Alternative titles; symbols
HGNC Approved Gene Symbol: TARS1
Cytogenetic location: 5p13.3 Genomic coordinates (GRCh38): 5:33,440,696-33,468,091 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.3 | Trichothiodystrophy 7, nonphotosensitive | 618546 | Autosomal recessive | 3 |
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-null and 1 catalytic domain-retained splice variants for ThrRS.
Arfin et al. (1985) assigned the gene for threonyl-tRNA synthetase to chromosome 5 by study of somatic cell hybrids. Of the 7 aminoacyl-tRNA synthetase genes mapped to that time, 4 were known to be on chromosome 5, which represents only about 7% of the total human genome. By study of human-hamster cell hybrids, Arfin et al. (1985) determined that TARS is very closely linked to LARS (151350); the latter is located at 5pter-q11, according to Arfin et al. (1985).
Gerken et al. (1986) mapped the TARS gene to 5p13-cen by an analysis of isoelectric focusing patterns of this enzyme from human x Chinese hamster interspecific somatic cell hybrids. The gene is close to the gene for LARS which, they stated, maps to 5cen-q11.
In 2 unrelated patients with nonphotosensitive trichothiodystrophy (TTD7; 618546), Theil et al. (2019) identified biallelic mutations in the TARS gene (187790.0001-187790.0003). Functional analysis demonstrated loss-of-function effects with the mutations.
In a patient (TTD18PV) with nonphotosensitive trichothiodystrophy (TTD7; 618546), Theil et al. (2019) identified compound heterozygosity for a c.1912C-T transition (c.1912C-T, NM_152295.4) in the TARS gene, resulting in an arg638-to-ter (R638X) substitution within the anticodon-binding domain, and a c.826A-G transition, resulting in a lys276-to-glu (K276E; 187790.0002) substitution at a highly conserved residue. The K276E mutation was not found in public variant databases, whereas the R638X mutation was present in the ExAC database, only in heterozygosity, at an allele frequency of 0.00008661. Familial segregation was not reported. Immunoblot analysis of patient fibroblast lysates revealed an approximately 80% reduction in full-length TARS compared to control fibroblasts. Allele-specific qRT-PCR showed that only 10% of total TARS mRNA in TTD18PV fibroblasts originated from R638X, suggesting that most TARS proteins contained the K276E variant, consistent with severe protein instability of the missense mutation. Plasmid-shuffling experiments in a yeast knockout strain deprived of the TARS ortholog Ths1 demonstrated dramatically reduced growth with either mutant compared to wildtype TARS. Analysis of steady-state aminoacylation reactions on protein lysates from patient fibroblasts showed an approximately 70 to 80% reduction of threonine tRNA charging activity compared to control fibroblasts, confirming a loss-of-function effect of the mutations.
For discussion of the c.826A-G transition (c.826A-G, NM_152295.4) in the TARS gene, resulting in a lys276-to-glu (K276E) substitution, that was found in compound heterozygous state in a patient with nonphotosensitive trichothiodystrophy (TTD7; 618546) by Theil et al. (2019), see 187790.0001.
In a patient (TTD5VI) with nonphotosensitive trichothiodystrophy (TTD7; 618546), Theil et al. (2019) identified homozygosity for a c.680T-C transition (c.680T-C, NM_152295.4) in the TARS gene, resulting in a leu227-to-pro (L227P) substitution at a highly conserved residue within the second additional domain. The authors referred to the nucleotide change as c.779T-C in Figure 1 of the report. The mutation was not found in public variant databases; familial segregation was not reported. Immunoblot analysis of patient fibroblast lysates revealed an approximately 80% reduction in full-length TARS compared to control fibroblasts. Plasmid-shuffling experiments in a yeast knockout strain deprived of the TARS ortholog Ths1 demonstrated dramatically reduced growth with the L227P mutant compared to wildtype TARS. Analysis of steady-state aminoacylation reactions on protein lysates from patient fibroblasts showed an approximately 70 to 80% reduction of threonine tRNA charging activity compared to control fibroblasts, confirming a loss-of-function effect of the mutation.
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 only, 1985.
Gerken, S. C., Wasmuth, J. J., Arfin, S. M. Threonyl-tRNA synthetase gene maps close to leucyl-tRNA synthetase gene on human chromosome 5. Somat. Cell Molec. Genet. 12: 519-522, 1986. [PubMed: 3464105] [Full Text: https://doi.org/10.1007/BF01539923]
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]
Theil, A. F., Botta, E., Raams, A., Smith, D. E. C., Mendes, M. I., Caligiuri, G., Giachetti, S., Bione, S., Carriero, R., Liberi, G., Zardoni, L., Swagemakers, S. M. A., Salomons, G. S., Sarasin, A., Lehmann, A., van der Spek, P. J., Ogi, T., Hoeijmakers, J. H. J., Vermeulen, W., Orioli, D. Bi-allelic TARS mutations are associated with brittle hair phenotype. Am. J. Hum. Genet. 105: 434-440, 2019. [PubMed: 31374204] [Full Text: https://doi.org/10.1016/j.ajhg.2019.06.017]