Alternative titles; symbols
HGNC Approved Gene Symbol: EEF1A2
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38): 20:63,488,014-63,499,083 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.33 | Developmental and epileptic encephalopathy 33 | 616409 | Autosomal dominant | 3 |
| Intellectual developmental disorder, autosomal dominant 38 | 616393 | Autosomal dominant | 3 |
The EEF1A2 gene encodes eukaryotic translation elongation factor-1, alpha-2, a protein that forms a complex with EEF1B2 (600655) and plays an essential role in protein synthesis by transporting aminoacyl-tRNA to the A-site of the ribosome. The protein likely has noncanonical functions as well (summary by Nakajima et al., 2015).
Chambers et al. (1998) used a positional cloning/positional candidate approach to isolate the wst gene, which is mutated in the 'wasted' (wst) mutant mouse (see ANIMAL MODEL), on distal chromosome 2. Because genes that map close to wst on chromosome 2 are located on distal human 20q, genes that map to 20q13 in the human were considered to be a source of new markers and/or candidate genes. One such gene encodes a protein that displays a high level of homology (92% identity) to the translation elongation factor EF1-alpha (EEF1A1; 130590) and is called EF1-alpha-2 or S1 (EEF1A2); see Ann et al. (1991) and Lund et al. (1996). EF1-alpha is distributed widely, although expression is very low or undetectable in skeletal and cardiac muscle postnatally, and expression in the brain declines between embryonic life and adulthood in rats. EF1-alpha-2 is found exclusively in terminally differentiated cells of skeletal muscle, heart, and certain areas of the brain. In those tissues where both genes are expressed, Eef1a2 is consistently more highly expressed than Eef1a. In rat muscle and heart, EF1-alpha levels declined by 95% within the first month of postnatal life; EF1-alpha-2 levels, on the other hand, increased during this period and are constant through adult life. There appears, therefore, to be some degree of reciprocal expression of the 2 genes. Although fibroblasts normally do not express Eef1a2, the mouse 3T3 fibroblast cell line does, and this line was used to study regulation of Eef1a2 at different stages of the cell cycle. It was found that the gene was highly expressed when cells were serum-starved, in G0 phase, but expression declined dramatically when cells were serum stimulated and reentered the cell cycle. Eef1a, however, was expressed at all stages of the cell cycle in this cell line (Ann et al., 1991). Whereas EEF1A2 appears to be a single-copy gene, numerous pseudogenes for EEF1A1 exist in the human genome (Lund et al., 1996).
By screening a genomic DNA library with probes derived from the 5-prime and 3-prime untranslated regions (UTRs) of EEF1A2, followed by PCR amplification, Bischoff et al. (2000) isolated the complete sequence of the EEF1A2 gene. The gene spans 12 kb, including a 2-kb upstream promoter region, and, like EEF1A1, contains 8 exons. Although the coding regions of the EEF1A genes are highly similar, the introns, UTRs, and promoter regions are highly divergent. Primer extension analysis localized the start site to an adenine 166 bp upstream of the initiator codon in exon 1. Sequence analysis revealed no TATA box but did identify a CpG island, 12 E boxes, 3 EGR-type binding sites, a GATA motif, and a MEF2 (see 600660)-binding site. Transient transfection analysis mapped the core promoter to a region spanning positions -16 to +92.
The wst gene maps within the most distal group of markers on mouse chromosome 2 (Chambers et al., 1998). This region shows syntenic homology with human chromosome 20q13.
Anand et al. (2002) found that the EEF1A2 gene is amplified in 25% of primary ovarian tumors and is highly expressed in approximately 30% of ovarian tumors and established cell lines. They also demonstrated that the EEF1A2 protein has oncogenic properties: it enhances focus formation, allows anchorage-independent growth, and decreases the doubling time of rodent fibroblasts. In addition, EEF1A2 expression made NIH 3T3 fibroblasts tumorigenic and increased the growth rate of ovarian carcinoma cells xenografted in nude mice. Thus, EEF1A2 and the process of protein elongation are likely to be critical in the development of ovarian cancer.
Developmental and Epileptic Encephalopathy 33
In a girl with developmental and epileptic encephalopathy (DEE33; 616409), de Ligt et al. (2012) identified a de novo heterozygous missense mutation in the EEF1A2 gene (G70S; 602959.0001). The patient was ascertained from a larger cohort of 100 patients with severe intellectual disability who underwent exome sequencing. Functional studies of the variant were not performed.
