title: Mutations in C12orf65 in patients with encephalomyopathy and a mitochondrial translation defect.
abstract: We investigated the genetic basis for a global and uniform decrease in mitochondrial translation in fibroblasts from patients in two unrelated pedigrees who developed Leigh syndrome, optic atrophy, and ophthalmoplegia. Analysis of the assembly of the oxidative phosphorylation complexes showed severe decreases of complexes I, IV, and V and a smaller decrease in complex III. The steady-state levels of mitochondrial mRNAs, tRNAs, and rRNAs were not reduced, nor were those of the mitochondrial translation elongation factors or the protein components of the mitochondrial ribosome. Using homozygosity mapping, we identified a 1 bp deletion in C12orf65 in one patient, and DNA sequence analysis showed a different 1 bp deletion in the second patient. Both mutations predict the same premature stop codon. C12orf65 belongs to a family of four mitochondrial class I peptide release factors, which also includes mtRF1a, mtRF1, and Ict1, all characterized by the presence of a GGQ motif at the active site. However, C12orf65 does not exhibit peptidyl-tRNA hydrolase activity in an in vitro assay with bacterial ribosomes. We suggest that it might play a role in recycling abortive peptidyl-tRNA species, released from the ribosome during the elongation phase of translation.
authors.affiliation: Montreal Neurological Institute and Department of Human Genetics, McGill University, Montreal H3A 2B4, Quebec, Canada.
authors.forename: Hana
authors.initials: H
authors.lastname: Antonicka
authors.forename: Elsebet
authors.initials: E
authors.lastname: Ostergaard
authors.forename: Florin
authors.initials: F
authors.lastname: Sasarman
authors.forename: Woranontee
authors.initials: W
authors.lastname: Weraarpachai
authors.forename: Flemming
authors.initials: F
authors.lastname: Wibrand
authors.forename: Anne Marie B
authors.initials: AM
authors.lastname: Pedersen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Zofia M
authors.initials: ZM
authors.lastname: Chrzanowska-Lightowlers
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
mesh_terms: D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007888:Leigh Disease / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D024101:Mitochondrial Proteins; D009154:Mutation; D009886:Ophthalmoplegia / Q000235:genetics* / Q000378:metabolism; D009896:Optic Atrophy / Q000235:genetics* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010375:Pedigree; D010445:Peptide Elongation Factors / Q000378:metabolism; D010454:Peptide Termination Factors / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D012335:RNA, Ribosomal / Q000378:metabolism; D012343:RNA, Transfer / Q000378:metabolism; D012270:Ribosomes / Q000378:metabolism; D055815:Young Adult
chemical_list: D045222:Electron Transport Chain Complex Proteins; D024101:Mitochondrial Proteins; D010445:Peptide Elongation Factors; D010454:Peptide Termination Factors; D012333:RNA, Messenger; D012335:RNA, Ribosomal; D012343:RNA, Transfer; C551030:MTRFR protein, human