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Journal of Pediatric Endocrinology and Metabolism

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Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Toppari, Jorma

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Volume 29, Issue 5


Resistance to thyroid hormone α, revelation of basic study to clinical consequences

Yaling Tang
  • Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, P. R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Miao Yu
  • Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, P. R. China
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Xiaolan LianORCID iD: http://orcid.org/0000-0001-5369-9466
Published Online: 2016-01-14 | DOI: https://doi.org/10.1515/jpem-2015-0286


In the past 3 years, 15 patients with resistance to thyroid hormone α (RTHα), nine THRA gene mutations have been reported, reforming classification of RTH. RTHα exhibits distinguished clinical manifestations from RTHβ, including growth retardation, skeletal dysplasia, impaired neurodevelopment, cardiovascular dysfunction, constipation and specific thyroid axis type. This review focuses on possible pathogenesis by revelatory basic science of RTHα animal models in vivo, and patients’ mutant thyroid hormone receptor α (TRα) in vitro. Clinical manifestations and L-T4 effects are summarized, showing strong correlation to the severity of mutation mostly within the domain which dominated TR interaction with T3 and its corepressors/coactivators. In particular, we propose the diagnosis clues and promising treatment for clinicians.

Keywords: clinical consequences; pathogenesis; resistance to thyroid hormone α; Thra mice gene mutant mice; thyroid hormone receptor α


  • 1.

    Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev 2010;31:139–70.Google Scholar

  • 2.

    Brent GA. Mechanisms of thyroid hormone action. J Clin Invest 2012;122:3035–43.Google Scholar

  • 3.

    Ortiga-Carvalho TM, Sidhaye AR, Wondisford FE. Thyroid hormone receptors and resistance to thyroid hormone disorders. Nature Reviews Endocrinology 2014;10:582–91.Google Scholar

  • 4.

    Fliers E, Kalsbeek A, Boelen A. Beyond the fixed setpoint of the hypothalamus-pituitary-thyroid axis. Eur J Endocrinol 2014;171:R197–208.Google Scholar

  • 5.

    Chiamolera MI, Wondisford FE. Minireview: thyrotropin-releasing hormone and the thyroid hormone feedback mechanism. Endocrinology 2009;150:1091–6.Google Scholar

  • 6.

    Sap J, Munoz A, Damm K, Goldberg Y, Ghysdael J, et al. The c-erb-A protein is a high-affinity receptor for thyroid hormone. Nature 1986;324:635-40.Google Scholar

  • 7.

    Refetoff S, Bassett JH, Beck-Peccoz P, Bernal J, Brent G, et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. Thyroid 2014;24:407–9.Google Scholar

  • 8.

    Lafranchi SH, Snyder DB, Sesser DE, Skeels MR, Singh N, Brent GA, Nelson JC. Follow-up of newborns with elevated screening T4 concentrations. J Pediatr 2003;143:296–301.Google Scholar

  • 9.

    Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med 2012;366:243–9.Google Scholar

  • 10.

    Dundar B, Bober E, Buyukgebiz A. Successful therapy with L-T4 in a 5 year-old boy with generalized thyroid hormone resistance. J Pediatr Endocrinol Metab 2003;16:1051–6.Google Scholar

  • 11.

    Guran T, Turan S, Bircan R, Bereket A. 9 years follow-up of a patient with pituitary form of resistance to thyroid hormones (PRTH): comparison of two treatment periods of D-thyroxine and triiodothyroacetic acid (TRIAC). J Pediatr Endocrinol Metab 2009;22:971–8.Google Scholar

  • 12.

    Ramos-Prol A, Antonia Perez-Lazaro M, Isabel Del Olmo-Garcia M, Leon-De Zayas B, Moreno-Macian F, et al. Differentiated thyroid carcinoma in a girl with resistance to thyroid hormone management with triiodothyroacetic acid. J Pediatr Endocrinol Metab 2013;26:133–6.Google Scholar

  • 13.

    Kaneshige M, Suzuki H, Kaneshige K, Cheng J, Wimbrow H, et al. A targeted dominant negative mutation of the thyroid hormone alpha 1 receptor causes increased mortality, infertility, and dwarfism in mice. Proc Natl Acad Sci USA 2001;98:15095–100.Google Scholar

  • 14.

    Moran C, Schoenmakers N, Agostini M, Schoenmakers E, Offiah A, et al. An adult female with resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha. J Clin Endocrinol Metab 2013;98:4254–61.Google Scholar

  • 15.

    Van Mullem A, Van Heerebeek R, Chrysis D, Visser E, Medici M, et al. Clinical phenotype and mutant TRalpha1. N Engl J Med 2012;366:1451–3.Google Scholar

  • 16.

