Alternative titles; symbols
HGNC Approved Gene Symbol: EEF2
SNOMEDCT: 718769009;
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:3,976,056-3,985,463 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | ?Spinocerebellar ataxia 26 | 609306 | Autosomal dominant | 3 |
The EEF2 gene encodes eukaryotic translation elongation factor-2, which is required for the translocation step in protein synthesis, where peptidyl-tRNA is moved to the next codon on mRNA from the acceptor site on the ribosome at the expense of the energy provided by hydrolysis of GTP bound to EF2 (summary by Kaneda et al., 1984 and Hekman et al., 2012).
Rapp et al. (1989) reported the complete sequence of the predicted 858-amino acid EF2 protein. Sequence comparisons revealed that the hamster, rat, and human EF2 protein sequences differ in only 8 positions.
Diphtheria toxin and Pseudomonas exotoxin A (PA toxin) inhibit protein synthesis by catalyzing covalent binding of the ADP-ribose moiety of NAD to elongation factor-2 (EF2). Class I diphtheria toxin resistance (sensitivity) is related to binding of the toxin, a function coded by chromosome 5. Class II resistance is due to a defect in protein synthesis such that EF2 is not ADP-ribosylated by diphtheria toxin or PA toxin. In one subclass this is due to a mutation in the structural gene for EF2; in a second subclass it is due to mutation in a gene for posttranslational modification of EF2 (Kaneda et al., 1984).
Ortiz et al. (2006) found that yeast strains expressing Eef2 with various mutations in the tip of domain IV displayed growth defects, sensitivity to translation inhibitors, and decreased total translation in vivo. Mutant strains showed increased -1 frameshifting. However, the mutations in domain IV of Eef2 did not affect Eef2 protein expression levels, GTP hydrolysis, or ribosome binding during translation. The authors noted that his699 of Eef2 is posttranslationally modified to diphthamide, and they found that deletion of enzymes involved in this modification led to increased -1 frameshifting. Diphthamide modification in Eef2 is also the target for Corynebacterium diphtheriae and Pseudomonas aeruginosa toxins, as ADP-ribosylation of Eef2 by these toxins inhibits Eef2 function and causes cell death. However, Eef2 domain IV mutations conferred dominant resistance to diphtheria toxin, as the mutant proteins were no longer capable of receiving the diphthamide modification.
Davydova et al. (2014) found that FAM86A (EEF2KMT; 615263) catalyzed trimethylation of EEF2 on lys525 (K525), which lies in domain III on the outer surface of a highly conserved alpha helix.
Kaneda et al. (1984) isolated cells with PA toxin resistance of the first class II type from primary cultures from human embryos. By analysis of hybrid cells constructed from these cells and mouse L cells, they showed that chromosome 19 carries the gene for the resistance, i.e., the EF2 structural locus.
By analysis of human-mouse hybrid cells, Kaneda et al. (1987) narrowed the assignment of EF2 to chromosome 19pter-q12.
In affected members of a family of Norwegian origin with autosomal dominant late-onset spinocerebellar ataxia-26 (SCA26; 609306), previously reported by Yu et al. (2005), Hekman et al. (2012) identified a heterozygous mutation in the EEF2 gene (P596H; 130610.0001). Detailed studies of the equivalent mutation in yeast (P580Y) showed that it caused impaired translocation with an increased rate of -1 programmed ribosomal frameshift read-through during translation. Yeast carrying this mutation also showed greater susceptibility to proteostatic disruption, as evidenced by a more robust activation of a reporter gene driven by unfolded protein response activation upon challenge. The results suggested that the mutation disrupted the normal mechanical processes involved in translocation, and indicated that proteostatic disruption can cause a neurodegenerative disease.
