Alternative titles; symbols
HGNC Approved Gene Symbol: EIF5A
Cytogenetic location: 17p13.1 Genomic coordinates (GRCh38): 17:7,306,999-7,312,463 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.1 | Faundes-Banka syndrome | 619376 | Autosomal dominant | 3 |
The EIF5A gene encodes a protein essential for cell viability that is critical for the synthesis of peptide bonds between consecutive proline residues and resolves ribosomal stalling. The functions of EIF5A include recognition of the correct start codon, global protein synthesis elongation and termination, promoting the elongation of many non-polyproline-specific tripeptide sequences, and eliciting nonsense-mediated decay (NMD) (summary by Faundes et al., 2021).
The eukaryotic initiation factor 5A is an 18-kD protein composed of 154 amino acids. It contains a unique amino acid residue, hypusine, that is formed posttranslationally via the transfer and hydroxylation of the butylamino-group from the polyamine spermidine to a lys50 within the EIF5A protein. Koettnitz et al. (1994) isolated and characterized the human EIF5A pseudogene. Subsequently, Koettnitz et al. (1995) identified a genomic clone encoding a functional EIF5A. The authors showed that this sequence could successfully complement yeast carrying the HYP2 mutation (the homolog of EIF5A), whereas the pseudogenes could not.
Koettnitz et al. (1995) found that the human EIF5A gene contains at least 4 exons and spans at least 4.8 kb.
Steinkasserer et al. (1995) mapped the EIF5A gene to 17p13-p12 by fluorescence in situ hybridization. Three pseudogenes were mapped to 10q23.3, 17q25, and 19q13.2.
Huang et al. (2007) found that nerve growth factor (NGF; 162030) stimulated arginine metabolism, increased hypusine synthesis, and enhanced formation of hypusinated Eif5a in primed rat PC12 cells, thereby inducing neurite outgrowth and neuronal survival. Inhibiting formation of hypusinated Eif5a attenuated neurite outgrowth and neuronal survival in primary PC12 cells, as well as in rat primary hippocampal neurons.
Saini et al. (2009) used molecular genetic and biochemical studies to show that EIF5A promotes translation elongation. Depletion or inactivation of EIF5A in the yeast S. cerevisiae resulted in the accumulation of polysomes and an increase in ribosomal transit times. Addition of recombinant EIF5A from yeast, but not a derivative lacking hypusine, enhanced the rate of tripeptide synthesis in vitro. Moreover, inactivation of EIF5A mimicked the effects of the EEF2 (130610) inhibitor sordarin, indicating that EIF5A might function together with EEF2 to promote ribosomal translocation. Because EIF5A is a structural homolog of the bacterial protein EF-P, Saini et al. (2009) proposed that EIF5A/EF-P is a universally conserved translation elongation factor.
To identify tumor suppressor genes in lymphoma (605027), Scuoppo et al. (2012) screened a short hairpin RNA library targeting genes deleted in human lymphomas and functionally confirmed those in a mouse lymphoma model. Of the 9 tumor suppressors identified, 8 corresponded to genes occurring in 3 physically linked 'clusters,' suggesting that the common occurrence of large chromosomal deletions in human tumors reflects selective pressure to attenuate multiple genes. Among the newly identified tumor suppressors were adenosylmethionine decarboxylase-1 (AMD1; 180980) and eukaryotic translation initiation factor 5A (eIF5A), 2 genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, Scuoppo et al. (2012) established the polyamine-hypusine axis as a new tumor suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas, and cosuppression of both genes promotes lymphomagenesis in mice. Thus, Scuoppo et al. (2012) concluded that some tumor suppressor functions can be disabled through a 2-step process targeting different genes acting in the same pathway.
Translation elongation factor P (EF-P) is critical for virulence in bacteria. EF-P is present in all bacteria and orthologous to archaeal and eukaryotic initiation factor 5A (a/eIF5A). Ude et al. (2013) demonstrated that EF-P is an elongation factor that enhances translation of polyproline-containing proteins: in the absence of EF-P, ribosomes stall at polyproline stretches, whereas the presence of EF-P alleviates the translational stalling. Moreover, Ude et al. (2013) demonstrated the physiologic relevance of EF-P to fine-tune the expression of the polyproline-containing pH receptor CadC to levels necessary for an appropriate stress response. Bacterial, archaeal, and eukaryotic cells have hundreds to thousands of polyproline-containing proteins of diverse function, suggesting that EF-P and a/elF5A are critical for copy number adjustment of multiple pathways across all kingdoms of life.
