around 4% are combined complex I, III and IV deficiencies. In this study we present two mutations in the mitochondrial tRNA(Trp) (MT-TW) and tRNA(Arg) (MT-TR) genes, m.5556G>A and m.10450A>G, respectively, which were detected in two unrelated patients showing combined OXPHOS complex I, III and IV deficiencies and progressive multisystemic diseases. Both mitochondrial tRNA mutations were almost homoplasmic in fibroblasts and muscle tissue of the two patients and not present in controls. Patient fibroblasts showed a general mitochondrial translation defect. The mutations resulted in lowered steady-state levels and altered conformations of the tRNAs. Cybrid cell lines showed similar tRNA defects and impairment of OXPHOS complex assembly as patient fibroblasts. Our results show that these tRNA(Trp) and tRNA(Arg) mutations cause the combined OXPHOS deficiencies in the patients, adding to the still expanding group of pathogenic mitochondrial tRNA mutations.
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