Alternative titles; symbols
HGNC Approved Gene Symbol: EPRS1
Cytogenetic location: 1q41 Genomic coordinates (GRCh38): 1:219,968,600-220,046,505 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q41 | Leukodystrophy, hypomyelinating, 15 | 617951 | Autosomal recessive | 3 |
Aminoacyl-tRNA synthetases are enzymes that charge tRNAs with their cognate amino acids. This is an essential first step in the translation of the genetic message because, together with codon-anticodon recognition, the specificity of this reaction determines the fidelity of mRNA translation. At least 1 synthetase exists in the cytoplasm for each amino acid (Kunze et al., 1990). In higher eukaryotes, 9 aminoacyl-tRNA synthetases are associated within a multienzyme complex that is composed of 11 polypeptides with molecular masses ranging from 18 to 150 kD. EPRS is a multifunctional aminoacyl-tRNA synthetase that catalyzes the aminoacylation of glutamic acid and proline tRNA species (Cerini et al., 1991).
Cerini et al. (1991) cloned a cDNA from Drosophila encoding the largest polypeptide of the aminoacyl-tRNA synthetase complex. They demonstrated that the corresponding protein is a multifunctional aminoacyl-tRNA synthetase specifying 2 distinct synthetase activities. The N- and C-terminal domains, when expressed separately in Escherichia coli, were found to catalyze the aminoacylation of glutamic acid and proline tRNA species, respectively. In prokaryotes, these 2 aminoacyl-tRNA synthetases are encoded by distinct genes. The emergence of a multifunctional synthetase by a gene fusion event seems to be a specific, but general attribute of all higher eukaryotic cells. This type of structural organization, in relation to the occurrence of multisynthetase complexes, could be a mechanism to integrate several catalytic domains within the same particle.
In humans, as in Drosophila, glutamyl-tRNA synthetase (GluRS) and prolyl-tRNA synthetase (ProRS) activities are contained within a single polypeptide chain, designated EPRS, even though these enzymes belong to different classes and are thought to have evolved along independent evolutionary pathways (Kaiser et al., 1994). From the open reading frame found in cDNA clones, Fett and Knippers (1991) concluded that the EPRS enzyme comprises 1,440 amino acids.
Jia et al. (2008) stated that human EPRS is a 172-kD protein containing an N-terminal elongation factor-1B-gamma (EEF1G; 130593)-like domain, followed by an ERS catalytic domain, a 300-amino acid linker region, and a C-terminal PRS catalytic domain. The linker region contains 3 tandem WHEP domains, which are 50-amino acid helix-turn-helix structures found in other aminoacyl-tRNA synthases.
Lo et al. (2014) reported the discovery of a large number of natural catalytic nulls for each human aminoacyl tRNA synthetase. Splicing events retain noncatalytic domains while ablating the catalytic domain to create catalytic nulls with diverse functions. Each synthetase is converted into several new signaling proteins with biologic activities 'orthogonal' to that of the catalytic parent. The recombinant aminoacyl tRNA synthetase variants had specific biologic activities across a spectrum of cell-based assays: about 46% across all species affect transcriptional regulation, 22% cell differentiation, 10% immunomodulation, 10% cytoprotection, and 4% each for proliferation, adipogenesis/cholesterol transport, and inflammatory response. Lo et al. (2014) identified in-frame splice variants of cytoplasmic aminoacyl tRNA synthetases. They identified 1 catalytic domain-retained splice variant for GluProRS.
Sampath et al. (2004) showed that EPRS has a regulated, noncanonical activity that blocks synthesis of ceruloplasmin (CP; 117700). They identified EPRS as a component of the gamma-interferon (IFNG; 147570)-activated inhibitor of translation (GAIT) complex by RNA affinity chromatography using the GAIT element in the 3-prime UTR of CP as ligand. Sampath et al. (2004) demonstrated that, in response to IFNG, EPRS is phosphorylated and released from the multisynthetase complex. It subsequently binds the 3-prime UTR of CP in an mRNA ribonucleoprotein complex containing GAPDH (138400), NSAP1 (SYNCRIP; 616686), and L13a (MRPL13; 610200) and silences CP mRNA translation.
