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

Jan A.M. Smeitink*, Orly Elpeleg, Hana Antonicka, Heleen Diepstra, Ann Saada, Paulien Smits, Florin Sasarman, Gert Vriend, Jasmine Jacob-Hirsch, Avraham Shaag, Gideon Rechavi, Brigitte Welling, Jürgen Horst, Richard J. Rodenburg, Bert Van Den Heuvel, Eric A. Shoubridge

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 evolutionary 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.

Original languageEnglish
Pages (from-to)869-877
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number5
StatePublished - Nov 2006
Externally publishedYes


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