Advertisement

Thyroid disease mediated by molecular defects in cell surface and nuclear receptors1

  • Donald L. Bodenner
    Correspondence
    Requests for reprints should be addressed to Dr. Donald L. Bodenner, Department of Internal Medicine, Division of Endocrinology and Metabolism, 4301 West Markham, Little Rock, Arkansas 72205
    Affiliations
    Department of Internal Medicine (DLB), Division of Endocrinology and Metabolism, Little Rock, Arkansas, USA
    Search for articles by this author
  • Robert W. Lash
    Affiliations
    Department of Internal Medicine (RWL), Division of Endocrinology and Metabolism, University of Michigan Health System, Ann Arbor, Michigan, USA
    Search for articles by this author
      Thyroid hormone homeostasis is regulated primarily by the action of thyroid-stimulating hormone (TSH) secreted by the pituitary. TSH, by binding to specific TSH receptors (TSH-R) on the surface of the thyroid follicular epithelium, stimulates glandular growth, thyroid hormone synthesis, and thyroid hormone release. In the euthyroid state, there is tightly regulated feedback between circulating concentrations of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) and TSH. TSH secretion is also controlled by the hypothalamic factor thyrotropin-releasing hormone (TRH). As shown in Figure 1, small decreases in circulating thyroid hormone levels are detected by the pituitary and hypothalamus, with compensatory increases in TSH (and TRH) synthesis and secretion. Higher levels of TSH, in turn, stimulate thyroid hormone synthesis, with a subsequent decrease in TSH concentration. In the euthyroid state, these changes in thyroid hormone and TSH concentrations are minimal, and occur within the normal range for each hormone. Given the central role of the TSH-R in maintaining thyroid hormone homeostasis, it is not surprising that abnormalities of TSH-R function are associated with both hypothyroidism and hyperthyroidism (
      • Russo D.
      • Arturi F.
      • Chiefari E.
      • Filetti S.
      Molecular insights into TSH receptor abnormality and thyroid disease.
      ,
      • Tonacchera M.
      • Van Sande J.
      • Parma J.
      • et al.
      TSH receptor and disease.
      ,
      • Paschke R.
      • Ludgate M.
      The thyrotropin receptor in thyroid diseases.
      ).
      Figure thumbnail GR1
      Figure 1The hypothalamic-pituitary-thyroid axis. Thyroid hormone homeostasis is controlled by feedback loops involving the hypothalamus, pituitary gland, and thyroid gland. Thyrotropin-releasing hormone (TRH) is released by the hypothalamus, stimulating the synthesis and secretion of thyroid-stimulating hormone (TSH). TSH, in turn, activates thyroid hormone synthesis, as well as the release of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). These thyroid hormones (primarily T3) provide negative feedback on both TRH and TSH secretion. In addition, hypothalamic somatostatin has an inhibitory effect on TSH secretion.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Russo D.
        • Arturi F.
        • Chiefari E.
        • Filetti S.
        Molecular insights into TSH receptor abnormality and thyroid disease.
        J Endocrinol Invest. 1997; 20: 36-47
        • Tonacchera M.
        • Van Sande J.
        • Parma J.
        • et al.
        TSH receptor and disease.
        Clin Endocrinol. 1996; 44: 621-633
        • Paschke R.
        • Ludgate M.
        The thyrotropin receptor in thyroid diseases.
        NEJM. 1997; 337: 1675-1681
        • Nagayama Y.
        • Kaufman K.D.
        • Seto P.
        • Rapoport B.
        Molecular cloning, sequence and functional expression of the cDNA for the human thyrotropin receptor.
        Biochem Biophys Res Comm. 1989; 165: 1184-1190
        • Libert F.
        • Lefort A.
        • Gerard C.
        • et al.
        Cloning, sequencing and expression of the human thyrotropin (TSH) receptor.
        Biochem Biophys Res Comm. 1989; 165: 1250-1255
        • Spiegel A.M.
        • Weinstein L.S.
        • Shenker A.
        Abnormalities in G protein-coupled signal transduction pathways in human disease.
        J Clin Invest. 1993; 92: 1119-1125
        • Pearce S.
        • Trump D.
        G-Protein-coupled receptors in endocrine disease.