Doerfel et al. (2013) showed that EF-P prevents the ribosome from stalling during synthesis of proteins containing consecutive prolines, such as PPG, PPP, or longer proline strings, in natural and engineered model proteins. EF-P promotes peptide-bond formation and stabilizes the peptidyl-transfer RNA in the catalytic center of the ribosome. EF-P is posttranslationally modified by a hydroxylated beta-lysine attached to a lysine residue. The modification enhances the catalytic proficiency of the factor mainly by increasing its affinity to the ribosome. Doerfel et al. (2013) proposed that EF-P and its eukaryotic homolog, elF5A, are essential for the synthesis of a subset of proteins containing proline stretches in all cells.
Gutierrez et al. (2013) found that Eif5a promoted translation of polyproline sequences in yeast and that expression of yeast polyproline-containing proteins required hypusine-modified Eif5a for their synthesis. Peptide synthesis assays revealed that Eif5a prevented ribosome stalling on at least 3 consecutive proline codons and was required for peptide bond formation between diprolyl-tRNA and pro-tRNA. Further analysis demonstrated that Eif5a bound the yeast 80S ribosome alongside the P-site tRNA, with the hypusine residue at the top of Eif5a near the aminoacyl end of the tRNA, and eIF5A domain II residue thr126 near the anticodon stem of the tRNA.
In 7 unrelated patients with Faundes-Banka syndrome (FABAS; 619376), comprising developmental delay, microcephaly, and variable dysmorphic features, Faundes et al. (2021) identified heterozygosity for de novo mutations in the EIF5A gene (see, e.g., 600187.0001-600187.0004). Functional analysis showed that the variants impair EIF5A function, reduce EIF5A-ribosome interactions, and impair the synthesis of polyproline tract-containing proteins.
Faundes et al. (2021) used a splice site morpholino to knock down eif5a in zebrafish, and observed micrognathia in the morphant larvae. Supplementation with spermidine resulted in partial rescue of the micrognathia.
In an 8.4-year-old girl (patient 3) with Faundes-Banka syndrome (FABAS; 619376), Faundes et al. (2021) identified heterozygosity for a de novo 1-bp duplication (c.324dupA, NM_001970.5) in the EIF5A gene, causing a frameshift predicted to result in a premature termination codon (Arg109ThrfsTer8). The mutation was identified by trio whole-exome sequencing. Lymphoblastoid cell lines derived from patient peripheral blood mononuclear cells showed a significant reduction in EIF5A mRNA compared to controls, and transcript with c.324dupA was not detected, suggesting nonsense-mediated decay of the mutant transcript. In addition, yeast colonies expressing the Arg109ThrfsTer8 mutant as the sole source of EIF5A could not be obtained after 10 days of growth. Western blot analysis revealed that the mutant was very poorly expressed, and even when expressed in high copy, it was very poorly hypusinated.
In a 6.9-year-old girl (patient 1) with Faundes-Banka syndrome (FABAS; 619376), Faundes et al. (2021) identified heterozygosity for a de novo c.143C-A transversion (c.143C-A, NM_001970.5) in the EIF5A gene, resulting in a thr48-to-asn (T48N) substitution at a highly conserved surface-exposed residue. Yeast colonies expressing the T48N mutant as the sole source of EIF5A showed slow growth compared to wildtype, suggesting partial loss of EIF5A function. Polysome profiling revealed a reduction in the 80S ribosome fraction, indicating a reduction in ribosome binding by the mutant EIF5A. Western blot analysis showed that in cells expressing the T48N mutant, total levels of EIF5A were normal, but levels of hypusination were reduced, suggesting that the T48N variant impairs hypusination of the adjacent K50 residue. Western blot analysis also revealed decreased levels of polyproline tract (PPT)-containing proteins, indicating that the variant impairs the synthesis of proteins containing PPTs in yeast. Spermadine treatment partially corrected the growth defects of the T48N yeast cells and improved the global polysome profile, with full restoration of the EIF5A interaction with the 80S ribosome. However, improved growth and protein synthesis was not explained by improved EIF5A expression levels or by enhanced hypusination of T48N mutant EIF5A, suggesting that spermidine can rescue and/or bypass impaired EIF5A functions in protein synthesis independent of its role as a substrate for hypusination of EIF5A K50.