Jia et al. (2008) showed that WHEP domains 1 and 2 of human EPRS directed high-affinity binding to GAIT element-bearing mRNAs, while WHEP domains 2 and 3 bound NSAP1, which inhibited mRNA binding. Interaction of EPRS with ribosomal protein L13a and GAPDH induced a conformational switch that rescued mRNA binding and restored translational control. Total reconstitution from purified components revealed that ERPS, NSAP1, GAPDH, and L13a were necessary and sufficient for self-assembly of a functional GAIT complex.
Arif et al. (2009) showed that sequential and independent phosphorylation of ser886 and ser999 in the central linker region of human EPRS was required for its noncanonical IFNG-induced gene silencing activity. Neither synthetase domain of EPRS was required. Phosphorylation of both serines was required for EPRS to exit its normal residence in the multisynthetase complex, and each phosphoserine was independently required for subsequent steps in the inhibitory process. Arif et al. (2009) presented a 2-step model in which released phospho-EPRS interacts with NSAP1 to form a pre-GAIT complex that does not bind the GAIT element. Subsequent binding of EPRS by phospho-L13a and GAPDH induces a conformational shift that displaces NSAP1 to form the active GAIT complex that binds GAIT elements in the 3-prime UTRs of target mRNAs.
Using mouse and human cells, Arif et al. (2017) found that EPRS was phosphorylated at ser999 by the mTORC1 (601231)-S6K1 (RPS6KB1; 608938) axis.
Kaiser et al. (1994) found that the EPRS gene consists of 29 exons spread over at least 90 kb of genomic DNA. The exons encoding the glutamyl-specific and prolyl-specific parts of the enzyme are each clustered in 10-kb sections located at opposite ends of the gene. These 2 exon clusters are separated by a long intervening DNA section with a number of exons encoding functions that may be involved in the organization of the mammalian multienzyme synthetase complex. The upstream region of the gene shows structural features of a regulated gene.
By analysis of a panel of rodent-human cell lines and by in situ hybridization, Kunze et al. (1990) mapped a human cDNA encoding an aminoacyl-tRNA synthetase to 1q32-q42. Although Kunze et al. (1990) considered the mapped cDNA to encode glutaminyl-tRNA synthetase (GlnRS; 603727), Kaiser et al. (1994) noted that the mapped gene actually encodes the human homolog of the Drosophila glutamyl-prolyl-tRNA synthetase characterized by Cerini et al. (1991). Kunze et al. (1990) stated that this was the ninth aminoacyl-tRNA synthetase gene to be mapped in the human genome. For others, see entries 107820, 108410, 142810, 151350, 156560, 187790, 191050, and 192150. By in situ chromosomal hybridization, Kaiser et al. (1994) refined the position to 1q41-q42 in the human and mapped the mouse homolog to 1H4-ter.
In 4 unrelated patients with hypomyelinating leukodystrophy-15 (HLD15; 617951), Mendes et al. (2018) identified homozygous or compound heterozygous mutations in the EPRS gene (138295.0001-138295.0005). Mutations in the first 3 patients were found by whole-exome sequencing and confirmed by Sanger sequencing; mutation in the fourth patient was found by direct sequencing of the EPRS gene. The mutations were confirmed by Sanger sequencing and segregated with the disorder in all families. Two of the mutations were nonsense and frameshift, and 3 were missense variants affecting tRNA synthetase core domains. In vitro functional studies using patient cells or a recombinant protein model of 2 of the missense mutations showed that they resulted in decreased protein levels and impaired aminoacylation activity of EPRS. Mendes et al. (2018) concluded that reduced translation capacity and protein availability resulting from the mutations causes insufficient myelin deposition in the developing brain.
