Alternative titles; symbols
HGNC Approved Gene Symbol: YARS1
SNOMEDCT: 765746008;
Cytogenetic location: 1p35.1 Genomic coordinates (GRCh38) : 1:32,775,239-32,817,358 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p35.1 | Charcot-Marie-Tooth disease, dominant intermediate C | 608323 | Autosomal dominant | 3 |
| Infantile-onset multisystem neurologic, endocrine, and pancreatic disease 2 | 619418 | Autosomal recessive | 3 |
The YARS1 gene encodes a tRNA synthetase that catalyzes the covalent attachment of the tyrosine amino acid to its corresponding tRNA in a 2-step aminoacylation process. This function is essential for translation and protein synthesis. The ARS family of proteins, which are highly conserved, also likely have noncanonical roles in transcription regulation, splicing, immune function, angiogenesis, apoptosis, and cell stress (summary by Williams et al., 2019).
Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAS, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Kleeman et al. (1997) cloned cDNAs encoding tyrosyl-tRNA synthetase (YARS) from several different human cDNA libraries. The YARS cDNA sequence encodes a 528-amino acid polypeptide. Sequence analysis revealed that the carboxyl end of the protein contains a region with 49% identity to endothelial monocyte-activating polypeptide II (EMAP II; 603605).
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 5 catalytic-null and 1 catalytic domain-retained splice variants for TyrRS.
While native human tyrosyl-tRNA synthetase is inactive as a cell-signaling molecule, it can be split into 2 distinct cytokines. The enzyme is secreted under apoptotic conditions in culture, where it is cleaved into an N-terminal fragment that harbors the catalytic site and into a C-terminal fragment found only in the mammalian enzyme. The N-terminal fragment is an interleukin-8 (IL8; 146930)-like cytokine, whereas the released C-terminal fragment is an EMAP II-like cytokine. Wakasugi and Schimmel (1999) found that the cytokine activities of split human tyrosyl-tRNA synthetase depend on highly differentiated motifs that are idiosyncratic to the mammalian system.
Jordanova et al. (2006) determined that YARS is expressed ubiquitously, including in brain and spinal cord.
Crystal Structure
Sajish and Schimmel (2015) presented a 2.1-angstrom cocrystal structure of resveratrol bound to the active site of TYRRS. Resveratrol nullifies the catalytic activity and redirects TYRRS to a nuclear function, stimulating NAD(+)-dependent auto-poly-ADP-ribosylation of PARP1 (173870). Downstream activation of key stress signaling pathways are causally connected to TYRRS-PARP1-NAD+ collaboration. This collaboration is also demonstrated in the mouse, and is specifically blocked in vivo by a resveratrol-displacing tyrosyl adenylate analog. Sajish and Schimmel (2015) concluded that, in contrast to functionally diverse tRNA synthetase catalytic nulls created by alternative splicing events that ablate active sites, a nonspliced TYRRS catalytic null revealed a novel PARP1- and NAD(+)-dependent dimension to the physiologic mechanism of resveratrol.
The YARS gene resides on chromosome 1p35-p34 (Jordanova et al., 2003).
Charcot-Marie-Tooth Disease, Dominant Intermediate C
Dominant intermediate Charcot-Marie-Tooth (DI-CMT) neuropathy is a genetic and phenotypic variant of classic CMT characterized by intermediate nerve conduction velocities and histologic evidence of both axonal and demyelinating features. In an American family with DI-CMTC (CMTDIC; 608323), Jordanova et al. (2006) identified a heterozygous transition in exon 2 of the YARS gene (G41R; 603623.0001), and in a Bulgarian family they found a heterozygous transition in exon 5 (E196K; 603623.0002). Furthermore, they identified a 12-bp in-frame deletion in exon 4 in an affected individual from Belgium (603623.0003).
In a Korean man with CMTDIC, Hyun et al. (2014) identified a heterozygous mutation in the YARS gene (D81I; 603623.0004). The mutation was found by exome sequencing; functional studies were not performed. The patient was 1 of 166 Korean individuals with CMT who underwent exome sequencing.
