TY - JOUR
T1 - Mutations in C12orf65 in Patients with Encephalomyopathy and a Mitochondrial Translation Defect
AU - Antonicka, H.
AU - Ostergaard, E.
AU - Sasarman, F.
AU - Weraarpachai, W.
AU - Wibrand, F.
AU - Pedersen, A.M.B.
AU - Rodenburg, R.J.
AU - van der Knaap, M.S.
AU - Smeitink, J.A.M.
AU - Chrzanowska-Lightowlers, ZM
AU - Shoubridge, E.A.
PY - 2010
Y1 - 2010
N2 - 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. © 2010 The American Society of Human Genetics. All rights reserved.
AB - 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. © 2010 The American Society of Human Genetics. All rights reserved.
U2 - 10.1016/j.ajhg.2010.06.004
DO - 10.1016/j.ajhg.2010.06.004
M3 - Article
SN - 0002-9297
VL - 87
SP - 115
EP - 122
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 1
ER -