Alternative titles; symbols
HGNC Approved Gene Symbol: TUFM
SNOMEDCT: 766876004;
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:28,842,411-28,846,348 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p11.2 | Combined oxidative phosphorylation deficiency 4 | 610678 | Autosomal recessive | 3 |
Mitochondrial elongation factor Tu (EF-TuMT, or TUFM) is encoded in the nucleus and functions in the translational apparatus of mitochondria. Ling et al. (1997) determined the complete human TUFM cDNA sequence of 1,677 bp, including a 101-bp 5-prime untranslated region and a 207-bp 3-prime untranslated region. The predicted protein is approximately 49.8 kD and is composed of 455 amino acids, with a putative N-terminal mitochondrial leader sequence of approximately 50 amino acids. The predicted amino acid sequence shows high similarity to other EF-Tu protein sequences from yeast and bacteria. Northern blot analysis detected an approximately 1.7-kb TUFM transcript in human liver.
Mitochondrial nucleoids are large complexes containing, on average, 5 to 7 mitochondrial DNA (mtDNA) genomes and several proteins involved in mtDNA replication and transcription, as well as related processes. Bogenhagen et al. (2008) had previously shown that TUFM was associated with native purified HeLa cell nucleoids. Using a formaldehyde crosslinking technique, they found that TUFM copurified with mtDNA and was a core nucleoid protein.
Ling et al. (1997) determined that the TUFM gene contains 10 exons and spans approximately 3.6 kb.
Ling et al. (1997) assigned the TUFM gene to 16p11.2 by isotopic in situ hybridization and by PCR analysis of somatic cell hybrid DNAs. In addition, they identified and mapped an intronless pseudogene to 17q11.2. By somatic cell hybrid analysis and radiation hybrid mapping, Shah et al. (1998) confirmed the assignment of the TUFM gene to 16p11.2. They also localized a TUFM pseudogene to the centromeric region of chromosome 17.
Crystal Structure
Schmeing et al. (2009) presented the crystal structure of the Thermus thermophilus 70S ribosome complexed with EF-Tu and aminoacyl-tRNA, refined to 3.6-angstrom resolution. The structure revealed details of the tRNA distortion that allows aminoacyl-tRNA to interact simultaneously with the decoding center of the 30S subunit and EF-Tu at the factor-binding site. A series of conformational changes in EF-Tu and aminoacyl-tRNA suggested a communication pathway between the decoding center and the guanosine triphosphatase center of EF-Tu.
Voorhees et al. (2010) determined the crystal structure of elongation factor Tu (EF-Tu) and aminoacyl tRNA bound to the ribosome with a GTP analog to 3.2-angstrom resolution. EF-Tu is in its active conformation, with the catalytic his84 coordinating the nucleophilic water in position for inline attack on the gamma-phosphate of GTP. This activated conformation is due to a critical and conserved interaction of his84 with A2662 of the sarcin-ricin loop of the 23S ribosomal RNA. Liljas et al. (2011) commented on the paper of Voorhees et al. (2010), stating that their identification of his84 of EF-Tu as deprotonating the catalytic water molecule is problematic in relation to the atomic structure, and suggested that the terminal phosphate of GTP is more likely to be the proper proton acceptor. Voorhees et al. (2011) replied that the experiments and model generated by Liljas et al. (2011) were also problematic and suggested that further study is required to definitively determine the mechanism of GTP hydrolysis by EF-Tu.
Mitochondrial protein translation is a complex process performed within mitochondria by an apparatus composed of mtDNA-encoded RNAs and nuclear DNA-encoded proteins. The vast majority of mitochondrial translation defects in humans have been associated with mutations in RNA-encoding mtDNA genes. Genetic investigation involving patients with defective mitochondrial translation led Valente et al. (2007) to the discovery of novel mutations in mitochondrial elongation factor G1 (EFG1; 606639) in 1 affected baby and, for the first time, in the mitochondrial elongation factor Tu in another one. Both patients were affected by severe lactic acidosis and rapidly progressive, fatal encephalopathy, consistent with combined oxidative phosphorylation deficiency-4 (COXPD4; 610678). The EFG1-mutant patient had early-onset Leigh syndrome, whereas the EF-Tu-mutant patient had severe infantile macrocystic leukodystrophy with micropolygyria.
In 4 infants from 2 unrelated families with COXPD4, Kohda et al. (2016) identified biallelic mutations in the TUFM gene (602389.0002-602389.0003). The mutations, which were found by high-throughput exome sequencing of 142 unrelated patients with childhood-onset mitochondrial respiratory chain disorders, were confirmed by Sanger sequencing. The mutations segregated with the disorder in the families. Complementation with wildtype TUFM restored the complex I and IV assembly and complex IV activity levels in fibroblasts from 1 of the patients.