Infantile-Onset Multisystem Neurologic, Endocrine, And Pancreatic Disease 2
In 2 sibs, born to nonconsanguineous Polish parents, with infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2; 619418), Nowaczyk et al. (2017) identified 'pathogenic-appearing' compound heterozygous missense mutations in the YARS gene (P213L, 603623.0005 and G525R, 603623.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the EVS and ExAC databases. Functional studies of the variants were not performed, but they were predicted to disrupt protein structure or function.
In a 26-year-old Swedish woman with IMNEPD2, Tracewska-Siemiatkowska et al. (2017) identified a homozygous missense mutation in the YARS1 gene (F269S; 603623.0007). The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.
In 7 affected children from a large highly consanguineous Amish kindred with IMNEPD2, Williams et al. (2019) identified a homozygous missense mutation in the YARS1 gene (P167T; 603623.0008). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the kindred. In vitro functional studies in HeLa cells transfected with the mutation showed that it caused reduced dimerization, which is essential for proper YARS1 function. Yeast complementation assays indicated that the P167T substitution caused poor growth and reduced gene function. The findings were consistent with a hypomorphic loss-of-function allele.
Reclassified Variants
The Y204C variant reported by Zeiad et al. (2021) has been reclassified as a variant of unknown significance; see 603623.0009. In a 12-month-old male African American infant with IMNEPD2, Zeiad et al. (2021) identified a homozygous c.611A-C homozygous mutation in the YARS1 gene (Y204C; 603623.0009). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but the authors postulated that the mutation results in impaired protein synthesis that fails to meet specific organ demands. Because of a discrepancy in the article between the reported nucleotide and protein changes, this variant has been reclassified as a variant of unknown significance.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human YARS is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
Spaulding et al. (2021) identified activation of the integrated stress response (ISR) in the alpha motor neurons of 7-month-old mice with a homozygous E196K mutation in the Yars gene (603623.0002). A similar but milder activation of ISR was demonstrated in mice with heterozygosity for the E196K mutation.
Ribas de Pouplana et al. (1996) performed multiple sequence alignments for the tRNA synthetases. They concluded that tyrosyl-tRNA synthetase and tryptophanyl-tRNA synthetase (191050) may have diverged after the separation of eukaryotes from eubacteria.
In a North American family with dominant intermediate Charcot-Marie-Tooth disease (CMTDIC; 608323), previously reported by Jordanova et al. (2003), Jordanova et al. (2006) found a heterozygous 121G-A transition in exon 2 of the YARS gene, resulting in a gly41-to-arg (G41R) substitution.
In a Bulgarian family with dominant intermediate Charcot-Marie-Tooth disease (CMTDIC; 608323), previously reported by Jordanova et al. (2003), Jordanova et al. (2006) identified a heterozygous 586G-A transition in exon 5 of the YARS gene that resulted in a glu196-to-lys (E196K) mutation.
In an individual from Belgium with dominant intermediate Charcot-Marie-Tooth disease (CMTDIC; 608323), Jordanova et al. (2006) identified a 12-bp in-frame deletion (153-156delVKQV) in exon 4 of the YARS gene. Mutation analysis and genotyping of her asymptomatic parents showed that this mutation occurred de novo.
In a Korean man with dominant intermediate Charcot-Marie-Tooth disease (CMTDIC; 608323), Hyun et al. (2014) identified a heterozygous c.241_242GA-AT mutation in the YARS gene, resulting in an asp81-to-ile (D81I) substitution at a highly conserved residue in the catalytic domain. The mutation, which was found by exome sequencing, segregated with the disorder in the family and was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases, or in 300 controls. Functional studies of the variant were not performed. The parents were unaffected, suggesting that the mutation occurred de novo.