        QJM. 1995; 88: 3-8
        • Laugwitz K.L.
        • Allgeier A.
        • Offermanns S.
        • et al.
        The human thyrotropin receptor.
        Proc Natl Acad Sci USA. 1996; 93: 116-120
        • Bygrave F.L.
        • Roberts H.R.
        Regulation of cellular calcium through signaling cross-talk involves an intricate interplay between the actions of receptors, G-proteins, and second messengers.
        FASEB J. 1995; 9: 1297-1303
        • Van Sande J.
        • Swillens S.
        • Gerard C.
        • et al.
        In Chinese hamster ovary K1 cells dog and human thyrotropin receptors activate both the cyclic AMP and the phosphatidylinositol 4,5-bisphosphate cascades in the presence of thyrotropin and the cyclic AMP cascade in its absence.
        Eur J Biochem. 1995; 229: 338-343
        • Landis C.A.
        • Masters S.B.
        • Spada A.
        • et al.
        GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours.
        Nature. 1989; 340: 692-696
        • Weinstein L.S.
        • Shenker A.
        • Gejman P.V.
        • et al.
        Activating mutations of the stimulatory G protein in the McCune-Albright syndrome.
        NEJM. 1991; 325: 1688-1695
        • Russo D.
        • Arturi F.
        • Wicker R.
        • et al.
        Genetic alterations in thyroid hyperfunctioning adenomas.
        J Clin Endocrinol Metab. 1995; 80: 1347-1351
        • O’Sullivan C.
        • Barton C.M.
        • Staddon S.L.
        • et al.
        Activating point mutations of the gsp oncogene in human thyroid adenomas.
        Molec Carcinogen. 1991; 4: 345-349
        • Derwahl M.
        TSH receptor and Gs-alpha gene mutations in the pathogenesis of toxic thyroid adenomas—a note of caution.
        J Clin Endocrinol Metab. 1996; 81: 2783-2785
        • Schwindinger W.F.
        • Francomano C.A.
        • Levine M.A.
        Identification of a mutation in the gene encoding the alpha subunit of the stimulatory G protein of adenylyl cyclase in McCune-Albright syndrome.
        Proc Natl Acad Sci USA. 1992; 89: 5152-5156
        • Van Sande J.
        • Parma J.
        • Tonacchera M.
        • et al.
        Genetic basis of endocrine disease, somatic and germline mutations of the TSH receptor gene in thyroid diseases.
        J Clin Endocrinol Metab. 1995; 80: 2577-2585
        • Parma J.
        • Van Sande J.
        • Swillens S.
        • et al.
        Somatic mutations causing constitutive activity of the thyrotropin receptor are the major cause of hyperfunctioning thyroid adenomas.
        Molec Endocrinol. 1995; 9: 725-733
        • Duprez L.
        • Parma J.
        • Van Sande J.
        • et al.
        Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism.
        Nat Genet. 1994; 7: 396-401
        • Kopp P.
        • van Sande J.
        • Parma J.
        • et al.
        Congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene.
        NEJM. 1995; 332: 150-154
        • Russo D.
        • Arturi F.
        • Suarez H.G.
        • et al.
        Thyrotropin receptor gene alterations in thyroid hyperfunctioning adenomas.
        J Clin Endocrinol Metab. 1996; 81: 1548-1551
        • Sunthornthepvarakui T.
        • Gottschalk M.E.
        • Hayashi Y.
        • Refetoff S.
        Resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene.
        NEJM. 1995; 332: 155-160
        • Xie J.
        • Pannain S.
        • Pohlenz J.
        • et al.
        Resistance to thyrotropin (TSH) in three families is not associated with mutations in the TSH receptor or TSH.
        J Clin Endocrinol Metab. 1997; 82: 3933-3940
        • Bahn R.S.
        • Dutton C.M.
        • Heufelder A.E.
        • Sarkar G.
        A genomic point mutation in the extracellular domain of the thyrotropin receptor in patients with Graves’ ophthalmopathy.
        J Clin Endocrinol Metab. 1994; 78: 256-260
        • Bohr U.R.
        • Behr M.
        • Loos U.
        A heritable point mutation in an extracellular domain of the TSH receptor involved in the interaction with Graves’ immunoglobulins.
