Skip to main content
SpringerLink
Log in

Genetic aspects of central hypothyroidism

  • Review Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Central hypothyroidism, characterized by insufficient TSH secretion in the presence of low levels of thyroid hormones, is a rare disorder. It has recently been found that, although mainly due to tumors or infiltrative diseases of the hypothalamo-pituitary area or to pituitary atrophy, central hypothyroidism may be caused by inactivating mutations in several of the genes that code for the various proteins involved in the regulation of the hypothalamo-pituitary-thyroid axis (HPTA). These experiments of nature allow us to better understand the pathophysiology but also the normal physiology of the HPTA. This review will analyze reports of mutations that affect the HPTA and result in either isolated central hypothyroidism or in the syndrome of combined pituitary hormone deficiency (CPHD). Mutations have been identified in the genes for the TRH receptor, the transcription factors Pit-1 and PROP1, and the TSH β-subunit.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Martino E., Bartalena L., Faglia G., Pinchera A. Central hypothyroidism. In: Braverman L.E., Utiger R.D. (Eds.), The Thyroid. Lippincott-Raven, Philadelphia, 1996, p. 779.

    Google Scholar 

  2. Walfish P.G., Tseng K.H. Thyroid physiology and pathology. In: Collu R., Ducharme J.R., Guyda H.J. (Eds.), Pediatric Endocrinology. Raven Press, New York, 1989, p. 367.

    Google Scholar 

  3. Collu R., Taché Y., Charpenet G. Behavioral and hormonal effects exerted by TRH through the CNS. In: Cummings L.A., Funder L.W., Mendelsohn F.A.O. (Eds.), Proceedings of the Sixth International Congress of Endocrinology. Australian Academy of Sciences, Canberra, 1980, p. 492.

    Google Scholar 

  4. Taché Y., Lesiège D., Vale W., Collu R. Gastric hypersecretion by intracisternal TRH: Dissociation from hypophysiotropic activity and role of central catecholamines. Eur. J. Pharmacol. 1985, 107: 149–152.

    Article  PubMed  Google Scholar 

  5. Mitnick M., Reichlin S. Enzymatic synthesis of thyrotropin-releasing hormone (TRH) by hypothalamic “TRH synthase”. Endocrinology 1972, 91: 1145–1148.

    Article  CAS  PubMed  Google Scholar 

  6. Kaji H., Takahashi Y., Chihara K. The regional distribution of thyrotropin-releasing hormone receptor messenger ribonucleic acid in the brain. Neurosci. Lett. 1993, 151: 81–84.

    Article  CAS  PubMed  Google Scholar 

  7. Fliers E., Noppen N.W.A., Wiersinga W.M., Visser T.J., Swaab D.F. Distribution of thyrotropin-releasing hormone (TRH)-containing cells and fibers in the human hypothalamus. J. Comp. Neurol. 1994, 350: 311–323.

    Article  CAS  PubMed  Google Scholar 

  8. Yamada M., Radovick S., Wondisford F.E., Nakayama Y., Weintraub B.D., Wilber J.F. Cloning and structure of human genomic DNA and hypothalamic cDNA encoding human preprothyrotropin-releasing hormone. Mol. Endocrinol. 1990, 4: 551–556.

    Article  CAS  PubMed  Google Scholar 

  9. Yamada M., Wondisford F.E., Radovick S., Nakayama Y., Weintraub B.D., Wilber J.F. Assignment of human preprothyrotropin-releasing hormone (TRH) gene to chromosome 3. Somat. Cell. Mol. Genet. 1991, 17: 97–100.

    Article  CAS  Google Scholar 

  10. Feng P., Carnell N.E., Kim U.J., Jacobs S., Wilber J.F. The human testis: a novel locus for thyrotropin-releasing hormone (TRH) and TRH mRNA. Trans. Assoc. Am. Physicians 1992, CV: 222–228.

    Google Scholar 

  11. Wilber J.F., Feng P., Li Q.-L., Shi Z.X. The thyrotropin-releasing hormone gene. Differential regulation, expression, and function in hypothalamus and two unexpected extrahypothalamic loci, the heart and testis. Trends Endocrinol. Metab. 1996, 7: 93–100.

    Article  CAS  PubMed  Google Scholar 

  12. Niimi H., Inomata H., Sasaki N., Nakajima H. Congenital isolated thyrotropin-releasing hormone deficiency. Arch. Dis. Child. 1982, 57: 877–878.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Strader C.D., Fong T.M., Graziano M.A., Tota M.R. The family of G-protein-coupled receptors. FASEB J. 1995, 9: 745–754.

