What is the Role of Thyroid Hormone Receptor Alpha 2 (TRα2) in Human Physiology?

Abstract

Thyroid hormone receptors are nuclear receptors that function as transcription factors and are regulated by thyroid hormones. To date, a number of variants and isoforms are known. This review focuses on the thyroid hormone receptor α (TRα), in particular TRα2, an isoform that arises from alternative splicing of the THRA mRNA transcript. Unlike the TRα1 isoform, which can bind T3, the TRα2 isoform lacks a ligand-binding domain but still binds to DNA thereby antagonizing the transcriptional activity of TRα1. Although a regulatory role has been proposed, the physiological function of this TRα2 antagonism is still unclear due to limited in vitro and mouse model data. Recently, the first patients with resistance to thyroid hormone due to mutations in THRA, the TRα encoding gene, affecting the antagonistic function of TRα2 were described, suggesting a significant role of this particular isoform in human physiology.

Key words

thyroid hormone receptor alpha - TRα2 - mutation - resistance to thyroid hormone - RTH - THRA

Publication History

Received: 30 September 2021
Received: 19 November 2021

Accepted: 25 November 2021

Article published online:
07 March 2022

• References

• 1 Brtko J. Thyroid hormone and thyroid hormone nuclear receptors: History and present state of art. Endocr Regul 2021; 55: 103-119 DOI: 10.2478/enr-2021-0012.
• 2 Refetoff S, Bassett JHD, Beck-Peccoz P. et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. J Clin Endocrinol Metab 2014; 99: 768-770 DOI: 10.1210/jc.2013-3393.
• 3 Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: Possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 1967; 27: 279-294 DOI: 10.1210/jcem-27-2-279.
• 4 Takeda K, Sakurai A, DeGroot LJ. et al. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-beta gene. J Clin Endocrinol Metab 1992; 74: 49-55 DOI: 10.1210/jcem.74.1.1727829.
• 5 Sakurai A, Takeda K, Ain K. et al. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta. Proc Natl Acad Sci 1989; 86: 8977-8981 DOI: 10.1073/pnas.86.22.8977.
• 6 Usala SJ, Tennyson GE, Bale AE. et al. A base mutation of the C-erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds. J Clin Invest 1990; 85: 93-100 DOI: 10.1172/JCI114438.
• 7 Pappa T, Refetoff S. Resistance to thyroid hormone beta: A focused review. Front Endocrinol 2021; 12: 656551 DOI: 10.3389/fendo.2021.656551.
• 8 Ohba K, Sasaki S, Misawa Nakamura H. et al. Clinical outcomes of 34 patients with resistance to thyroid hormone beta: A twenty-year experience in Japan. Endocr J 2021; DOI: 10.1507/endocrj.EJ21-0390.
• 9 Kakucska I, Rand W, Lechan RM. Thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus is dependent upon feedback regulation by both triiodothyronine and thyroxine. Endocrinology 1992; 130: 2845-2850 DOI: 10.1210/endo.130.5.1572297.
• 10 Dyess EM, Segerson TP, Liposits Z. et al. Triiodothyronine exerts direct cell-specific regulation of thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus. Endocrinology 1988; 123: 2291-2297 DOI: 10.1210/endo-123-5-2291.
• 11 Bochukova E, Schoenmakers N, Agostini M. et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med 2012; 366: 243-249 DOI: 10.1056/NEJMoa1110296.
