Distinct clinical phenotypes associated with a mutation in the mitochondrial translation elongation factor EFTs

Am J Hum Genet. 2006 Nov;79(5):869-77. doi: 10.1086/508434. Epub 2006 Sep 15.


The 13 polypeptides encoded in mitochondrial DNA (mtDNA) are synthesized in the mitochondrial matrix on a dedicated protein-translation apparatus that resembles that found in prokaryotes. Here, we have investigated the genetic basis for a mitochondrial protein-synthesis defect associated with a combined oxidative phosphorylation enzyme deficiency in two patients, one of whom presented with encephalomyopathy and the other with hypertrophic cardiomyopathy. Sequencing of candidate genes revealed the same homozygous mutation (C997T) in both patients in TSFM, a gene coding for the mitochondrial translation elongation factor EFTs. EFTs functions as a guanine nucleotide exchange factor for EFTu, another translation elongation factor that brings aminoacylated transfer RNAs to the ribosomal A site as a ternary complex with guanosine triphosphate. The mutation predicts an Arg333Trp substitution at an evolutionarily conserved site in a subdomain of EFTs that interacts with EFTu. Molecular modeling showed that the substitution disrupts local subdomain structure and the dimerization interface. The steady-state levels of EFTs and EFTu in patient fibroblasts were reduced by 75% and 60%, respectively, and the amounts of assembled complexes I, IV, and V were reduced by 35%-91% compared with the amounts in controls. These phenotypes and the translation defect were rescued by retroviral expression of either EFTs or EFTu. These data clearly establish mutant EFTs as the cause of disease in these patients. The fact that the same mutation is associated with distinct clinical phenotypes suggests the presence of genetic modifiers of the mitochondrial translation apparatus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cells, Cultured
  • DNA Primers / genetics
  • DNA, Mitochondrial / genetics
  • Electron Transport Chain Complex Proteins / metabolism
  • Fibroblasts / metabolism
  • Humans
  • Mitochondria / genetics*
  • Mitochondria / metabolism*
  • Mitochondrial Proteins / chemistry
  • Mitochondrial Proteins / genetics*
  • Mitochondrial Proteins / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Multiprotein Complexes
  • Muscle, Skeletal / metabolism
  • Mutation*
  • Oxidative Phosphorylation
  • Peptide Elongation Factor Tu / chemistry
  • Peptide Elongation Factor Tu / genetics
  • Peptide Elongation Factor Tu / metabolism
  • Peptide Elongation Factors / chemistry
  • Peptide Elongation Factors / genetics*
  • Peptide Elongation Factors / metabolism*
  • Phenotype
  • Sequence Homology, Amino Acid


  • DNA Primers
  • DNA, Mitochondrial
  • Electron Transport Chain Complex Proteins
  • Mitochondrial Proteins
  • Multiprotein Complexes
  • Peptide Elongation Factors
  • elongation factor Ts
  • Peptide Elongation Factor Tu

Associated data

  • OMIM/604723
  • RefSeq/NM_003321
  • RefSeq/NM_005726