Alternative titles; symbols
HGNC Approved Gene Symbol: TXNRD2
Cytogenetic location: 22q11.21 Genomic coordinates (GRCh38) : 22:19,875,522-19,941,818 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.21 | ?Glucocorticoid deficiency 5 | 617825 | Autosomal recessive | 3 |
Thioredoxin reductases (EC 1.6.4.5), such as TXNRD2, are selenocysteine (sec)-containing flavoenzymes that maintain thioredoxins, small proteins that catalyze redox reactions, in the reduced state using the reducing power of NADPH. The sec residue, which is essential for enzyme activity, is located in the penultimate C-terminal position and is encoded by a UGA codon. Sec differs from cys in that it substitutes selenium, a better nucleophile, for sulfur. Termination of polypeptide synthesis is prevented by a stem-loop structure called the selenocysteine insertion sequence, or SECIS, which is located in the 3-prime UTR (Gasdaska et al., 1999; Sun et al., 1999).
By screening placenta, heart, and fetal heart cDNA libraries with a fragment of TR-alpha (TXNRD1; 601112) as probe, Gasdaska et al. (1999) isolated a cDNA encoding TXNRD2, which they called TR-beta. The deduced 524-amino acid protein, which is 54% identical to TXNRD1, has a high content of positively charged residues in the N terminus and a conserved penultimate sec residue. Analysis of the 3-prime UTR revealed the presence of a region with the sequence and structure of a SECIS, although it is distinct from that of TXNRD1. Northern blot analysis detected ubiquitous expression of a 2.4-kb TXNRD2 transcript, with highest levels in prostate, testis, liver, uterus, and small intestine; this expression pattern is distinct from that of TXNRD1. Western blot analysis showed expression of a 54-kD cytosolic protein.
By searching an EST database for sequences homologous to TXNRD1, Miranda-Vizuete et al. (1999) obtained a nearly complete cDNA encoding TXNRD2, which they called TRXR2. The predicted protein contains an N-terminal mitochondrial localization sequence (MLS), conserved FAD- and NADPH-binding domains, and a conserved active site. Fluorescence microscopy and mutation analysis demonstrated a mitochondrial localization that requires the presence of the N-terminal MLS.
By EST database searching, Sun et al. (1999) identified TXNRD2, which they called TR3, as well as TXNRD3 (606235), which they called TR2.
By EST database searching for sequences that could adopt a SECIS-like secondary structure, glutathione peroxidase functional analysis, and 5-prime RACE, Lescure et al. (1999) identified 2 cDNAs encoding isoforms of TXNRD2, which they termed SELZ.
Prasad et al. (2014) observed ubiquitous expression of TXNRD2 mRNA in human tissues tested, with highest expression in adrenal cortex.
By genomic sequence analysis, Miranda-Vizuete et al. (1999) determined that the TXNRD2 gene contains 18 exons and spans 67 kb.
By STS analysis and genomic sequence analysis, respectively, Miranda-Vizuete et al. (1999) and Sun et al. (1999) mapped the TXNRD2 gene to chromosome 22q11.2. Miranda-Vizuete et al. (1999) and Kawai et al. (2000) mapped the mouse gene to chromosome 16.
Gasdaska et al. (1999) showed that TXNRD2 was a thioredoxin reductase that could directly reduce proteins such as insulin.
Prasad et al. (2014) knocked down TXNRD2 in the H295R human adrenocortical cell line by shRNA and observed no effect on cell vitality. However, a clear impact on mitochondrial redox homeostasis was demonstrated, with increased pressure on the glutathione system as evidenced by a decrease in the oxidized (GSH) to reduced glutathione (GSSG) ratio. The ability to maintain mitochondrial PRDX3 (604769) in its reduced form was impaired, with a significant decrease in the ratio of the reduced monomeric to the oxidized dimeric form in TXNRD2-deficient cells compared to controls. In addition, knocked-down cells showed an approximately 3-fold increase in levels of mitochondrial reactive oxygen species, further demonstrating impairment of redox regulation.
Glucocorticoid Deficiency 5
In a consanguineous Kashmiri kindred with glucocorticoid deficiency (GCCD5; 617825), Prasad et al. (2014) identified homozygosity for a nonsense mutation in the TXNRD2 gene (Y447X; 606448.0001) that segregated with disease. Heterozygotes in the family were clinically unaffected, and none of the family members, heterozygous or homozygous, had any evidence of cardiomyopathy or conduction disease.