    CAS  PubMed  Google Scholar 

  14. Aragay A.M., Katz A., Simon M.I. The Gαq and Gα11 proteins couple the thyrotropinreleasing hormone receptor to phospholipase C in GH(3) cells. J. Biol. Chem. 1992, 267: 24983–24988.

    CAS  PubMed  Google Scholar 

  15. Hsieh K.A., Martin T.F.J. Thyrotropin-releasing hormone and gonadotropin-releasing hormone receptors activate phospholipase C by coupling to the guanosine triphosphatebinding protein Gq and G11. Mol. Endocrinol. 1992, 6: 1673–1681.

    CAS  PubMed  Google Scholar 

  16. PauIssen R.A., PauIssen E.J., Gautvik K.M., Gordeladze J.O. The thyroliberin receptor interacts directly with a stimulatory guanine-nucleotide-binding protein in the activation of adenylyl cyclase in GH3 rat pituitary tumor cells. Evidence obtained by the use of antisense RNA inhibition and immunoblocking of the stimulatory guanine-nucleotide-binding protein. Eur. J. Biochem. 1992, 204: 413–418.

    Article  Google Scholar 

  17. Straub R.E., Freeh G.C., Joho R.H., Gershengorn M.C. Expression cloning of a cDNA encoding the mouse pituitary thyrotropin-releasing hormone receptor. Proc. Natl. Acad. Sci. USA 1990, 87: 9514–9518.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Duthie S.M., Taylor P.M., Anderson L., Cook L., Eidne K.A. Cloning and functional characterization of the human TRH receptor. Mol. Cell. Endocrinol. 1993, 95: R11–R15.

    Article  CAS  PubMed  Google Scholar 

  19. Yamada M., Monden T., Satoh T., Satoh N., Murakami M., Iriushijima T., Kakegawa T., Mori M. Pituitary adenomas of patients with acromegaly express thyrotropin-releasing hormone messenger RNA: cloning and functional expression of the human thyrotropin-releasing hormone gene. Biochem. Biophys. Res. Commun. 1993, 195: 727–745.

    Google Scholar 

  20. Hinuma S., Hosoya M., Ogi K., Tanaka H., Nagai Y., Onda H. Molecular cloning and functional expression of a human thyrotropin-releasing hormone (TRH) receptor gene. Biochem. Biophys. Acta 1994, 1219: 251–259.

    CAS  PubMed  Google Scholar 

  21. Morrison N., Duthie S.M., Boyd E., Eidne K.A., Connor J.M. Assignment of the gene encoding the human thyrotropin-releasing hormone receptor to 8q23 by fluorescence in situ hybridization. Hum. Genet. 1994, 93: 716–718.

    CAS  PubMed  Google Scholar 

  22. Matre V., Hovring P.H., Orstavik S., Frengen E., Rian E., Velickovic Z., Murray-McIntosh R.A., Gautvik K.M. Structural and functional organization of the gene encoding the thyrotropin-releasing hormone receptor. J. Neurochem. 1999, 72: 40–51.

    Article  CAS  PubMed  Google Scholar 

  23. de Roux N., Young L., Misrahi M., Genet R., Chanson P., Schaison G., Milgrom E. A family with hypogonadoptropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N. Engl. J. Med. 1997, 337: 1597–1602.

    Article  PubMed  Google Scholar 

  24. Wajnrajch M.A., Genner L.M., Harbison M.D., Streamson C.C.Jr., Leibel R.L. Nonsense mutation in the human growth hormone-releasing hormone receptor causes growth failure analogous to the little (lit) mouse. Nature Genetics 1996, 12: 85–90.

    Article  Google Scholar 

  25. Collu R., Tang J.-Q., Castagné J., Lagacé G., Masson N., Huot C., Deal C., Delvin E., Faccenda E., Eidne K.A., Van Vliet G. A novel mechanism for isolated central hypothyroidism: Inactivating mutations in the thyrotropin-releasing hormone receptor gene. J. Clin. Endocrinol. Metab. 1997, 82: 1561–1565.

    CAS  PubMed  Google Scholar 

  26. Periman J.H., Laakkonen L., Osman R., Gershengorn M.C. A model of the Thyrotropin-releasing hormone (TRH) receptor binding pocket. Evidence for a second direct interaction between transmembrane helix 3 and TRH. J. Biol. Chem. 1994, 269: 23383–23386.

    Google Scholar 

  27. Bodner M., Castrillo J.L., Theill L.E., Derink T., Ellismann M., Karin M. The pituitary-specific transcription factor GHF-1 is a homeobox-containing protein. Cell 1988, 55: 505–518.