Veeramah et al. (2013) identified a de novo heterozygous G70S mutation in the EEF1A2 gene in a 14-year-old boy with DEE33. The patient was 1 of 10 probands with epileptic encephalopathy who underwent whole-exome sequencing. Functional studies of the variant were not performed.
Autosomal Dominant Intellectual Developmental Disorder 38
In 2 unrelated Japanese girls with autosomal dominant intellectual developmental disorder-38 (MRD38; 616393), Nakajima et al. (2015) identified different de novo heterozygous mutations in the EEF1A2 gene (D252H, 602959.0002 and E122K, 602959.0003). The mutations were found by whole-exome sequencing. Functional studies of the variants were not performed.
The autosomal recessive mutation 'wasted' (wst) arose spontaneously in an inbred mouse colony at the Jackson laboratory in 1972 (Shultz et al., 1982). Homozygous wst/wst mice have neurologic defects, waste away, and show immune system abnormalities that include a defective response to DNA damage in lymphoid cells. Homozygous mice appear completely normal until weaning; at approximately 21 days, they develop tremors and ataxia. Histologic examination shows extensive neuronal vacuolar degeneration of anterior horn cells of the spinal cord with less severe abnormalities of motor nuclei in the brainstem. The mice then lose weight (presumably through muscle wasting), develop progressive paralysis, and die by approximately 28 days of age. The time course of the disease progression varies little, regardless of genetic background, weaning time, or environmental factors such as specific pathogen-free conditions. During the postweaning period, wst/wst mice also develop progressive atrophy of the spleen and thymus and a concomitant decrease in circulating lymphocytes. Cells derived from lymphoid tissues of wasted mice from 26 days onward show a defective response to radiation-induced DNA damage, which is reminiscent of a checkpoint defect; however, this defect is not seen in fibroblasts nor is it seen in lymphoid-derived cells of mice at 22 days.
Chambers et al. (1998) showed that the wasted mutation is a deletion spanning 15.8 kb that removes the promoter region and first noncoding exon of the mouse Eef1a2 gene, abolishing transcription of the gene. No other gene was detected within the deleted region. Expression of Eef1a2 was reciprocal with that of Eef1a. Expression of Eef1a2 takes over from Eef1a in heart and muscle at precisely the time at which the wasted phenotype becomes manifest. The findings suggested that there are tissue-specific forms of the translation elongation apparatus essential for postnatal survival in the mouse.
In a 22-year-old woman (trio 91) with developmental and epileptic encephalopathy-33 (DEE33; 616409), de Ligt et al. (2012) identified a de novo heterozygous c.208G-A transition in the EEF1A2 gene, resulting in a gly70-to-ser (G70S) substitution at a highly conserved residue. The patient had neonatal hypotonia and developed seizures at age 4 months. She had severely delayed psychomotor development, with limited speech, autistic features, and aggressive behavior. The patient was ascertained from a larger cohort of 100 patients with severe intellectual disability who underwent exome sequencing. Functional studies of the variant were not performed.
Veeramah et al. (2013) identified a de novo heterozygous G70S substitution in a 14-year-old boy with DEE33. He developed refractory seizures with hypsarrhythmia at age 10 weeks, and later showed severe developmental delay, with episodic regression, acquired microcephaly, hypotonia, incoordination, and gait instability. He was nonverbal. The phenotype was consistent with a clinical diagnosis of West syndrome. The mutation, which was found by whole-exome sequencing, was not present in the 1000 Genomes Project or Exome Sequencing Project databases. The patient was 1 of 10 probands with epileptic encephalopathy who underwent whole-exome sequencing. Functional studies of the variant were not performed.
In an 8-year-old Japanese girl with autosomal dominant intellectual developmental disorder-38 (MRD38; 616393), Nakajima et al. (2015) identified a de novo heterozygous c.754G-C transversion (c.754G-C, NM_001958.3) in exon 5 of the EEF1A2 gene, resulting in an asp252-to-his (D252H) substitution at a highly conserved residue in the first beta-strand of domain II. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 135/build 137) or Exome Sequencing Project (ESP6500) databases, or in 575 in-house control Japanese exomes. Residue D252 is involved in the binding with EEF1B2, and domain II is associated with the binding of aminoacyl-tRNA; however, functional studies of the variant were not performed.