Associations Pending Confirmation
Sibbing et al. (2011) sequenced the TXNRD2 gene in 227 German patients diagnosed with dilated cardiomyopathy (CMD; see 115200) and detected 2 heterozygous missense mutations in 3 patients: an A59T substitution in 2 of them, and a G375R substitution in 1. In addition to CMD, all 3 patients exhibited conduction disease, with left bundle-branch block, right bundle-branch block, and first-degree atrioventricular block in 1 patient each. The mutations involved highly conserved residues within the FAD-binding domain, and neither mutation was found in 683 healthy population-based controls. Functional analysis in Txnrd2 -/- mouse embryonic fibroblasts showed that reconstitution with wildtype Txnrd2 fully rescued cell death, whereas rescue did not occur with the Txnrd2 mutants, and Txnrd2 +/+ cells transduced with either mutant showed reduced survival, suggesting a dominant-negative effect.
Duplications of human chromosome 22q11.2 (608363) are associated with elevated rates of mental retardation, autism, and many other behavioral phenotypes. Suzuki et al. (2009) determined the developmental impact of overexpression of an approximately 190-kb segment of human 22q11.2, which includes the genes TXNRD2, COMT (116790), and ARVCF (602269), on behaviors in bacterial artificial chromosome (BAC) transgenic mice. BAC transgenic mice and wildtype mice were tested for their cognitive capacities, affect- and stress-related behaviors, and motor activity at 1 and 2 months of age. BAC transgenic mice approached a rewarded goal faster (i.e., incentive learning), but were impaired in delayed rewarded alternation during development. In contrast, BAC transgenic and wildtype mice were indistinguishable in rewarded alternation without delays, spontaneous alternation, prepulse inhibition, social interaction, anxiety-, stress-, and fear-related behaviors, and motor activity. Compared with wildtype mice, BAC transgenic mice had a 2-fold higher level of COMT activity in the prefrontal cortex, striatum, and hippocampus. Suzuki et al. (2009) suggested that overexpression of this 22q11.2 segment may enhance incentive learning and impair the prolonged maintenance of working memory, but has no apparent affect on working memory per se, affect- and stress-related behaviors, or motor capacity. High copy numbers of this 22q11.2 segment may contribute to a highly selective set of phenotypes in learning and cognition during development.
Horstkotte et al. (2011) generated mice with cardiomyocyte-specific loss of Txnrd2 and observed no impairment of left ventricular function in the absence of ischemia/reperfusion (I/R) stress. After I/R, homozygous mice showed more severe systolic dysfunction and cardiomyocyte death than heterozygotes. The homozygotes also showed loss of mitochondrial integrity and function, which resolved on pretreatment with the reactive oxygen species scavenger N-acetylcysteine and the mitochondrial permeability transition pore blocker cyclosporin A. Txnrd2 deletion in mouse embryonic endothelial precursor cells and embryonic stem cell-derived cardiomyocytes, or Txnrd2 silencing by shRNA in adult HL-1 cardiomyocytes, resulted in increased cell death after I/R unless N-acetylcysteine was coadministered. Horstkotte et al. (2011) suggested that TXNRD2 may play a role in reducing mitochondrial reactive oxygen species, thereby preventing opening of the mitochondrial permeability transition pore.
Fernandez et al. (2019) found that knockdown of Txnrd2 in layer 2/3 projection neurons (PNs) of mice elevated mitochondrial reactive oxygen species levels and diminished growth and differentiation of layer 2/3 PNs, recapitulating the phenotype of LgDel mice, a model of 22q11 deletion syndrome. Treatment with antioxidant N-acetylcysteine corrected mitochondrial stress-related underconnectivity by restoring cytologic, mitochondrial, and synaptic integrity of layer 2/3 PNs in LgDel mice and resolved their corticocortical-related cognitive deficits.
In affected members of a consanguineous Kashmiri kindred with glucocorticoid deficiency (GCCD5; 617825), Prasad et al. (2014) identified homozygosity for a c.1341T-G transversion (c.1341T-G, NM_006440.3) in exon 15 of the TXNRD2 gene, resulting in a tyr447-to-ter (Y447X) substitution. The mutation segregated with disease in the family and was not found in the NHLBI ESP6500 database; however, it was submitted to the dbSNP database ({dbSNP ss491568437}) and was present in heterozygosity at a minor allele frequency of 1.04% in a control population of 1,000 healthy adult British Pakistanis. Western blot of patient lysates revealed absence of the protein in homozygous patients compared to a heterozygous carrier and control; however, patients showed normal expression of cytoplasmic TXNRD1 (601112). TXNRD2 cDNA was absent on RT-PCR, consistent with nonsense-mediated decay; direct sequencing of the amplicon from a heterozygous carrier confirmed amplification of the wildtype sequence alone.
