title: Functional consequences of mitochondrial tRNA Trp and tRNA Arg mutations causing combined OXPHOS defects.
abstract: 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.
authors.affiliation: Department of Pediatrics, Nijmegen Center for Mitochondrial Disorders, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Paulien
authors.initials: P
authors.lastname: Smits
authors.forename: Sandy
authors.initials: S
authors.lastname: Mattijssen
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Mariël
authors.initials: M
authors.lastname: van den Brand
authors.forename: Frans
authors.initials: F
authors.lastname: van den Brandt
authors.forename: Frits
authors.initials: F
authors.lastname: Wijburg
authors.forename: Ger
authors.initials: G
authors.lastname: Pruijn
authors.forename: Jan
authors.initials: J
authors.lastname: Smeitink
authors.forename: Leo
authors.initials: L
authors.lastname: Nijtmans
authors.forename: Richard
authors.initials: R
authors.lastname: Rodenburg
authors.forename: Lambert
authors.initials: L
authors.lastname: van den Heuvel
mesh_terms: 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*
chemical_list: D004272:DNA, Mitochondrial; D012346:RNA, Transfer, Amino Acyl; D042967:Electron Transport Complex I