        Biochimica et Biophysica Acta. 1993; 1216: 504-508
        • Prabhakar B.S.
        • Fan J.-L.
        • Seetharamaiah G.S.
        Thyrotropin-receptor-mediated diseases.
        Immunol Today. 1997; 18: 437-442
        • Vitti P.
        • Rotella C.M.
        • Valente W.A.
        • et al.
        Characterization of the optimal stimulatory effects of graves’ monoclonal and serum immunoglobulin G on adenosine 3′,5′-monophosphate production in fRTL-5 thyroid cells.
        J Clin Endocrinol Metab. 1983; 57: 782-791
        • Zakarija M.
        • McKenzie J.M.
        • Munro D.S.
        Immunoglobulin G inhibitor of thyroid-stimulating antibody is a cause of delay in the onset of neonatal Graves’ disease.
        J Clin Invest. 1983; 72: 1352-1356
        • Pierce J.G.
        • Parsons T.F.
        Glycoprotein hormones.
        Ann Rev Biochem. 1981; 50: 465-495
        • Fradkin J.E.
        • Eastman R.C.
        • Lesniak M.A.
        • Roth J.
        Specificity spillover at the hormone receptor—exploring its role in human disease.
        NEJM. 1989; 320: 640-645
        • Anasti J.N.
        • Flack M.R.
        • Froehlich J.
        • et al.
        A potential novel mechanism for precocious puberty in juvenile hypothyroidism.
        J Clin Endocrinol Metab. 1995; 80: 276-279
        • Harada A.
        • Hershman J.M.
        • Reed A.W.
        • et al.
        Comparison of thyroid stimulators and thyroid hormone concentrations in the sera of pregnant women.
        J Clin Endocrinol Metab. 1979; 48: 793-797
        • Hershman J.M.
        Trophoblastic tumors.
        in: Bleau R.D. Werner and Ingbar’s The Thyroid. Lippincott-Raven, Philadelphia1996: 573-576
        • Goodwin T.M.
        • Hershman J.M.
        Hyperthyroidism due to inappropriate production of human chorionic gonadotropin.
        Clin Obstet Gynecol. 1997; 40: 32-44
        • Ledent C.
        • Dumont J.E.
        • Vassart G.
        • Parmentier M.
        Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism.
        EMBO J. 1992; 11: 537-542
        • Refetoff S.
        • DeWind L.T.
        • DeGroot L.J.
        Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI.
        J Clin Endocrinol Metab. 1967; 27: 279-294
        • Refetoff S.
        • Weiss R.E.
        • Usala S.J.
        The syndromes of resistance to thyroid hormone.
        Endoc Rev. 1993; 14: 348-399
        • Refetoff S.
        Resistance to thyroid hormone and its molecular basis.
        Acta Paediatrica Japonica. 1994; 36: 1-15
        • Refetoff S.
        Resistance to thyroid hormone.
        Thyroid. 1994; 4: 345-349
        • Beck-Peccoz P.
        • Chatterjee V.K.
        The variable clinical phenotype in thyroid hormone resistance syndrome.
        Thyroid. 1994; 4: 225-232
        • Rivkees S.A.
        • Bode H.H.
        • Crawford J.D.
        Long-term growth in juvenile acquired hypothyroidism.
        NEJM. 1988; 318: 599-602
        • Weiss R.E.
        • Refetoff S.
        Effect of thyroid hormone on growth.
        Lessons from the syndrome of resistance to thyroid hormone. Endocrinol Metab Clin North Am. 1996; 25: 719-730
        • Brucker-Davis F.
        • Skarulis M.C.
        • Grace M.B.
        • et al.
        Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study.
        Ann Intern Med. 1995; 123: 572-583
        • Leonard C.M.
        • Martinez P.
        • Weintraub B.D.
        • Hauser P.
        Magnetic resonance imaging of cerebral anomalies in subjects with resistance to thyroid hormone.
        Am J Med Genet. 1995; 60: 238-243
        • Beck-Peccoz P.
        • Forloni F.
        • Cortelazzi D.
        • et al.
        Pituitary resistance to thyroid hormones.
        Horm Res. 1992; 38: 66-72
        • Beck-Peccoz P.
        • Brucker-Davis F.
        • Persani L.
        • et al.