Arif et al. (2017) generated homozygous phosphodefective (S999A) and phosphomimetic (S999D) Eprs-knockin mice on a C57BL/6 background. Homozygous S999A mice had the same body length as wildtype mice, but they had small adipocytes, reduced adiposity and body weight, improved glucose homeostasis in adults, increased oxygen consumption and energy expenditure, and increased life span. Adipocytes of homozygous S999A mice had reduced insulin-stimulated Eprs binding to fatty acid transporter-1 (FATP1, or SLC27A1; 600691) and long-chain fatty acid uptake, as well as enhanced basal lipolysis. These changes were not observed in homozygous S999D mice. However, substitution of the EPRS S999D allele in S6k1-deficient mice normalized body mass and adiposity, indicating that Eprs phosphorylation mediates S6k1-dependent metabolic responses.
In a 16-year-old boy (patient 1), born of consanguineous parents, with hypomyelinating leukodystrophy-15 (HLD15; 617951), Mendes et al. (2018) identified a homozygous c.3344C-G transversion (c.3344C-G, NM_004446.2) in exon 23 of the EPRS gene, resulting in a pro1115-to-arg (P1115R) substitution at a conserved residue in 1 of the tRNA synthetase core domains. An unrelated woman (patient 2) with HLD15 was compound heterozygous for P1115R and a c.1015C-T transition in exon 9, resulting in an arg339-to-ter (R339X; 138295.0002) in the first tRNA synthetase domain. The c.1015C-T transition was predicted to result in nonsense-mediated mRNA decay. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The R339X variant was found at a low frequency (0.012%) in the ExAC database, whereas P1115R was not found in the ExAC database. Patient fibroblasts showed decreased amounts of EPRS protein compared to controls. Transfection of the P1115R mutation into E.coli showed that the variant had decreased EPRS activity compared to controls. However, the P1115R variant did not affect the assembly of the multisynthetase complex (MSC) as monitored by mass spectrometry.
For discussion of the c.1015C-T transition (c.1015C-T, NM_004446.2) in exon 9 of the EPRS gene, resulting in an arg339-to-ter (R339X) substitution, that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-15 (HLD15; 617951) by Mendes et al. (2018), see 138295.0001.
In a 9-year-old girl (patient 3) with hypomyelinating leukodystrophy-15 (HLD15; 617951), Mendes et al. (2018) identified compound heterozygous mutations in the EPRS gene: a c.3478C-T transition (c.3478C-T, NM_004446.2) in exon 24, resulting in a pro1160-to-ser (P1160S) substitution at a conserved residue in 1 of the tRNA synthetase core domains, and a 1-bp deletion (c.3667delA; 138295.0004) in exon 26, predicted to result in a frameshift and premature termination (Thr1223LeufsTer3). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was found in the ExAC database. Functional studies of the variants and studies of patient cells were not performed, but the frameshift mutation was predicted to result in nonsense-mediated mRNA decay.
For discussion of the 1-bp deletion (c.3667delA, NM_004446.2) in exon 26 of the EPRS gene, predicted to result in a frameshift and premature termination (Thr1223LeufsTer3), that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-15 (HLD15; 617951) by Mendes et al. (2018), see 138295.0003.
In a 2-year-old girl (patient 4) with hypomyelinating leukodystrophy-15 (HLD15; 617951), Mendes et al. (2018) identified a homozygous c.3377T-C transition (c.3377T-C, NM_004446.2) in exon 24 of the EPRS gene, resulting in a met1126-to-thr (M1126T) substitution at a conserved residue in 1 of the tRNA synthetase domains. The mutation, which was found by direct sequencing, segregated with the disorder in the family. It was not found in the ExAC database. Patient lymphoblasts showed significantly decreased EPRS activity compared to controls.