    Moran C, Agostini M, Visser WE, Schoenmakers E, Schoenmakers N, et al. Resistance to thyroid hormone caused by a mutation in thyroid hormone receptor (TR)alpha1 and TRalpha2: clinical, biochemical, and genetic analyses of three related patients. Lancet Diabetes Endocrinol 2014;2:619–26.Google Scholar

  • 17.

    Tylki-Szymanska A, Acuna-Hidalgo R, Krajewska-Walasek M, Lecka-Ambroziak A, Steehouwer M, et al. Thyroid hormone resistance syndrome due to mutations in the thyroid hormone receptor alpha gene (Thra). J Med Genet, 2015;52:312–6.Google Scholar

  • 18.

    Espiard S, Savagner F, Flamant F, Vlaeminck-Guillem V, Guyot R, et al. A novel mutation in Thra gene associated with an atypical phenotype of resistance to thyroid hormone. J Clin Endocrinol Metab 2015;100:2841-8.Google Scholar

  • 19.

    Yuen RK, Thiruvahindrapuram B, Merico D, Walker S, Tammimies K, et al. Whole-genome sequencing of quartet families with autism spectrum disorder. Nat Med 2015;21:185–91.Google Scholar

  • 20.

    Fraichard A, Chassande O, Plateroti M, Roux JP, Trouillas J, et al. The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production. Embo J 1997;16:4412–20.Google Scholar

  • 21.

    Wikstrom L, Johansson C, Salto C, Barlow C, Campos Barros A, et al. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. Embo J 1998;17:455–61.Google Scholar

  • 22.

    Gloss B, Trost S, Bluhm W, Swanson E, Clark R, et al. Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor alpha or beta. Endocrinology 2001;142:544–50.Google Scholar

  • 23.

    Mansen A, YU F, Forrest D, Larsson L, Vennstrom B. TRs have common and isoform-specific functions in regulation of the cardiac myosin heavy chain genes. Mol Endocrinol 2001;15:2106–14.Google Scholar

  • 24.

    Morte B, Manzano J, Scanlan T, Vennstrom B, Bernal J. Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism. Proc Natl Acad Sci USA 2002;99:3985–9.Google Scholar

  • 25.

    Makino A, Wang H, Scott BT, Yuan JX, Dillmann WH. Thyroid hormone receptor-alpha and vascular function. Am J Physiol Cell Physiol 2012;302:C1346–52.Google Scholar

  • 26.

    Van Mullem AA, Visser TJ, Peeters RP. Clinical consequences of mutations in thyroid hormone receptor-alpha1. Eur Thyroid J 2014;3:17–24.Google Scholar

  • 27.

    O’shea PJ, Bassett JH, Sriskantharajah S, Ying H, Cheng SY, et al. Contrasting skeletal phenotypes in mice with an identical mutation targeted to thyroid hormone receptor alpha1 or beta. Mol Endocrinol 2005;19:3045–59.Google Scholar

  • 28.

    Bassett JH, Boyde A, Zikmund T, Evans H, Croucher PI, et al. Thyroid hormone receptor alpha mutation causes a severe and thyroxine-resistant skeletal dysplasia in female mice. Endocrinology 2014;155:3699–712.Google Scholar

  • 29.

    Tinnikov A, Nordstrom K, Thoren P, Kindblom JM, Malin S, et al. Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1. Embo J 2002;21: 5079–87.Google Scholar

  • 30.

    Tavi P, Sjogren M, Lunde PK, Zhang SJ, Abbate F, et al. Impaired Ca2+ handling and contraction in cardiomyocytes from mice with a dominant negative thyroid hormone receptor alpha1. J Mol Cell Cardiol 2005;38:655–63.Google Scholar

  • 31.

    Venero C, Guadano-Ferraz A, Herrero AI, Nordstrom K, Manzano J, et al. Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor alpha1 can be ameliorated by T3 treatment. Genes Dev 2005;19:2152–63.Google Scholar

  • 32.

    Bassett JH, Nordstrom K, Boyde A, Howell PG, Kelly S, et al. Thyroid status during skeletal development determines adult bone structure and mineralization. Mol Endocrinol 2007;21:1893–904.Google Scholar

  • 33.

    Ying H, Araki O, Furuya F, Kato Y, Cheng SY. Impaired adipogenesis caused by a mutated thyroid hormone alpha1 receptor. Mol Cell Biol 2007;27:2359–71.Google Scholar

  • 34.

    Liu YY, Schultz JJ, Brent GA. A thyroid hormone receptor alpha gene mutation (P398H) is associated with visceral adiposity and impaired catecholamine-stimulated lipolysis in mice. J Biol Chem 2003;278:38913–20.Google Scholar

  • 35.