In affected members of a 5-generation family of Norwegian origin with late-onset autosomal dominant spinocerebellar ataxia-26 (SCA26; 609306), previously reported by Yu et al. (2005), Hekman et al. (2012) identified a heterozygous C-to-A transversion in exon 12 of the EEF2 gene, resulting in a pro596-to-his (P596H) substitution at a highly conserved residue in a domain critical for maintaining the reading frame during translation. The mutation was found by deep sequencing of the critical interval identified by linkage analysis on chromosome 19p13.3. The mutation was found in 24 affected individuals and 2 unaffected individuals, suggesting incomplete penetrance. The mutation was not present in the dbSNP, 1000 Genomes Project, or CEPH databases, or in 104 Norwegian control individuals. In vitro expression studies showed that the mutant protein was properly expressed, localized properly to the endoplasmic reticulum, and was able to sustain growth in a yeast model. However, detailed studies of the equivalent mutation in yeast (P580Y) showed that it caused impaired translocation with an increased rate of -1 programmed ribosomal frameshift read-through during translation. Yeast carrying this mutation also showed greater susceptibility to proteostatic disruption, as evidenced by a more robust activation of a reporter gene driven by unfolded protein response activation upon challenge. The results indicated that proteostatic disruption can cause a neurodegenerative disease.
Davydova, E., Ho, A. Y. Y., Malecki, J., Moen, A., Enserink, J. M., Jakobsson, M. E., Loenarz, C., Falnes, P. O. Identification and characterization of a novel evolutionarily conserved lysine-specific methyltransferase targeting eukaryotic translation elongation factor 2 (eEF2). J. Biol. Chem. 289: 30499-30510, 2014. [PubMed: 25231979] [Full Text: https://doi.org/10.1074/jbc.M114.601658]
Hekman, K. E., Yu, G.-Y., Brown, C. D., Zhu, H., Du, X., Gervin, K., Undlien, D. E., Peterson, A., Stevanin, G., Clark, H. B., Pulst, S. M., Bird, T. D., White, K. P., Gomez, C. M. A conserved eEF2 coding variant in SCA26 leads to loss of translational fidelity and increased susceptibility to proteostatic insult. Hum. Molec. Genet. 21: 5472-5483, 2012. [PubMed: 23001565] [Full Text: https://doi.org/10.1093/hmg/dds392]
Kaneda, Y., Hayes, H., Uchida, T., Yoshida, M. C., Okada, Y. Regional assignment of five genes on human chromosome 19. Chromosoma 95: 8-12, 1987. [PubMed: 3034518] [Full Text: https://doi.org/10.1007/BF00293835]
Kaneda, Y., Yoshida, M. C., Kohno, K., Uchida, T., Okada, Y. Chromosomal assignment of the gene for human elongation factor-2. Proc. Nat. Acad. Sci. 81: 3158-3162, 1984. [PubMed: 6427766] [Full Text: https://doi.org/10.1073/pnas.81.10.3158]
Ortiz, P. A., Ulloque, R., Kihara, G. K., Zheng, H., Kinzy, T. G. Translation elongation factor 2 anticodon mimicry domain mutants affect fidelity and diphtheria toxin resistance. J. Biol. Chem. 281: 32639-32648, 2006. [PubMed: 16950777] [Full Text: https://doi.org/10.1074/jbc.M607076200]
Rapp, G., Klaudiny, J., Hagendorff, G., Luck, M. R., Scheit, K. H. Complete sequence of the coding region of human elongation factor 2 (EF-2) by enzymatic amplification of cDNA from human ovarian granulosa cells. Biol. Chem. Hoppe Seyler 370: 1071-1075, 1989. [PubMed: 2610926] [Full Text: https://doi.org/10.1515/bchm3.1989.370.2.1071]
Yu, G.-Y., Howell, M. J., Roller, M. J., Xie, T.-D., Gomez, C. M. Spinocerebellar ataxia type 26 maps to chromosome 19p13.3 adjacent to SCA6. Ann. Neurol. 57: 349-354, 2005. [PubMed: 15732118] [Full Text: https://doi.org/10.1002/ana.20371]