• 12 van Mullem A, van Heerebeek R, Chrysis D. et al. Clinical phenotype and mutant TRα1. N Engl J Med 2012; 366: 1451-1453 DOI: 10.1056/NEJMc1113940.
• 13 Moran C, Agostini M, Visser WE. et al. Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)α1 and TRα2: Clinical, biochemical, and genetic analyses of three related patients. Lancet Diabetes Endocrinol 2014; 2: 619-626 DOI: 10.1016/S2213-8587(14)70111-1.
• 14 Tylki-Szymańska A, Acuna-Hidalgo R, Agostini M. et al. Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor α gene (THRA). J Med Genet 2015; 52: 312-316 DOI: 10.1136/jmedgenet-2014-102936.
• 15 Espiard S, Savagner F, Flamant F. et al. A Novel Mutation in THRA gene associated with an atypical phenotype of resistance to thyroid hormone. J Clin Endocrinol Metab 2015; 100: 2841-2848 DOI: 10.1210/jc.2015-1120.
• 16 Demir K, van Gucht ALM, Büyükinan M. et al. Diverse genotypes and phenotypes of three novel thyroid hormone receptor-α mutations. J Clin Endocrinol Metab 2016; 101: 2945-2954 DOI: 10.1210/jc.2016-1404.
• 17 van Gucht ALM, Meima ME, Zwaveling-Soonawala N. et al. Resistance to thyroid hormone alpha in an 18-month-old girl: Clinical, therapeutic, and molecular characteristics. Thyroid Off J Am Thyroid Assoc 2016; 26: 338-346 DOI: 10.1089/thy.2015.0463.
• 18 van Gucht ALM, Moran C, Meima ME. et al. Resistance to thyroid hormone due to heterozygous mutations in thyroid hormone receptor alpha. Curr Top Dev Biol 2017; 125: 337-355 DOI: 10.1016/bs.ctdb.2017.02.001.
• 19 Kalikiri MK, Mamidala MP, Rao AN. et al. Analysis and functional characterization of sequence variations in ligand binding domain of thyroid hormone receptors in autism spectrum disorder (ASD) patients. Autism Res 2017; 10: 1919-1928 DOI: 10.1002/aur.1838.
• 20 Moran C, Agostini M, McGowan A. et al. Contrasting phenotypes in resistance to thyroid hormone alpha correlate with divergent properties of thyroid hormone receptor α1 mutant proteins. Thyroid Off J Am Thyroid Assoc 2017; 27: 973-982 DOI: 10.1089/thy.2017.0157.
• 21 Korkmaz O, Ozen S, Ozdemir TR. et al. A novel thyroid hormone receptor alpha gene mutation, clinic characteristics, and follow-up findings in a patient with thyroid hormone resistance. Hormones 2019; 18: 223-227
• 22 le Maire A, Bouhours-Nouet N, Soamalala J. et al. Two novel cases of resistance to thyroid hormone due to THRA mutation. Thyroid Off J Am Thyroid Assoc 2020; 30: 1217-1221 DOI: 10.1089/thy.2019.0602.
• 23 Paisdzior S, Knierim E, Kleinau G. et al. A new mechanism in THRA resistance: The first disease-associated variant leading to an increased inhibitory function of THRA2. Int J Mol Sci 2021; 22: 5338 DOI: 10.3390/ijms22105338.
• 24 Sap J, Muñoz A, Damm K. et al. The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature 1986; 324: 635-640 DOI: 10.1038/324635a0.
• 25 Weinberger C, Thompson CC, Ong ES. et al. The c-erb-A gene encodes a thyroid hormone receptor. Nature 1986; 324: 641-646 DOI: 10.1038/324641a0.
• 26 Saatcioglu F, Deng T, Karin M. A novel cis element mediating ligand-independent activation by c-ErbA: Implications for hormonal regulation. Cell 1993; 75: 1095-1105 DOI: 10.1016/0092-8674(93)90319-L.
