Alternative titles; symbols
HGNC Approved Gene Symbol: RARS1
SNOMEDCT: 1220600004;
Cytogenetic location: 5q34 Genomic coordinates (GRCh38): 5:168,486,471-168,519,301 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q34 | Leukodystrophy, hypomyelinating, 9 | 616140 | Autosomal recessive | 3 |
The RARS gene encodes ArgRS, the cytoplasmic tRNA synthetase for arginine, which is a component of the multienzyme aminoacyl-tRNA synthetase complex (summary by Wolf et al., 2014).
Girjes et al. (1995) isolated a full-length cDNA corresponding to the RARS gene and identified an open reading frame of 1983 nucleotides with 87% homology to other mammalian RARS. Northern blot analysis revealed the presence of a single mRNA species of approximately 2.2 kb.
Using forward genetic screens in Caenorhabditis elegans, Anderson et al. (2009) isolated a hypoxia-resistant reduction-of-function mutant of rrt1 (whose human homolog is RARS1), which encodes an arginyl-transfer RNA synthetase, an enzyme essential for protein translation. Knockdown of rrt1, and of most other genes encoding aminoacyl-tRNA synthetases, rescued animals from hypoxia-induced death, and the level of hypoxia resistance was inversely correlated with translation rate. The unfolded protein response was induced by hypoxia and was required for the hypoxia resistance of the reduction-of-function mutant of rrt1. Thus, Anderson et al. (2009) concluded that translational suppression produces hypoxia resistance, in part by reducing unfolding protein toxicity.
By fractionation analysis in mouse and human cells, Cui et al. (2023) showed that ArgRS was localized to the nucleus in response to external arginine levels. Nuclear ArgRS was decreased in response to inflammatory arginine depletion in mice in vivo. Using mass spectrometric analysis in 293T and HepG2 cells, Cui et al. (2023) identified serine/arginine repetitive matrix protein-2 (SRRM2; 606032) as a nuclear proteins that interacts with ArgRS. Pulldown assays confirmed the interaction, and domain mapping revealed that the catalytic domain of ArgRS was necessary for the interaction. ArgRS catalytically inactivated by point mutations also retrieved SRRM2 from cell lysates. Deletion of the ArgRS leucine zipper, which integrates ArgRS into the multisynthetase complex (MSC) and thereby regulates its nuclear import, did not abolish the interaction with SRRM2; this and other findings indicated that ArgRS interacts with SRRM2 outside of the complete MSC. Immunofluorescence assay revealed the colocalization of ArgRS and SRRM2 in the nucleus, and the colocalization was ArgRS-specific and MSC-independent. ArgRS interaction with SRRM2 was modulated by external arginine concentrations, which in turn controlled nuclear ArgRS levels. ArgRS knockdown analysis showed that arginine-mediated changes in nuclear ArgRS levels affected SRRM2 mobility and changed the levels of SRRM2 available for RNA splicing in the nucleus, thereby impacting the processing of protein-coding mRNAs but not small noncoding RNAs (ncRNAs) and resulting in alternative splicing changes that led to different protein isoforms. Among the identified SRRM2-dependent splicing changes, a number of genes were shared between ArgRS and SRRM2, and the splicing of those genes was inversely regulated by both proteins. Moreover, the inverse regulation by ArgRS and SRRM2 likely contributed to changes in cellular metabolism and communication as part of a response to inflammation.
Arfin et al. (1985) assigned the gene for arginyl-tRNA synthetase to chromosome 5 by study of somatic cell hybrids. Of the 7 aminoacyl-tRNA synthetase genes mapped to that time, 4 were on chromosome 5, which represents only about 7% of the total human genome.
In 4 patients from 3 unrelated families from the Netherlands with hypomyelinating leukodystrophy-9 (HLD9; 616140), Wolf et al. (2014) identified compound heterozygous mutations in the RARS gene (107820.0001-107820.0005). Mutations in 2 of the families were found by whole-exome sequencing and confirmed by Sanger sequencing. All patients carried 1 missense mutation and a mutation predicted to result in the loss of a functional protein in trans; functional studies of the variants were not performed. All patients presented in the first year of life with severe spasticity of the lower limbs, mild spasticity of the upper limbs, nystagmus, and mental retardation. Brain imaging was consistent with hypomyelination affecting the supra- and infratentorial regions. The severity of the overall phenotype was variable.
In a sister and brother with hypomyelinating leukodystrophy-9, who were born to unrelated Maltese parents, Nafisinia et al. (2017) identified homozygosity for one of the mutations in the RARS gene (D2G; 107820.0001) previously reported in patients with HLD9 by Wolf et al. (2014). The mutation, found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Using Sanger sequencing of all 15 exons of the RARS gene, Nafisinia et al. (2017) screened a cohort of 45 patients with a hypomyelinating disorder who did not have a molecular diagnosis and identified a male patient, born to first-cousin Turkish parents, with compound heterozygous mutations in the RARS gene (107820.0006-107820.0007). Using fibroblast extracts from one of the affected sibs, Nafisinia et al. (2017) found that levels of RARS protein and the multi-RNA synthetase complex into which it assembles were significantly reduced.
In 2 sisters from the Netherlands with hypomyelinating leukodystrophy-9 (HLD9; 616140), Wolf et al. (2014) identified compound heterozygous mutations in the RARS gene: a c.5A-G transition (c.5A-G, NM_002887.3) in exon 1, resulting in an asp2-to-gly (D2G) substitution, and a G-to-T transversion in the donor splice site of exon 1 (c.45+1G-T; 107820.0002), predicted to result in the loss of a canonical splice site. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Variant Server databases. The D2G substitution is located in a 72-amino acid domain essential for integration of RARS into the multi-tRNA synthetase complex. Another child from the Netherlands with a similar phenotype was compound heterozygous for D2G and a 2-bp deletion (c.96_97del) in exon 2, resulting in a frameshift and premature termination (Cys32TrpfsTer39; 107820.0003).