        Thyrotropin-secreting pituitary tumors.
        Endoc Rev. 1996; 17: 610-638
        • Dorey F.
        • Strauch G.
        • Gayno J.P.
        Thyrotoxicosis due to pituitary resistance to thyroid hormones. Successful control with D thyroxine: a study in three patients.
        Clin Endocrinol. 1990; 32: 221-228
        • Beck-Peccoz P.
        • Piscitelli G.
        • Cattaneo M.G.
        • Faglia G.
        Successful treatment of hyperthyroidism due to nonneoplastic pituitary TSH hypersecretion with 3,5,3′-triiodothyroacetic acid (TRIAC).
        J Endocrinol Invest. 1983; 6: 217-223
        • Dulgeroff A.J.
        • Geffner M.E.
        • Koyal S.N.
        • et al.
        Bromocriptine and Triac therapy for hyperthyroidism due to pituitary resistance to thyroid hormone.
        J Clin Endocrinol Metab. 1992; 75: 1071-1075
        • Evans R.M.
        The steroid and thyroid hormone receptor superfamily.
        Science. 1988; 240: 889-895
        • Lazar M.A.
        • Hodin R.A.
        • Darling D.S.
        • Chin W.W.
        Identification of a rat c-erbA alpha-related protein which binds deoxyribonucleic acid but does not bind thyroid hormone.
        Molec Endocrinol. 1988; 2: 893-901
        • Lazar M.A.
        • Hodin R.A.
        • Chin W.W.
        Human carboxyl-terminal variant of alpha-type c-erbA inhibits trans-activation by thyroid hormone receptors without binding thyroid hormone.
        Proc Natl Acad Sci USA. 1989; 86: 7771-7774
        • Hodin R.A.
        • Lazar M.A.
        • Wintman B.I.
        • et al.
        Identification of a thyroid hormone receptor that is pituitary-specific.
        Science. 1989; 244: 76-79
        • Forrest D.
        • Hanebuth E.
        • Smeyne R.J.
        • et al.
        Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta.
        Embo J. 1996; 15: 3006-3015
        • Umesono K.
        • Evans R.M.
        Determinants of target gene specificity for steroid/thyroid hormone receptors.
        Cell. 1989; 57: 1139-1146
        • Brent G.A.
        • Harney J.W.
        • Chen Y.
        • et al.
        Mutations of the rat growth hormone promoter which increase and decrease response to thyroid hormone define a consensus thyroid hormone response element.
        Molec Endocrinol. 1989; 3: 1996-2004
        • Umesono K.
        • Murakami K.K.
        • Thompson C.C.
        • Evans R.M.
        Direct repeats as selective response elements for the thyroid hormone, retinoic acid, and vitamin D3 receptors.
        Cell. 1991; 65: 1255-1266
        • Yang Y.Z.
        • Burgos-Trinidad M.
        • Wu Y.
        • Koenig R.J.
        Thyroid hormone receptor variant alpha2. Role of the ninth heptad in DNA binding, heterodimerization with retinoid X receptors, and dominant negative activity.
        J Biolog Chem. 1996; 271: 28235-28242
        • Au-Fliegner M.
        • Helmer E.
        • Casanova J.
        • et al.
        The conserved ninth C-terminal heptad in thyroid hormone and retinoic acid receptors mediates diverse responses by affecting heterodimer but not homodimer formation.
        Molec Cell Biol. 1993; 13: 5725-5737
        • Kliewer S.A.
        • Umesono K.
        • Mangelsdorf D.J.
        • Evans R.M.
        Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling.
        Nature. 1992; 355: 446-449
        • Schrader M.
        • Muller K.M.
        • Nayeri S.
        • et al.
        Vitamin D3-thyroid hormone receptor heterodimer polarity directs ligand sensitivity of transactivation.
        Nature. 1994; 370: 382-386
        • Bogazzi F.
        • Hudson L.D.
        • Nikodem V.M.
        A novel heterodimerization partner for thyroid hormone receptor. Peroxisome proliferator-activated receptor.
        J Biolog Chem. 1994; 269: 11683-11686
        • Zhang X.K.
        • Wills K.N.
        • Husmann M.
        • et al.
        Novel pathway for thyroid hormone receptor action through interaction with jun and fos oncogene activities.
