Functional consequences of mitochondrial tRNA Trp and tRNA Arg mutations causing combined OXPHOS defects.
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.
Smits
Paulien
P
Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
Mattijssen
Sandy
S
Morava
Eva
E
van den Brand
Mariël
M
van den Brandt
Frans
F
Wijburg
Frits
F
Pruijn
Ger
G
Smeitink
Jan
J
Nijtmans
Leo
L
Rodenburg
Richard
R
van den Heuvel
Lambert
L
D001483:Base Sequence; D015152:Blotting, Northern; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D028361:Mitochondrial Diseases / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009690:Nucleic Acid Conformation; D011247:Pregnancy; D014176:Protein Biosynthesis; D012346:RNA, Transfer, Amino Acyl / Q000737:chemistry / Q000235:genetics*
D004272:DNA, Mitochondrial; D012346:RNA, Transfer, Amino Acyl; D042967:Electron Transport Complex I