• 27 Ribeiro RCJ, Kushner PJ, Baxter JD. The nuclear hormone receptor gene superfamily. Annu Rev Med 1995; 46: 443-453 DOI: 10.1146/annurev.med.46.1.443.
• 28 Dahlman-Wright K, Grandien K, Nilsson S. et al. Protein-protein interactions between the DNA-binding domains of nuclear receptors: Influence on DNA-binding. J Steroid Biochem Mol Biol 1993; 45: 239-250 DOI: 10.1016/0960-0760(93)90338-W.
• 29 Bernal J, Morte B. Thyroid hormone receptor activity in the absence of ligand: Physiological and developmental implications. Biochim Biophys Acta BBA - Gen Subj 2013; 1830: 3893-3899 DOI: 10.1016/j.bbagen.2012.04.014.
• 30 Nelson CC, Hendy SC, Faris JS. et al. The effects of P-box substitutions in thyroid hormone receptor on DNA binding specificity. Mol Endocrinol 1994; 8: 829-840 DOI: 10.1210/mend.8.7.7984145.
• 31 Näär AM, Boutin J-M, Lipkin SM. et al. The orientation and spacing of core DNA-binding motifs dictate selective transcriptional responses to three nuclear receptors. Cell 1991; 65: 1267-1279 DOI: 10.1016/0092-8674(91)90021-P.
• 32 Mendoza A, Hollenberg AN. New insights into thyroid hormone action. Pharmacol Ther 2017; 173: 135-145 DOI: 10.1016/j.pharmthera.2017.02.012.
• 33 Zubkova I, Subauste JS. Sequences required for the transition from monomeric to homodimeric forms of thyroid hormone receptor α and v-erbA. Mol Cell Endocrinol 2003; 199: 61-72 DOI: 10.1016/S0303-7207(02)00299-X.
• 34 Li D, Li T, Wang F. et al. Functional evidence for retinoid X receptor (RXR) as a nonsilent partner in the thyroid hormone receptor/RXR heterodimer. Mol Cell Biol 2002; 22: 5782-5792 DOI: 10.1128/MCB.22.16.5782-5792.2002.
• 35 Li D, Yamada T, Wang F. et al. Novel roles of retinoid X receptor (RXR) and RXR ligand in dynamically modulating the activity of the thyroid hormone receptor/RXR heterodimer. J Biol Chem 2004; 279: 7427-7437 DOI: 10.1074/jbc.M311596200.
• 36 Muscat GE, Griggs R, Downes M. et al. Characterization of the thyroid hormone response element in the skeletal alpha-actin gene: Negative regulation of T3 receptor binding by the retinoid X receptor. Cell Growth Differ 1993; 4: 269-279
• 37 Flamant F, Cheng S-Y, Hollenberg AN. et al. Thyroid hormone signaling pathways: Time for a more precise nomenclature. Endocrinology 2017; 158: 2052-2057 DOI: 10.1210/en.2017-00250.
• 38 Mitsuhashi T, Tennyson GE, Nikodem VM. Alternative splicing generates messages encoding rat c-erbA proteins that do not bind thyroid hormone. Proc Natl Acad Sci 1988; 85: 5804-5808 DOI: 10.1073/pnas.85.16.5804.
• 39 Miyajima N, Horiuchi R, Shibuya Y. et al. Two erbA homologs encoding proteins with different T3 binding capacities are transcribed from opposite DNA strands of the same genetic locus. Cell 1989; 57: 31-39 DOI: 10.1016/0092-8674(89)90169-4.
• 40 Koenig RJ, Lazar MA, Hodin RA. et al. Inhibition of thyroid hormone action by a non-hormone binding c-erbA protein generated by alternative mRNA splicing. Nature 1989; 337: 659-661 DOI: 10.1038/337659a0.
• 41 Farsetti A, Lazar J, Phyillaier M. et al. Active repression by thyroid hormone receptor splicing variant alpha2 requires secific regulatory elements in the context of native triiodothyronine-regulated gene promoters. Endocrinology 1997; 138: 4705-4712 DOI: 10.1210/endo.138.11.5541.