        Molec Cell Biol. 1991; 11: 6016-6025
        • Refetoff S.
        Resistance to thyroid hormone.
        Clin Lab Med. 1993; 13: 563-581
        • Yen P.M.
        • Brubaker J.H.
        • Apriletti J.W.
        • et al.
        Roles of 3,5,3′-triiodothyronine and deoxyribonucleic acid binding on thyroid hormone receptor complex formation.
        Endocrinology. 1994; 134: 1075-1081
        • O’Donnell A.L.
        • Rosen E.D.
        • Darling D.S.
        • Koenig R.J.
        Thyroid hormone receptor mutations that interfere with transcriptional activation also interfere with receptor interaction with a nuclear protein.
        Molec Endocrinol. 1991; 5: 94-99
        • Saatcioglu F.
        • Bartunek P.
        • Deng T.
        • et al.
        A conserved C-terminal sequence that is deleted in v-ErbA is essential for the biological activities of c-ErbA (the thyroid hormone receptor).
        Molec Cell Biol. 1993; 13: 3675-3685
        • Fondell J.D.
        • Roy A.L.
        • Roeder R.G.
        Unliganded thyroid hormone receptor inhibits formation of a functional preinitiation complex.
        Genes Develop. 1993; 7: 1400-1410
        • Baniahmad A.
        • Ha I.
        • Reinberg D.
        • et al.
        Interaction of human thyroid hormone receptor beta with transcription factor TFIIB may mediate target gene derepression and activation by thyroid hormone.
        Proc Natl Acad Sci USA. 1993; 90: 8832-8836
        • Shibata H.
        • Spencer T.E.
        • Onate S.A.
        • et al.
        Role of co-activators and co-repressors in the mechanism of steroid/thyroid receptor action.
        Recent Prog Horm Res. 1997; 52: 141-165
        • Chen J.D.
        • Evans R.M.
        A transcriptional co-repressor that interacts with nuclear hormone receptors.
        Nature. 1995; 377: 454-457
        • Usala S.J.
        • Bale A.E.
        • Gesundheit N.
        • et al.
        Tight linkage between the syndrome of generalized thyroid hormone resistance and the human c-erbA beta gene.
        Molec Endocrinol. 1988; 2: 1217-1220
        • Usala S.J.
        Thyroid hormone resistance.
        in: Weintraub B.D. Molecular Endocrinology. Raven Press, New York1995: 393-409
        • Sone T.
        • Scott R.A.
        • Hughes M.R.
        • et al.
        Mutant vitamin D receptors which confer hereditary resistance to 1,25-dihydroxyvitamin D3 in humans are transcriptionally inactive in vitro.
        J Biolog Chem. 1989; 264: 20230-20234
        • Usala S.J.
        • Menke J.B.
        • Watson T.L.
        • et al.
        A homozygous deletion in the c-erbA beta thyroid hormone receptor gene in a patient with generalized thyroid hormone resistance.
        Molec Endocrinol. 1991; 5: 327-335
        • Nagaya T.
        • Madison L.D.
        • Jameson J.L.
        Thyroid hormone receptor mutants that cause resistance to thyroid hormone. Evidence for receptor competition for DNA sequences in target genes.
        J Biolog Chem. 1992; 267: 13014-13019
        • Hayashi Y.
        • Janssen O.E.
        • Weiss R.E.
        • et al.
        The relative expression of mutant and normal thyroid hormone receptor genes in patients with generalized resistance to thyroid hormone determined by estimation of their specific messenger ribonucleic acid products.
        J Clin Endocrinol Metab. 1993; 76: 64-69
        • Mixson A.J.
        • Hauser P.
        • Tennyson G.
        • et al.
        Differential expression of mutant and normal beta T3 receptor alleles in kindreds with generalized resistance to thyroid hormone.
        J Clin Invest. 1993; 91: 2296-2300
        • Yoh S.M.
        • Chatterjee V.K.
        • Privalsky M.L.
        Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors.
        Mol Endocrinol. 1997; 11: 470-480
        • Collingwood T.N.
        • Rajanayagam O.
        • Adams M.
        • et al.
        A natural transactivation mutation in the thyroid hormone beta receptor.
        Proc Natl Acad Sci USA. 1997; 94: 248-253