Alternative titles; symbols
HGNC Approved Gene Symbol: TRU-TCA1-1
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38): 19:45,478,601-45,478,687 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.32 | Thyroid hormone metabolism, abnormal, 3 | 620198 | Autosomal recessive | 3 |
Opal suppressor phosphoserine tRNAs are the only authentic, naturally occurring suppressor tRNAs in higher eukaryotes. The human genome contains a single opal suppressor phosphoserine tRNA gene, TRNAU1 (O'Neill et al., 1985).
O'Neill et al. (1985) isolated an opal suppressor phosphoserine tRNA gene and pseudogene from a human DNA library. The functional gene is 87 nucleotides in length without intervening sequences. It has a TCA anticodon, demonstrating that the mature tRNA reads the termination codon UGA. The 5-prime internal control region for transcription has 2 extra nucleotides compared with the consensus sequence for eukaryotic tRNA genes, while the 3-prime internal control region is normal.
Crystal Structure
O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase (SEPSECS; 613009) catalyzes the final step of selenocysteine formation. Palioura et al. (2009) determined the crystal structure of human tRNA(Sec) in complex with SEPSECS, phosphoserine, and thiophosphate, at a 2.8-angstrom resolution. Together with in vivo and in vitro enzyme assays, these data supported a pyridoxal phosphate-dependent mechanism of Sec-tRNA(Sec) formation. Two tRNA(Sec) molecules, with a fold distinct from other canonical tRNAs, bind to each SEPSECS tetramer through their 13-bp acceptor-T-psi(pseudouridine)-C arm. The tRNA binding is likely to induce a conformational change in the enzyme's active site that allows a phosphoserine covalently attached to tRNA(Sec), but not free phosphoserine, to be oriented properly for the reaction to occur.
McBride et al. (1987) used a fragment of the gene as a probe for mapping. By studies in somatic cell hybrids, they assigned the functional gene to chromosome 19 and the pseudogene to chromosome 22. By in situ hybridization, Mitchell et al. (1992) localized the TRSP gene to 19q13.2-q13.3 and ordered the locus with respect to other genes and anonymous DNA markers by linkage analysis in the 40 CEPH pedigrees. The order of loci was cen--CYP2A (see 122720)--CYP2F1 (124070)--APOC2 (608083)--TRSP, CKM (123310). These loci span about 10 cM in males and about 30 cM in females. Ohama et al. (1994) mapped the corresponding gene to mouse chromosome 7 in a region of known homology to 19q.
In an 8-year-old boy with abnormal thyroid hormone metabolism mapping to chromosome 19q13 (THMA3; 620198), Schoenmakers et al. (2016) sequenced the TRU-TCA1-1 gene and identified homozygosity for a point mutation (n.65C-G; 165060.0001) that segregated fully with disease in his consanguineous family and was not found in the ExAC database.
In a 19-year-old man with euthyroid hyperthyroxinemia, Geslot et al. (2021) identified homozygosity for the same n.65C-G mutation previously identified by Schoenmakers et al. (2016). His father, who had normal thyroid function tests, was heterozygous for the variant, which was not present in his mother; the patient was proven to present paternal uniparental disomy.
In an 8-year-old boy with abnormal thyroid hormone metabolism mapping to chromosome 19q13 (THMA3; 620198), Schoenmakers et al. (2016) sequenced the TRU-TCA1-1 gene and identified homozygosity for a point mutation (n.65C-G). His unaffected parents and an unaffected sib were heterozygous for the variant, which was not found in the ExAC database. In the heterozygous father, tRNA[Ser]Sec levels were reduced by 40% and comprised 74% wildtype and 26% mutant tRNAs, whereas in the proband, mutant tRNA[Ser]Sec levels were reduced by 70%. The authors noted that tRNA[Ser]Sec undergoes maturation into 2 major isoforms, mcm(5)U, upon which synthesis of housekeeping selenoproteins is dependent, and mcm(5)Um, required for production of stress-related selenoproteins. Quantification of the isoform populations in proband-derived primary cells revealed a 5-fold decrease in mcm(5)Um levels, consistent with the observed reduction in expression of stress-related selenoproteins in the proband. The heterozygous parents had normal selenoprotein levels. Experiments in Xenopus oocytes showed significantly attenuated post-transcription modifications with mutant tRNA[Ser]Sec compared to wildtype, confirming impairment of maturation of mutant tRNA[Ser]Sec. Complementation studies in proband-derived dermal fibroblasts demonstrated that expression of wildtype tRNA[Ser]Sec restored selenoprotein synthesis.
In a 19-year-old man with euthyroid hyperthyroxinemia, Geslot et al. (2021) identified homozygosity for the same n.65C-G mutation previously identified by Schoenmakers et al. (2016). His father, who had normal thyroid function tests, was heterozygous for the variant, which was not present in his mother; the patient was proven to present paternal uniparental disomy. Both father and son showed low-normal to low levels of the selenium-dependent enzymes GPX3 (138321) and SOD (see 147450).
Geslot, A., Savagner, F., Caron, P. Inherited selenocysteine transfer RNA mutation: clinical and hormonal evaluation of 2 patients. Europ. Thyroid J. 10: 542-547, 2021. [PubMed: 34956927] [Full Text: https://doi.org/10.1159/000518275]
McBride, O. W., Rajagopalan, M., Hatfield, D. Opal suppressor phosphoserine tRNA gene and pseudogene are located on human chromosomes 19 and 22, respectively. J. Biol. Chem. 262: 11163-11166, 1987. [PubMed: 3038909]
Mitchell, A., Bale, A. E., Lee, B. J., Hatfield, D., Harley, H., Rundle, S. A., Fan, Y. S., Fukushima, Y., Shows, T. B., McBride, O. W. Regional localization of the selenocysteine tRNA gene (TRSP) on human chromosome 19. Cytogenet. Cell Genet. 61: 117-120, 1992. [PubMed: 1395717] [Full Text: https://doi.org/10.1159/000133385]
O'Neill, V. A., Eden, F. C., Pratt, K., Hatfield, D. L. A human opal suppressor tRNA gene and pseudogene. J. Biol. Chem. 260: 2501-2508, 1985. [PubMed: 3156131]
Ohama, T., Choi, I. S., Hatfield, D. L., Johnson, K. R. Mouse selenocysteine tRNA(ser)-sec gene (Trsp) and its localization on chromosome 7. Genomics 19: 595-596, 1994. [PubMed: 8188307] [Full Text: https://doi.org/10.1006/geno.1994.1116]
Palioura, S., Sherrer, R. L., Steitz, T. A., Soll, D., Simonovic, M. The human SepSecS-tRNA(Sec) complex reveals the mechanism of selenocysteine formation. Science 325: 321-325, 2009. [PubMed: 19608919] [Full Text: https://doi.org/10.1126/science.1173755]
Schoenmakers, E., Carlson, B., Agostini, M., Moran, C., Rajanayagam, O., Bochukova, E., Tobe, R., Peat, R., Gevers, E., Muntoni, F., Guicheney, P., Schoenmakers, N., Farooqi, S., Lyons, G., Hatfield, D., Chatterjee, K. Mutation in human selenocysteine transfer RNA selectively disrupts selenoprotein synthesis. J. Clin. Invest. 126: 992-996, 2016. [PubMed: 26854926] [Full Text: https://doi.org/10.1172/JCI84747]