• 42 Tagami T, Kopp P, Johnson W. et al. The thyroid hormone receptor variant α2 is a weak antagonist because it is deficient in interactions with nuclear receptor corepressors*. Endocrinology 1998; 139: 2535-2544 DOI: 10.1210/endo.139.5.6011.
• 43 Burgos-Trinidad M, Koenig RJ. Dominant negative activity of thyroid hormone receptor variant alpha2 and interaction with nuclear corepressors. Mol Cell Endocrinol 1999; 149: 107-114 DOI: 10.1016/s0303-7207(98)00253-6.
• 44 Lazar MA, Hodin RA, Chin WW. Human carboxyl-terminal variant of alpha-type c-erbA inhibits trans-activation by thyroid hormone receptors without binding thyroid hormone. Proc Natl Acad Sci 1989; 86: 7771-7774 DOI: 10.1073/pnas.86.20.7771.
• 45 Nagaya T, Jameson JL. Thyroid hormone receptor dimerization is required for dominant negative inhibition by mutations that cause thyroid hormone resistance. J Biol Chem 1993; 268: 15766-15771 DOI: 10.1016/S0021-9258(18)82321-3.
• 46 Liu RT, Suzuki S, Miyamoto T. et al. The dominant negative effect of thyroid hormone receptor splicing variant alpha 2 does not require binding to a thyroid response element. Mol Endocrinol 1995; 9: 86-95 DOI: 10.1210/mend.9.1.7760853.
• 47 Katz D, Reginato MJ, Lazar MA. Functional regulation of thyroid hormone receptor variant TR alpha 2 by phosphorylation. Mol Cell Biol 1995; 15: 2341-2348 DOI: 10.1128/MCB.15.5.2341.
• 48 Rentoumis A, Krishna V, Chatterjee K. et al. Negative and positive transcriptional regulation by thyroid hormone receptor isoforms. Mol Endocrinol 1990; 4: 1522-1531 DOI: 10.1210/mend-4-10-1522.
• 49 Minakhina S, Bansal S, Zhang A. et al. A direct comparison of thyroid hormone receptor protein levels in mice provides unexpected insights into thyroid hormone action. Thyroid Off J Am Thyroid Assoc 2020; 30: 1193-1204 DOI: 10.1089/thy.2019.0763.
• 50 Visser WE, Swagemakers SMA, Ozgur Z. et al. Transcriptional profiling of fibroblasts from patients with mutations in MCT8 and comparative analysis with the human brain transcriptome. Hum Mol Genet 2010; 19: 4189-4200 DOI: 10.1093/hmg/ddq337.
• 51 Casas F, Busson M, Grandemange S. et al. Characterization of a novel thyroid hormone receptor α variant involved in the regulation of myoblast differentiation. Mol Endocrinol 2006; 20: 749-763 DOI: 10.1210/me.2005-0074.
• 52 Plateroti M, Gauthier K, Domon-Dell C. et al. Functional interference between thyroid hormone receptor (TR) and natural truncated TR isoforms in the control of intestine development. Mol Cell Biol 2001; Jul (21) 14
• 53 Chassande O, Fraichard A, Gauthier K. et al. Identification of transcripts initiated from an internal promoter in the c-erbAα locus that encode inhibitors of retinoic acid receptor-α and triiodothyronine receptor activities. Mol Endocrinol 1997; 11: 1278-1290 DOI: 10.1210/mend.11.9.9972.
• 54 Kalyanaraman H, Schwappacher R, Joshua J. et al. Nongenomic thyroid hormone signaling occurs through a plasma membrane – localized receptor. Sci Signal 2014; 7: ra48 DOI: 10.1126/scisignal.2004911.
• 55 Wrutniak-Cabello C, Casas F, Cabello G. Mitochondrial T3 receptor and targets. Mol Cell Endocrinol 2017; 458: 112-120 DOI: 10.1016/j.mce.2017.01.054.