In an Italian infant with combined oxidative phosphorylation deficiency (COXPD4; 610678), Valente et al. (2007) identified a homozygous missense mutation in the TUFM gene: a 1016G-A transition causing an arg339-to-gln substitution (R339Q) in mitochondrial elongation factor Tu. The patient had an extremely severe syndrome dominated by lactic acidosis and rapidly fatal encephalopathy, with diffuse cystic leukodystrophy and micropolygyria, a developmental abnormality of the brain that occurs well before birth. Modest elevation of hepatic enzymes in blood and episodic hyperammonemia indicated mild liver involvement that never progressed to hepatic failure. Other tissues, notably the heart, were clinically spared. The patient died at age 14 months.
In 2 sibs (proband 559) with combined oxidative phosphorylation deficiency-4 (COXPD4; 610678), Kohda et al. (2016) identified a homozygous c.440T-A transversion (c.440T-A, NM_003321) in the TUFM gene, resulting in a leu147-to-his (L147H) substitution. Two similarly affected sibs (proband 622) from an unrelated family were compound heterozygous for the L147H mutation and a 1-bp deletion (c.162delC; 602389.0003), resulting in a tyr54-to-ter (Y54X) substitution. The mutations, which were found by high-throughput exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The variants were filtered against the dbSNP (build 137), Exome Sequencing Project (ESP6500), and ExAC (February 2014) databases. Complementation with wildtype TUFM restored the complex I and IV assembly defects and complex IV activity levels in fibroblasts from proband 622.
For discussion of the 1-bp deletion (c.162delC, NM_003321) in the TUFM gene, resulting in a tyr54-to-ter (Y54X) substitution, that was found in compound heterozygous state in 2 sibs with combined oxidative phosphorylation deficiency-4 (COXPD4; 610678) by Kohda et al. (2016), see 602389.0002.
Bogenhagen, D. F., Rousseau, D., Burke, S. The layered structure of human mitochondrial DNA nucleoids. J. Biol. Chem. 283: 3665-3675, 2008. [PubMed: 18063578] [Full Text: https://doi.org/10.1074/jbc.M708444200]
Kohda, M., Tokuzawa, Y., Kishita, Y., Nyuzuki, H., Moriyama, Y., Mizuno, Y., Hirata, T., Yatsuka, Y., Yamashita-Sugahara, Y., Nakachi, Y., Kato, H., Okuda, A., and 23 others. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet. 12: e1005679, 2016. Note: Electronic Article. [PubMed: 26741492] [Full Text: https://doi.org/10.1371/journal.pgen.1005679]
Liljas, A., Ehrenberg, M., Aqvist, J. Comment on 'The mechanism for activation of GTP hydrolysis on the ribosome.' Science 333: 37 only, 2011. [PubMed: 21719661] [Full Text: https://doi.org/10.1126/science.1202532]
Ling, M., Merante, F., Chen, H.-S., Duff, C., Duncan, A. M. V., Robinson, B. H. The human mitochondrial elongation factor tu (EF-Tu) gene: cDNA sequence, genomic localization, genomic structure, and identification of a pseudogene. Gene 197: 325-336, 1997. [PubMed: 9332382] [Full Text: https://doi.org/10.1016/s0378-1119(97)00279-5]
Schmeing, T. M., Voorhees, R. M., Kelley, A. C., Gao, Y.-G., Murphy, F. V., IV, Weir, J. R., Ramakrishnan, V. The crystal structure of the ribosome bound to EF-Tu and aminoacyl-tRNA. Science 326: 688-694, 2009. [PubMed: 19833920] [Full Text: https://doi.org/10.1126/science.1179700]
Shah, Z. H., Migliosi, V., Miller, S. C. M., Wang, A., Friedman, T. B., Jacobs, H. T. Chromosomal locations of three human nuclear genes (RPSM12, TUFM, and AFG3L1) specifying putative components of the mitochondrial gene expression apparatus. Genomics 48: 384-388, 1998. [PubMed: 9545647] [Full Text: https://doi.org/10.1006/geno.1997.5166]
Valente, L., Tiranti, V., Marsano, R. M., Malfatti, E., Fernandez-Vizarra, E., Donnini, C., Mereghetti, P., De Gioia, L., Burlina, A., Castellan, C., Comi, G. P., Savasta, S., Ferrero, I., Zeviani, M. Infantile encephalopathy and defective mitochondrial DNA translation in patients with mutations of mitochondrial elongation factors EFG1 and EFTu. Am. J. Hum. Genet. 80: 44-58, 2007. Note: Erratum: Am. J. Hum. Genet. 80: 580 only, 2007. [PubMed: 17160893] [Full Text: https://doi.org/10.1086/510559]
Voorhees, R. M., Schmeing, T. M., Kelley, A. C., Ramakrishnan, V. The mechanisms for activation of GTP hydrolysis on the ribosome. Science 330: 835-838, 2010. [PubMed: 21051640] [Full Text: https://doi.org/10.1126/science.1194460]
Voorhees, R. M., Schmeing, T. M., Kelley, A. C., Ramakrishnan, V. Response to comment on 'The mechanism for activation of GTP hydrolysis on the ribosome.' Science 333: 37 only, 2011. [PubMed: 21719661] [Full Text: https://doi.org/10.1126/science.1202532]