In an 18-year-old man (patient 4) with Faundes-Banka syndrome (FABAS; 619376), Faundes et al. (2021) identified heterozygosity for a de novo c.325C-G transversion (c.325C-G, NM_001970.5) in the EIF5A gene, resulting in an arg109-to-gly (R109G) substitution at a highly conserved surface-exposed residue. Patient cells were unavailable for analysis.
In an 8-month-old boy (patient 5) with Faundes-Banka syndrome (FABAS; 619376), Faundes et al. (2021) identified heterozygosity for a de novo c.325C-T transition (c.325C-T, NM_001970.5) in the EIF5A gene, resulting in an arg109-to-ter (R109X) substitution. Patient cells were unavailable for analysis.
Doerfel, L. K., Wohlgemuth, I., Kothe, C., Peske, F., Urlaub, H., Rodnina, M. V. EF-P is essential for rapid synthesis of proteins containing consecutive proline residues. Science 339: 85-88, 2013. [PubMed: 23239624] [Full Text: https://doi.org/10.1126/science.1229017]
Faundes, V., Jennings, M. D., Crilly, S., Legraie, S., Withers, S. E., Cuvertino, S., Davies, S. J., Douglas, A. G. L., Fry, A. E., Harrison, V., Amiel, J., Lehalle, D., and 12 others. Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine. Nature Commun. 12: 833, 2021. [PubMed: 33547280] [Full Text: https://doi.org/10.1038/s41467-021-21053-2]
Gutierrez, E., Shin, B.-S., Woolstenhulme, C. J., Kim, J.-R., Saini, P., Buskirk, A. R., Dever, T. E. eIF5A promotes translation of polyproline motifs. Molec. Cell 51: 35-45, 2013. [PubMed: 23727016] [Full Text: https://doi.org/10.1016/j.molcel.2013.04.021]
Huang, Y., Higginson, D. S., Hester, L., Park, M. H., Snyder, S. H. Neuronal growth and survival mediated by eIF5A, a polyamine-modified translation initiation factor. Proc. Nat. Acad. Sci. 104: 4194-4199, 2007. [PubMed: 17360499] [Full Text: https://doi.org/10.1073/pnas.0611609104]
Koettnitz, K., Kappel, B., Baumruker, T., Hauber, J., Bevec, D. The genomic structure encoding human initiation factor eIF-5A. Gene 144: 249-252, 1994. [PubMed: 7545941] [Full Text: https://doi.org/10.1016/0378-1119(94)90385-9]
Koettnitz, K., Wohl, T., Kappel, B., Lottspeich, F., Hauber, J., Bevec, D. Identification of a new member of the human eIF-5A gene family. Gene 159: 283-284, 1995. [PubMed: 7622067] [Full Text: https://doi.org/10.1016/0378-1119(95)00136-t]
Saini, P., Eyler, D. E., Green, R., Dever, T. E. Hypusine-containing protein eIF5A promotes translation elongation. Nature 459: 118-121, 2009. [PubMed: 19424157] [Full Text: https://doi.org/10.1038/nature08034]
Scuoppo, C., Miething, C., Lindqvist, L., Reyes, J., Ruse, C., Appelmann, I., Yoon, S., Krasnitz, A., Teruya-Feldstein, J., Pappin, D., Pelletier, J., Lowe, S. W. A tumour suppressor network relying on the polyamine-hypusine axis. Nature 487: 244-248, 2012. [PubMed: 22722845] [Full Text: https://doi.org/10.1038/nature11126]
Steinkasserer, A., Jones, T., Sheer, D., Koettnitz, K., Hauber, J., Bevec, D. The eukaryotic cofactor for the human immunodeficiency virus type 1 (HIV-1) rev protein, eIF-5A, maps to chromosome 17p12-p13: three eIF-5A pseudogenes map to 10q23.3, 17q25, and 19q13.2. Genomics 25: 749-752, 1995. [PubMed: 7759117] [Full Text: https://doi.org/10.1016/0888-7543(95)80025-h]
Ude, S., Lassak, J., Starosta, A. L., Kraxenberger, T., Wilson, D. N., Jung, K. Translation elongation factor EF-P alleviates ribosome stalling at polyproline stretches. Science 339: 82-85, 2013. [PubMed: 23239623] [Full Text: https://doi.org/10.1126/science.1228985]