Arif, A., Jia, J., Mukhopadhyay, R., Willard, B., Kinter, M., Fox, P. L. Two-site phosphorylation of EPRS coordinates multinodal regulation of noncanonical translational control activity. Molec. Cell 35: 164-180, 2009. [PubMed: 19647514] [Full Text: https://doi.org/10.1016/j.molcel.2009.05.028]
Arif, A., Terenzi, F., Potdar, A. A., Jia, J., Sacks, J., China, A., Halawani, D., Vasu, K., Li, X., Brown, J. M., Chen, J., Kozma, S. C., Thomas, G., Fox, P. L. EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature 542: 357-361, 2017. [PubMed: 28178239] [Full Text: https://doi.org/10.1038/nature21380]
Cerini, C., Kerjan, P., Astier, M., Gratecos, D., Mirande, M., Semeriva, M. A component of the multisynthetase complex is a multifunctional aminoacyl-tRNA synthetase. EMBO J. 10: 4267-4277, 1991. [PubMed: 1756734] [Full Text: https://doi.org/10.1002/j.1460-2075.1991.tb05005.x]
Fett, R., Knippers, R. The primary structure of human glutaminyl-tRNA synthetase: a highly conserved core, amino acid repeat regions, and homologies with translation elongation factors. J. Biol. Chem. 266: 1448-1455, 1991. [PubMed: 1988429]
Jia, J., Arif, A., Ray, P. S., Fox, P. L. WHEP domains direct noncanonical function of glutamyl-prolyl tRNA synthetase in translational control of gene expression. Molec. Cell 29: 679-690, 2008. [PubMed: 18374644] [Full Text: https://doi.org/10.1016/j.molcel.2008.01.010]
Kaiser, E., Hu, B., Becher, S., Eberhard, D., Schray, B., Baack, M., Hameister, H., Knippers, R. The human EPRS locus (formerly the QARS locus): a gene encoding a class I and a class II aminoacyl-tRNA synthetase. Genomics 19: 280-290, 1994. [PubMed: 8188258] [Full Text: https://doi.org/10.1006/geno.1994.1059]
Kunze, N., Bittler, E., Fett, R., Schray, B., Hameister, H., Wiedorn, K. H., Knippers, R. The human QARS locus: assignment of the human gene for glutaminyl-tRNA synthetase to chromosome 1q32-42. Hum. Genet. 85: 527-530, 1990. [PubMed: 2227938] [Full Text: https://doi.org/10.1007/BF00194231]
Lo, W.-S., Gardiner, E., Xu, Z., Lau, C.-F., Wang, F., Zhou, J. J., Mendlein, J. D., Nangle, L. A., Chiang, K. P., Yang, X.-L., Au, K.-F., Wong, W. H., Guo, M., Zhang, M., Schimmel, P. Human tRNA synthetase catalytic nulls with diverse functions. Science 345: 328-332, 2014. [PubMed: 25035493] [Full Text: https://doi.org/10.1126/science.1252943]
Mendes, M. I., Gutierrez Salazar, M., Guerrero, K., Thiffault, I., Salomons, G. S., Gauquelin, L., Tran, L. T., Forget, D., Gauthier, M.-S., Waisfisz, Q., Smith, D. E. C., Simons, C., and 9 others. Bi-allelic mutations in EPRS, encoding the glutamyl-prolyl-aminoacyl-tRNA synthetase, cause a hypomyelinating leukodystrophy. Am. J. Hum. Genet. 102: 676-684, 2018. [PubMed: 29576217] [Full Text: https://doi.org/10.1016/j.ajhg.2018.02.011]
Sampath, P., Mazumder, B., Seshadri, V., Gerber, C. A., Chavatte, L., Kinter, M., Ting, S. M., Dignam, J. D., Kim, S., Driscoll, D. M., Fox, P. L. Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of translation. Cell 119: 195-208, 2004. [PubMed: 15479637] [Full Text: https://doi.org/10.1016/j.cell.2004.09.030]