    Liu YY, Heymann RS, Moatamed F, Schultz JJ, Sobel D, Brent GA. A mutant thyroid hormone receptor alpha antagonizes peroxisome proliferator-activated receptor alpha signaling in vivo and impairs fatty acid oxidation. Endocrinology 2007;148:1206–17.Google Scholar

  • 36.

    Quignodon L, Vincent S, Winter H, Samarut J, Flamant F. A point mutation in the activation function 2 domain of thyroid hormone receptor alpha1 expressed after CRE-mediated recombination partially recapitulates hypothyroidism. Mol Endocrinol 2007;21:2350–60.Google Scholar

  • 37.

    Desjardin C, Charles C, Benoist-Lasselin C, Riviere J, Gilles M, et al. Chondrocytes play a major role in the stimulation of bone growth by thyroid hormone. Endocrinology 2014;155:3123–35.Google Scholar

  • 38.

    Wojcicka A, Bassett JH, Williams GR. Mechanisms of action of thyroid hormones in the skeleton. Biochim Biophys Acta 2013;1830:3979–86.Google Scholar

  • 39.

    Xing W, Govoni KE, Donahue LR, Kesavan C, Wergedal J, et al. Genetic evidence that thyroid hormone is indispensable for prepubertal insulin-like growth factor-I expression and bone acquisition in mice. J Bone Miner Res 2012;27:1067–79.Google Scholar

  • 40.

    Williams GR. Thyroid hormone actions in cartilage and bone. Eur Thyroid J 2013;2:3–13.Google Scholar

  • 41.

    Sandler B, Webb P, Apriletti JW, Huber BR, Togashi M, et al. Thyroxine-thyroid hormone receptor interactions. J Biol Chem 2004;279:55801–8.Google Scholar

  • 42.

    Wallis K, Dudazy S, Van Hogerlinden M, Nordstrom K, Mittag J, et al. The thyroid hormone receptor alpha1 protein is expressed in embryonic postmitotic neurons and persists in most adult neurons. Mol Endocrinol 2010;24:1904–16.Google Scholar

  • 43.

    Schwartz HL, Strait KA, Ling NC, Oppenheimer JH. Quantitation of rat tissue thyroid hormone binding receptor isoforms by immunoprecipitation of nuclear triiodothyronine binding capacity. J Biol Chem 1992;267:11794–9.Google Scholar

  • 44.

    Chatonnet F, Guyot R, Benoit G, Flamant F. Genome-wide analysis of thyroid hormone receptors shared and specific functions in neural cells. Proc Natl Acad Sci USA 2013;110:E766–75.Google Scholar

  • 45.

    Faustino LC, Ortiga-Carvalho TM. Thyroid hormone role on cerebellar development and maintenance: a perspective based on transgenic mouse models. Front Endocrinol (Lausanne) 2014;5:75.Google Scholar

  • 46.

    Picou F, Fauquier T, Chatonnet F, Flamant F. A bimodal influence of thyroid hormone on cerebellum oligodendrocyte differentiation. Mol Endocrinol 2012;26:608-18.Google Scholar

  • 47.

    Avci HX, Lebrun C, Wehrle R, Doulazmi M, Chatonnet F, et al. Thyroid hormone triggers the developmental loss of axonal regenerative capacity via thyroid hormone receptor alpha1 and kruppel-like factor 9 in Purkinje cells. Proc Natl Acad Sci USA 2012;109:14206–11.Google Scholar

  • 48.

    Fauquier T, Chatonnet F, Picou F, Richard S, Fossat N, et al. Purkinje cells and Bergmann glia are primary targets of the TRalpha1 thyroid hormone receptor during mouse cerebellum postnatal development. Development 2014;141:166–75.Google Scholar

  • 49.

    Wallis K, Sjogren M, Van Hogerlinden M, Silberberg G, Fisahn A, et al. Locomotor deficiencies and aberrant development of subtype-specific GABAergic interneurons caused by an unliganded thyroid hormone receptor alpha1. J Neurosci 2008;28:1904–15.Google Scholar

  • 50.

    Schroeder AC, Privalsky ML. Thyroid hormones, t3 and t4, in the brain. Front Endocrinol (Lausanne) 2014;5:40.Google Scholar

  • 51.

    Pantos C, Mourouzis I. The emerging role of TRalpha1 in cardiac repair: potential therapeutic implications. Oxid Med Cell Longev 2014;2014:481–2.Google Scholar

  • 52.

    Stock A, Sies H. Thyroid hormone receptors bind to an element in the connexin43 promoter. Biol Chem 2000;381:973–9.Google Scholar

  • 53.

    Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev 2014;94:355–82.Google Scholar

  • 54.

    Van Mullem AA, Chrysis D, Eythimiadou A, Chroni E, Tsatsoulis A, et al. Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRalpha1 receptor: consequences of LT4 treatment. J Clin Endocrinol Metab 2013;98:3029–38.Google Scholar

  • 55.

    Dittrich R, Beckmann MW, Oppelt PG, Hoffmann I, Lotz L, et al. Thyroid hormone receptors and reproduction. J Reprod Immunol 2011;90:58–66.Google Scholar

  • 56.

    Aghajanova L, Lindeberg M, Carlsson IB, Stavreus-Evers A, Zhang P, et al. Receptors for thyroid-stimulating hormone and thyroid hormones in human ovarian tissue. Reprod Biomed Online 2009;18:337–47.Google Scholar

  • 57.

    Jannini EA, Crescenzi A, Rucci N, Screponi E, Carosa E, et al. Ontogenetic pattern of thyroid hormone receptor expression in the human testis. J Clin Endocrinol Metab 2000;85:3453–7.Google Scholar

  • 58.

    Roef G, Lapauw B, Goemaere S, Zmierczak HG, Toye K, et al. Body composition and metabolic parameters are associated with variation in thyroid hormone levels among euthyroid young men. Eur J Endocrinol 2012;167:719–26.Google Scholar

  • 59.

    Gereben B, Zavacki AM, Ribich S, KIM BW, Huang SA, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008;29:898–938.Google Scholar

  • 60.

    Marsili A, Zavacki AM, Harney JW, Larsen PR. Physiological role and regulation of iodothyronine deiodinases: a 2011 update. J Endocrinol Invest 2011;34:395–407.Google Scholar

  • 61.

    Zavacki AM, Ying H, Christoffolete MA, Aerts G, So, E, et al. Type 1 iodothyronine deiodinase is a sensitive marker of peripheral thyroid status in the mouse. Endocrinology 2005;146:1568–75.Google Scholar

  • 62.

    Barca-Mayo O, Liao XH, Alonso M, Di Cosmo C, Hernandez A, et al. Thyroid hormone receptor alpha and regulation of type 3 deiodinase. Mol Endocrinol 2011;25:575–83.Google Scholar

  • 63.

    Gauthier K, Chassande O, Plateroti M, Roux JP, Legrand C, et al. Different functions for the thyroid hormone receptors TRalpha and TRbeta in the control of thyroid hormone production and post-natal development. Embo J 1999;8:623–31.Google Scholar

  • 64.

    Schneider MJ, Fiering SN, Pallud SE, Parlow AF, St Germain DL, et al. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol 2001;15:2137–48.Google Scholar

  • 65.

    Martinez De Mena R, Scanlan TS, Obregon MJ. The T3 receptor beta1 isoform regulates UCP1 and D2 deiodinase in rat brown adipocytes. Endocrinology 2010;151:5074–83.Google Scholar

  • 66.

    Schneider MJ, Davey JC, Galton VA. Rana catesbeiana tadpole red blood cells express an alpha, but not a beta, c-erbA gene. Endocrinology 1993;133:2488–95.Google Scholar

  • 67.

    Dasmahapatra AK, Thomas CR, Frieden E. Isolation, stabilization, and molecular weight estimation of thyroid hormone receptors of tadpole and chick embryo erythrocytes. Receptor 1992;2:213–23.Google Scholar

  • 68.

    Wong CC, Chiu KW. Putative thyroid hormone receptors in red blood cells of some reptiles. Gen Comp Endocrinol 1987;66:434–40.Google Scholar

  • 69.

    Ono S, Schwartz ID, Mueller OT, Root AW, Usala SJ, et al. Homozygosity for a dominant negative thyroid hormone receptor gene responsible for generalized resistance to thyroid hormone. J Clin Endocrinol Metab 1991;73: 990–4.Google Scholar

  • 70.

    Kim DW, Park JW, Willingham MC, Cheng SY. A histone deacetylase inhibitor improves hypothyroidism caused by a TRalpha1 mutant. Hum Mol Genet 2014;23:2651–64.Google Scholar

  • 71.

    Schoenmakers N, Moran C, Peeters RP, Visser T, Gurnell M, Chatterjee K. Resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha. Biochim Biophys Acta 2013;1830:4004–8.Google Scholar

About the article

Corresponding author: Xiaolan Lian, Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Beijing, P. R. China, Phone/Fax: +86-106-915-5358, E-mail: .

Received: 2015-07-16

Accepted: 2015-12-07

Published Online: 2016-01-14

Published in Print: 2016-05-01

Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 29, Issue 5, Pages 511–522, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2015-0286.

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