Fernandez, A., Meechan, D. W., Karpinski, B. A., Paronett, E. M., Bryan, C. A., Rutz, H. L., Radin, E. A., Lubin, N., Bonner, E. R., Popratiloff, A., Rothblat, L. A., Maynard, T. M., LaMantia, A.-S. Mitochondrial dysfunction leads to cortical under-connectivity and cognitive impairment. Neuron 102: 1127-1142, 2019. [PubMed: 31079872] [Full Text: https://doi.org/10.1016/j.neuron.2019.04.013]
Gasdaska, P. Y., Berggren, M. M., Berry, M. J., Powis, G. Cloning, sequencing, and functional expression of a novel human thioredoxin reductase. FEBS Lett. 442: 105-111, 1999. [PubMed: 9923614] [Full Text: https://doi.org/10.1016/s0014-5793(98)01638-x]
Horstkotte, J., Perisic, T., Schneider, M., Lange, P., Schroeder, M., Kiermayer, C., Hinkel, R., Ziegler, T., Mandal, P. K., David, R., Schulz, S., Schmitt, S., and 11 others. Mitochondrial thioredoxin reductase is essential for early postischemic myocardial protection. Circulation 124: 2892-2902, 2011. [PubMed: 22144571] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.111.059253]
Kawai, H., Ota, T., Suzuki, F., Tatsuka, M. Molecular cloning of mouse thioredoxin reductases. Gene 242: 321-330, 2000. [PubMed: 10721726] [Full Text: https://doi.org/10.1016/s0378-1119(99)00498-9]
Lescure, A., Gautheret, D., Carbon, P., Krol, A. Novel selenoproteins identified in silico and in vivo by using a conserved RNA structural motif. J. Biol. Chem. 274: 38147-38154, 1999. [PubMed: 10608886] [Full Text: https://doi.org/10.1074/jbc.274.53.38147]
Miranda-Vizuete, A., Damdimopoulos, A. E., Pedrajas, J. R., Gustafsson, J.-A., Spyrou, G. Human mitochondrial thioredoxin reductase: cDNA cloning, expression, and genomic organization. Europ. J. Biochem. 261: 405-412, 1999. [PubMed: 10215850] [Full Text: https://doi.org/10.1046/j.1432-1327.1999.00286.x]
Miranda-Vizuete, A., Damdimopoulos, A. E., Spyrou, G. cDNA cloning, expression and chromosomal localization of the mouse mitochondrial thioredoxin reductase gene. Biochim. Biophys. Acta 1447: 113-118, 1999. [PubMed: 10500251] [Full Text: https://doi.org/10.1016/s0167-4781(99)00129-3]
Prasad, R., Chan, L. F., Hughes, C. R., Kaski, J. P., Kowalczyk, J. C., Savage, M. O., Peters, C. J., Nathwani, N., Clark, A. J. L., Storr, H. L., Metherell, L. A. Thioredoxin reductase 2 (TXNRD2) mutation associated with familial glucocorticoid deficiency (FGD). J. Clin. Endocr. Metab. 99: E1556-E1563, 2014. Note: Electronic Article. [PubMed: 24601690] [Full Text: https://doi.org/10.1210/jc.2013-3844]
Sibbing, D., Pfeufer, A., Perisic, T., Mannes, A. M., Fritz-Wolf, K., Unwin, S., Sinner, M. F., Gieger, C., Gloeckner, C. J., Wichmann, H.-E., Kremmer, E., Schafer, Z., and 10 others. Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy. Europ. Heart J. 32: 1121-1133, 2011. [PubMed: 21247928] [Full Text: https://doi.org/10.1093/eurheartj/ehq507]
Sun, Q.-A., Wu, Y., Zappacosta, F., Jeang, K.-T., Lee, B. J., Hatfield, D. L., Gladyshev, V. N. Redox regulation of cell signaling by selenocysteine in mammalian thioredoxin reductases. J. Biol. Chem. 274: 24522-24530, 1999. [PubMed: 10455115] [Full Text: https://doi.org/10.1074/jbc.274.35.24522]
Suzuki, G., Harper, K. M., Hiramoto, T., Funke, B., Lee, M., Kang, G., Buell, M., Geyer, M. A., Kucherlapati, R., Morrow, B., Mannisto, P. T., Agatsuma, S., Hiroi, N. Over-expression of a human chromosome 22q11.2 segment including TXNRD2, COMT and ARVCF developmentally affects incentive learning and working memory in mice. Hum. Molec. Genet. 18: 3914-3925, 2009. [PubMed: 19617637] [Full Text: https://doi.org/10.1093/hmg/ddp334]