TY - JOUR
T1 - Functional consequences of mitochondrial tRNA(Trp) and tRNA(Arg) mutations causing combined OXPHOS defects
AU - Smits, Paulien
AU - Mattijssen, Sandy
AU - Morava, Eva
AU - van den Brand, Mariël
AU - van den Brandt, Frans
AU - Wijburg, Frits
AU - Pruijn, Ger
AU - Smeitink, Jan
AU - Nijtmans, Leo
AU - Rodenburg, Richard
AU - van den Heuvel, Lambert
PY - 2010
Y1 - 2010
N2 - 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
AB - 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
U2 - https://doi.org/10.1038/ejhg.2009.169
DO - https://doi.org/10.1038/ejhg.2009.169
M3 - Article
C2 - 19809478
SN - 1018-4813
VL - 18
SP - 324
EP - 329
JO - European journal of human genetics
JF - European journal of human genetics
IS - 3
ER -