• 56 Furman AE, Dumitrescu AM, Refetoff S. et al. Early diagnosis and treatment of an infant with a novel thyroid hormone receptor α gene (pC380SfsX9) mutation. Thyroid 2021; 31: 1003-1005 DOI: 10.1089/thy.2020.0695.
• 57 Moran C, Schoenmakers N, Agostini M. et al. An adult female with resistance to thyroid hormone mediated by defective thyroid hormone receptor α. J Clin Endocrinol Metab 2013; 98: 4254-4261 DOI: 10.1210/jc.2013-2215.
• 58 Yuen RKC, Thiruvahindrapuram B, Merico D. et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat Med 2015; 21: 185-191 DOI: 10.1038/nm.3792.
• 59 Sun H, Wu H, Xie R. et al. New case of thyroid hormone resistance α caused by a mutation of THRA/TRα1. J Endocr Soc 2019; 3: 665-669 DOI: 10.1210/js.2019-00011.
• 60 van Mullem AA, Chrysis D, Eythimiadou A. et al. Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRα1 receptor: Consequences of LT4 treatment. J Clin Endocrinol Metab 2013; 98: 3029-3038 DOI: 10.1210/jc.2013-1050.
• 61 Wejaphikul K, van Gucht ALM, Groeneweg S. et al. The in vitro functional impairment of thyroid hormone receptor alpha 1 isoform mutants is mainly dictated by reduced ligand sensitivity. Thyroid. 2019; 29: 1834-1842 DOI: 10.1089/thy.2019.0019.
• 62 Macchia PE, Takeuchi Y, Kawai T. et al. Increased sensitivity to thyroid hormone in mice with complete deficiency of thyroid hormone receptor α. Proc Natl Acad Sci 2001; 98: 349-354 DOI: 10.1073/pnas.98.1.349.
• 63 Pilhatsch M, Winter C, Nordström K. et al. Increased depressive behaviour in mice harboring the mutant thyroid hormone receptor alpha 1. Behav Brain Res 2010; 214: 187-192 DOI: 10.1016/j.bbr.2010.05.016.
• 64 Hönes GS, Rakov H, Logan J. et al. Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo. Proc Natl Acad Sci 2017; 114: E11323-E11332 DOI: 10.1073/pnas.1706801115.
• 65 Bao L, Roediger J, Park S. et al. Thyroid hormone receptor alpha mutations lead to epithelial defects in the adult intestine in a mouse model of resistance to thyroid hormone. Thyroid 2019; 29: 439-448 DOI: 10.1089/thy.2018.0340.
• 66 Liang Y, Zhao D, Wang R. et al. Generation and characterization of a new resistance to thyroid hormone mouse model with thyroid hormone receptor alpha gene mutation. Thyroid 2021; 31: 678-691 DOI: 10.1089/thy.2019.0733.
• 67 Saltó C, Kindblom JM, Johansson C. et al. Ablation of TRα2 and a concomitant overexpression of α1 yields a mixed hypo- and hyperthyroid phenotype in mice. Mol Endocrinol 2001; 15: 2115-2128 DOI: 10.1210/mend.15.12.0750.
• 68 Mansouri A, Chowdhury K, Gruss P. Follicular cells of the thyroid gland require Pax8 gene function. Nat Genet 1998; 19: 87-90 DOI: 10.1038/ng0598-87.
• 69 Gauthier K, Plateroti M, Harvey CB. et al. Genetic analysis reveals different functions for the products of the thyroid hormone receptor α locus. Mol Cell Biol 2001; 21: 4748-4760 DOI: 10.1128/MCB.21.14.4748-4760.2001.
• 70 Flamant F, Poguet A-L, Plateroti M. et al. Congenital hypothyroid Pax8−/− mutant mice can be rescued by inactivating the TRα gene. Mol Endocrinol 2002; 16: 24-32 DOI: 10.1210/mend.16.1.0766.
• 71 Mittag J, Friedrichsen S, Heuer H. et al. Athyroid Pax8−/− mice cannot be rescued by the inactivation of thyroid hormone receptor α1. Endocrinology 2005; 146: 3179-3184 DOI: 10.1210/en.2005-0114.