In 2 sibs, born to nonconsanguineous Polish parents, with infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2; 619418), Nowaczyk et al. (2017) identified 'pathogenic-appearing' compound heterozygous missense mutations in the YARS gene: a c.638C-T transition (c.638C-T, NM_003680.3), resulting in a pro213-to-leu (P213L) substitution, inherited from the father, and a c.1573G-A transition, resulting in a gly525-to-arg (G525R; 603623.0006) substitution, inherited from the mother. Both mutations occur at highly conserved residues, pro213 in the catalytic domain close to the boundary with the anticodon binding domain, and gly525 in the catalytic domain. The mutations, which were confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the EVS and ExAC databases. Functional studies of the variants and studies of patient cells were not performed, but both variants were predicted to disrupt protein structure or function.
For discussion of the c.1573G-A transition (c.1573G-A, NM_003680.3) in the YARS gene, resulting in a gly525-to-arg (G525R) substitution, that was found in compound heterozygous state in 2 sibs with infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2; 619418), see 603623.0005.
In a 26-year-old Swedish woman with infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2; 619418), Tracewska-Siemiatkowska et al. (2017) identified a homozygous c.806C-T transition (c.806C-T, NM_003680) in the YARS1 gene, resulting in a phe269-to-ser (F269S) substitution at a conserved residue just outside of the tyrosine tRNA ligase domain. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The patient had a multisystemic disorder with progressive retinal degeneration, deafness, transient fatty liver, and primary amenorrhea. Development and cognitive function were normal.
In 7 affected children from a large highly consanguineous Amish kindred with infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2; 619418), Williams et al. (2019) identified a homozygous c.499C-A transversion (c.499C-A, NM_003680.3) in the YARS1 gene, resulting in a pro167-to-thr (P167T) substitution in a highly conserved interface required for protein homodimerization, an essential step in catalytic function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the kindred. In vitro functional studies in HeLa cells transfected with the mutation showed that it caused reduced dimerization, which is essential for proper YARS1 function. Yeast complementation assays indicated that the P167T substitution caused poor growth and reduced gene function. The findings were consistent with a hypomorphic loss-of-function allele. The affected children had a severe multisystem disorder with developmental delay, poor growth, deafness, liver disease, pancreatic dysfunction, and renal and hematologic abnormalities. Several died in early childhood.
This variant, formerly titled NEUROLOGIC, ENDOCRINE, AND PANCREATIC DISEASE, MULTISYSTEM, INFANTILE-ONSET 2, has been reclassified because of a discrepancy between the reported nucleotide and protein changes in the article by Zeiad et al. (2021).
In a 12-month-old male African American infant with infantile-onset multisystem neurologic, endocrine, and pancreatic disease-2 (IMNEPD2; 619418), Zeiad et al. (2021) identified a homozygous c.611A-C transversion in exon 6 of the YARS1 gene, resulting in a tyr204-to-cys (Y204C) substitution in the catalytic domain. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. It was present in 1 of 31,388 total alleles and in 1 of 8,871 African/African American alleles in the gnomAD database. Functional studies of the variant were not performed, but the authors postulated that the mutation results in impaired protein synthesis that fails to meet specific organ demands. The patient died of multiorgan failure at 12 months of age.