In a sister and brother, born to unrelated Maltese parents, with HLD9, Nafisinia et al. (2017) identified homozygosity for the D2G mutation in the RARS gene. Fibroblast extracts from one of the sibs showed that levels of RARS protein and the multi-RNA synthetase complex into which it assembles were significantly reduced.
For discussion of the splice site mutation in the RARS gene (c.45+1G-T, NM_002887.3) that was found in compound heterozygous state in 2 sisters with hypomyelinating leukodystrophy-9 (HLD9; 616140) by Wolf et al. (2014), see 107820.0001.
For discussion of the 2-bp deletion in the RARS gene (c.96_97del, NM_002887.3) that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-9 (HLD9; 616140) by Wolf et al. (2014), see 107820.0001.
In a child from the Netherlands with hypomyelinating leukodystrophy-9 (HLD9; 616140), Wolf et al. (2014) identified compound heterozygous mutations in the RARS gene: a c.1A-G transition (c.1A-G, NM_002887.3) in exon 1 affecting the initiation codon, and a c.1535G-A transition in exon 13 resulting in an arg512-to-gln (R512Q; 107820.0005) substitution at a highly conserved residue in the core domain. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variants were filtered against the dbSNP (build 137), 1000 Genomes Project, and Exome Variant Server databases.
For discussion of the c.1535G-A transition (c.1535G-A, NM_002887.3) in exon 13 of the RARS gene, resulting in an arg512-to-gln (R512Q) substitution, that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-9 (HLD9; 616140) by Wolf et al. (2014), see 107820.0004.
In a male patient with hypomyelinating leukodystrophy-9 (HLD9; 616140), born of first-cousin Turkish parents, Nafisinia et al. (2017) identified compound heterozygosity for 2 mutations in the RARS gene: a c.1367C-T transition (c.1367C-T, NM_002887.3), resulting in a ser456-to-leu (S456L) substitution, and a 2-bp deletion (c.1846_1847delTA; 107820.0007), which resulted in a frameshift (Tyr61LeufsTer6) and a premature termination codon. Testing of the parents showed that the mother was heterozygous for the c.1376C-T mutation, whereas the father was variant negative, suggesting that the patient's deletion was either a de novo event or a consequence of nonpaternity. The patient was part of a cohort of 45 patients with a hypomyelinating disorder without a molecular diagnosis who were screened for mutation in the RARS gene.
For discussion of the 2-bp deletion (c.1846_1847delTA, NM_002887.3) in the RARS gene, resulting in a frameshift (Tyr616LeufsTer6), that was found in compound heterozygous state in a patient with hypomyelinating leukodystrophy-9 (HLD9; 616140) by Nafisinia et al. (2017), see 107820.0006.
Anderson, L. L., Mao, X., Scott, B. A., Crowder, C. M. Survival from hypoxia in C. elegans by inactivation of aminoacyl-tRNA synthetases. Science 323: 630-633, 2009. [PubMed: 19179530] [Full Text: https://doi.org/10.1126/science.1166175]
Arfin, S., Carlock, L., Gerken, S., Wasmuth, J. Clustering of genes encoding aminoacyl-tRNA synthetases on human chromosome 5. (Abstract) Am. J. Hum. Genet. 37: A228, 1985.
Carlock, L. R., Skarecky, D., Dana, S. L., Wasmuth, J. J. Deletion mapping of human chromosome 5 using chromosome-specific DNA probes. Am. J. Hum. Genet. 37: 839-852, 1985. [PubMed: 2996334]
Cui, H., Diedrich, J. K., Wu, D. C., Lim, J. J., Nottingham, R. M., Moresco, J. J., Yates, J. R., III, Blencowe, B. J., Lambowitz, A. M., Schimmel, P. Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2. Nature Cell Biol. 25: 592-603, 2023. Note: Erratum: Nature Cell Biol. 25: 1073 only, 2023. [PubMed: 37059883] [Full Text: https://doi.org/10.1038/s41556-023-01118-8]
Girjes, A. A., Hobson, K., Chen, P., Lavin, M. F. Cloning and characterization of cDNA encoding a human arginyl-tRNA synthetase. Gene 164: 347-350, 1995. [PubMed: 7590355] [Full Text: https://doi.org/10.1016/0378-1119(95)00502-w]
Nafisinia, M., Sobreira, N., Riley, L., Gold, W., Uhlenberg, B., Weiss, C., Boehm, C., Prelog, K., Ouvrier, R., Christodoulou, J. Mutations in RARS cause a hypomyelination disorder akin to Pelizaeus-Merzbacher disease. Europ. J. Hum. Genet. 25: 1134-1141, 2017. [PubMed: 28905880] [Full Text: https://doi.org/10.1038/ejhg.2017.119]
Wolf, N. I., Salomons, G. S., Rodenburg, R. J., Pouwels, P. J. W., Schieving, J. H., Derks, T. G. J., Fock, J. M., Rump, P., van Beek, D. M., van der Knaap, M. S., Waisfisz, Q. Mutations in RARS cause hypomyelination. Ann. Neurol. 76: 134-139, 2014. [PubMed: 24777941] [Full Text: https://doi.org/10.1002/ana.24167]