In a 12-year-old Japanese girl with autosomal dominant intellectual developmental disorder-38 (MRD38; 616393), Nakajima et al. (2015) identified a de novo heterozygous c.364G-A transition (c.364G-A, NM_001958.3) in exon 4 of the EEF1A2 gene, resulting in a glu122-to-lys (E122K) substitution at a highly conserved residue in the fifth alpha-helix of domain I. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 135/build 137) or Exome Sequencing Project (ESP6500) databases, or in 575 in-house control Japanese exomes. Domain I is involved in GTP/GDP binding, and the mutation may affect translational fidelity; however, functional studies of the variant were not performed.
Anand, N., Murthy, S., Amann, G., Wernick, M., Porter, L. A., Cukier, I. H., Collins, C., Gray, J. W., Diebold, J., Demetrick, D. J., Lee, J. M. Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer. Nature Genet. 31: 301-305, 2002. [PubMed: 12053177] [Full Text: https://doi.org/10.1038/ng904]
Ann, D. K., Moutsatsos, I. K., Nakamura, T., Lin, H. H., Mao, P.-L., Lee, M.-J., Chin, S., Liem, R. K. H., Wang, E. Isolation and characterization of the rat chromosomal gene for a polypeptide (p21) antigenically related to statin. J. Biol. Chem. 266: 10429-10437, 1991. [PubMed: 1709933]
Bischoff, C., Kahns, S., Lund, A., Jorgensen, H. F., Praestegaard, M., Clark, B. F. C., Leffers, H. The human elongation factor 1 A-2 gene (EEF1A2): complete sequence and characterization of gene structure and promoter activity. Genomics 68: 63-70, 2000. [PubMed: 10950927] [Full Text: https://doi.org/10.1006/geno.2000.6271]
Chambers, D. M., Peters, J., Abbott, C. M. The lethal mutation of the mouse wasted (wst) is a deletion that abolishes expression of a tissue-specific isoform of translation elongation factor 1-alpha, encoded by the Eef1a2 gene. Proc. Nat. Acad. Sci. 95: 4463-4468, 1998. [PubMed: 9539760] [Full Text: https://doi.org/10.1073/pnas.95.8.4463]
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., Vissers, L. E. L. M. Diagnostic exome sequencing in persons with severe intellectual disability. New Eng. J. Med. 367: 1921-1929, 2012. [PubMed: 23033978] [Full Text: https://doi.org/10.1056/NEJMoa1206524]
Lund, A., Knudsen, S. M., Vissing, H., Clark, B., Tommerup, N. Assignment of human elongation factor 1-alpha genes: EEF1A maps to chromosome 6q14 and EEF1A2 to 20q13.3. Genomics 36: 359-361, 1996. [PubMed: 8812466] [Full Text: https://doi.org/10.1006/geno.1996.0475]
Nakajima, J., Okamoto, N., Tohyama, J., Kato, M., Arai, H., Funahashi, O., Tsurusaki, Y., Nakashima, M., Kawashima, H., Saitsu, H., Matsumoto, N., Miyake, N. De novo EEF1A2 mutations in patients with characteristic facial features, intellectual disability, autistic behaviors and epilepsy. Clin. Genet. 87: 356-361, 2015. [PubMed: 24697219] [Full Text: https://doi.org/10.1111/cge.12394]
Shultz, L. D., Sweet, H. O., Davisson, M. T., Coman, D. R. 'Wasted,' a new mutant of the mouse with abnormalities characteristic of ataxia telangiectasia. Nature 297: 402-404, 1982. [PubMed: 7078649] [Full Text: https://doi.org/10.1038/297402a0]
Veeramah, K. R., Johnstone, L., Karafet, T. M., Wolf, D., Sprissler, R., Salogiannis, J., Barth-Maron, A., Greenberg, M. E., Stuhlmann, T., Weinert, S., Jentsch, T. J., Pazzi, M., Restifo, L. L., Talwar, D., Erickson, R. P., Hammer, M. F. Exome sequencing reveals new causal mutations in children with epileptic encephalopathies. Epilepsia 54: 1270-1281, 2013. [PubMed: 23647072] [Full Text: https://doi.org/10.1111/epi.12201]