Journal
EUROPEAN JOURNAL OF HUMAN GENETICS
Volume 18, Issue 3, Pages 324-329Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ejhg.2009.169
Keywords
combined OXPHOS defects; mitochondrial DNA; tRNA(Trp); tRNA(Arg); molecular mechanism
Funding
- European Union [LSHMCT-2004-005260]
- Council for Chemical Sciences (NWO-CW)
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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 tRNATrp and tRNAArg mutations cause the combined OXPHOS deficiencies in the patients, adding to the still expanding group of pathogenic mitochondrial tRNA mutations. European Journal of Human Genetics (2010) 18, 324-329; doi: 10.1038/ejhg.2009.169; published online 7 October 2009
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