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Hyun, Y. S., Park, H. J., Heo, S.-H., Yoon, B. R., Nam, S. H., Kim, S.-B., Park, C. I., Choi, B.-O., Chung, K. W. Rare variants in methionyl- and tyrosyl-tRNA synthetase genes in late-onset autosomal dominant Charcot-Marie-Tooth neuropathy. (Letter) Clin. Genet. 86: 592-594, 2014. [PubMed: 24354524] [Full Text: https://doi.org/10.1111/cge.12327]
Jordanova, A., Irobi, J., Thomas, F. P., Van Dijck, P., Meerschaert, K., Dewil, M., Dierick, I., Jacobs, A., De Vriendt, E., Guergueltcheva, V., Rao, C. V., Tournev, I., and 12 others. Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nature Genet. 38: 197-202, 2006. [PubMed: 16429158] [Full Text: https://doi.org/10.1038/ng1727]
Jordanova, A., Thomas, F. P., Guergueltcheva, V., Tournev, I., Gondim, F. A. A., Ishpekova, B., De Vriendt, E., Jacobs, A., Litvinenko, I., Ivanova, N., Buzhov, B., De Jonghe, P., Kremensky, I., Timmerman, V. Dominant intermediate Charcot-Marie-Tooth type C maps to chromosome 1p34-p35. Am. J. Hum. Genet. 73: 1423-1430, 2003. [PubMed: 14606043] [Full Text: https://doi.org/10.1086/379792]
Kleeman, T. A., Wei, D., Simpson, K. L., First, E. A. Human tyrosyl-tRNA synthetase shares amino acid sequence homology with a putative cytokine. J. Biol. Chem. 272: 14420-14425, 1997. [PubMed: 9162081] [Full Text: https://doi.org/10.1074/jbc.272.22.14420]
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]
Nowaczyk, M. J. M., Huang, L., Tarnopolsky, M., Schwartzentruber, J., Majewski, J., Bulman, D. E., FORGE Canada Consortium, Care4Rare Canada Consortium, Hartley, T., Boycott, K. M. A novel multisystem disease associated with recessive mutations in the tyrosyl-tRNA synthetase (YARS) gene. Am. J. Med. Genet. 173A: 126-134, 2017. [PubMed: 27633801] [Full Text: https://doi.org/10.1002/ajmg.a.37973]
Ribas de Pouplana, L., Frugier, M., Quinn, C. L., Schimmel, P. Evidence that two present-day components needed for the genetic code appeared after nucleated cells separated from eubacteria. Proc. Nat. Acad. Sci. 93: 166-170, 1996. [PubMed: 8552597] [Full Text: https://doi.org/10.1073/pnas.93.1.166]
Sajish, M., Schimmel, P. A human tRNA synthetase is a potent PARP1-activating effector target for resveratrol. Nature 519: 370-373, 2015. [PubMed: 25533949] [Full Text: https://doi.org/10.1038/nature14028]
Spaulding, E. L., Hines, T. J., Bais, P., Tadenev, A. L. D., Schneider, R., Jewett, D., Pattavina, B., Pratt, S. L., Morelli, K. H., Stum, M. G., Hill, D. P., Gobet, C., and 11 others. The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy. Science 373: 1156-1161, 2021. [PubMed: 34516839] [Full Text: https://doi.org/10.1126/science.abb3414]
Tracewska-Siemiatkowska, A., Haer-Wigman, L., Bosch, D. G. M., Nickerson, D., Bamshad, M. J., University of Washington Center for Mendelian Genomics, van de Vorst, M., Rendtorff, N. D., Moller, C., Kjellstrom, U., Andreasson, S., Cremers, F. P. M., Tranebjaerg, L. An expanded multi-organ disease phenotype associated with mutations in YARS. Genes (Basel) 8: 381, 2017. [PubMed: 29232904] [Full Text: https://doi.org/10.3390/genes8120381]
Wakasugi, K., Schimmel, P. Highly differentiated motifs responsible for two cytokine activities of a split human tRNA synthetase. J. Biol. Chem. 274: 23155-23159, 1999. [PubMed: 10438485] [Full Text: https://doi.org/10.1074/jbc.274.33.23155]
Williams, K. B., Brigatti, K. W., Puffenberger, E. G., Gonzaga-Jauregui, C., Griffin, L. B., Martinez, E. D., Wenger, O. K., Yoder, M. A., Kandula, V. V. R., Fox, M. D., and 10 others. Homozygosity for a mutation affecting the catalytic domain of tyrosyl-tRNA synthetase (YARS) causes multisystem disease. Hum. Molec. Genet. 28: 525-538, 2019. [PubMed: 30304524] [Full Text: https://doi.org/10.1093/hmg/ddy344]
Zeiad, R. K. H. M., Ferren, E. C., Young, D. D., De Lancy, S. J., Dedousis, D., Schillaci, L.-A., Redline, R. W., Saab, S. T., Crespo, M., Bhatti, T. R., Ackermann, A. M., Bedoyan, J. K., Wood, J. R. A novel homozygous missense mutation in the YARS gene: expanding the phenotype of YARS multisystem disease. J. Endocr. Soc. 5: bvaa196, 2021. [PubMed: 33490854] [Full Text: https://doi.org/10.1210/jendso/bvaa196]