    Article  CAS  PubMed  Google Scholar 

  28. Herr W., Sturin R.A., Clew A.G., Corcoran L.M., Baltimore D., Sharp P.A., Ingraham H.A., Rosenfeld M.G., Finney M., Ruvkin G., Horvitz H.R. The POU domain: a large conserved region in the mammalian Pit-1, oct-1, and Caenorhabditis elegans unc-86 gene products. Genes Dev. 1988, 2: 1513–1516.

    Article  CAS  PubMed  Google Scholar 

  29. Ohta K., Nobukuni Y., Mitsubuchi H., Ohta T., Tohma T., Jinno H., Endo F., Matsuda I. Characterization of the gene encoding human pituitary-specific transcription factor, Pit-1. Gene 1992, 122: 387–388.

    Article  CAS  PubMed  Google Scholar 

  30. Delhase M., Vila V., Hooghe-Peters E.L., Castrillo J.L. A novel pituitary transcription factor is produced by alternative splicing of the human GHF-1/PIT-1 gene. Gene 1995, 155: 273–275.

    Article  CAS  PubMed  Google Scholar 

  31. Schanke J.T., Conwell C.M., Durning M., Fisher J.M., Golos T.G. Pit-1/growth hormone factor 1 splice variant expression in the rhesus monkey pituitary gland and the rhesus and human placenta. J. Clin. Endocrinol. Metab. 1997, 82: 800–807.

    CAS  PubMed  Google Scholar 

  32. Nelson C., Albert V.R., Elsholtz H.P., Lu L.I.-W., Rosenfeld M.G. Activation of cell-specific expression of rat growth hormone and prolactin genes by a common transcription factor. Science 1988, 239: 1400–1405.

    Article  CAS  PubMed  Google Scholar 

  33. Mangalam H.J., Albert V.R., Jngraham H.A., Kapiloff M., Wilson J., Nelson C., Elsholtz H., Rosenfeld M.G. A pituitary POU domain protein, Pit-1, activates both growth hormone and prolactin promoters transcriptionally. Genes Dev. 1989, 3: 946–958.

    Article  CAS  PubMed  Google Scholar 

  34. Simmons D.M., Voss J.W., Ingraham H.A., Holloway J.M., Broide R.S., Rosenfeld M.G., Swanson J.M. Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors. Genes Dev. 1990, 4: 695–711.

    Article  CAS  PubMed  Google Scholar 

  35. Day R.N., Maurer R.A. The distal enhancer region of the rat prolactin gene contains elements conferring response to multiple hormones. Mol. Endocrinol. 1989, 3: 3–9.

    Article  CAS  PubMed  Google Scholar 

  36. Peers B., Monget P., Nalda M.A., Voz M.L., Berwaer M., Belayew A., Martial A. Transcriptional induction of the human prolactin gene by cAMP requires two cis-acting elements and at least the pituitary-specific factor Pit-1. J. Biol. Chem. 1991, 266: 18127–18134.

    CAS  PubMed  Google Scholar 

  37. Voss L.W., Rosenfeld M.G. Anterior pituitary development: short tales from dwarf mice. Cell 1992, 70: 527–530.

    Article  CAS  PubMed  Google Scholar 

  38. Li S., Crenshaw E.B., Rawson E.J., Simmons D.M., Swanson L.W., Rosenfeld M.G. Dwarf locus mutants three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature 1990, 347: 528–533.

    Article  CAS  PubMed  Google Scholar 

  39. Ohta K., Nobukuni Y., Mitsubuchi H., Fujimoto S., Matsuo N., Inagaki H., Endo F., Matsuda I. Mutations in the Pit-1 gene in children with combined pituitary hormone deficiency. Biochem. Biophys. Res. Commun. 1992, 189: 851–855.

    Article  CAS  PubMed  Google Scholar 

  40. Pfaffle R.W., DiMattia G.E., Parks L.S., Brown M.R., Wit J.M., Jansen M., Van der Nat H., Van den Brande J.L., Rosenfeld M.G., Ingraham H.A. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia. Science 1992, 257: 1118–1121.

    Article  CAS  PubMed  Google Scholar 

  41. Radovick S., Nations M., Du Y., Berg L.A., Weintraub B.D., Wondisford F.E. A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science 1992, 257: 1115–1118.

    Article  CAS  PubMed  Google Scholar 

  42. Tatsumi K.-I., Miayi K., Notomi T., Kaibe K., Amino N., Mizuno Y., Kohno H. Cretinism with combined hormone deficiency caused by a mutation in the Pit-1 gene. Nature Genet. 1992, 1: 56–58.

    Article  CAS  PubMed  Google Scholar 

  43. Okamoto N., Wada Y., Ida S., Koga R., Ozono K., Chiyo H., Hayashi A., Tatsumi K. Monoallelic expression of normal mRNA in the Pit-1 mutation heterozygotes with normal phenotype and biallelic expression in the abnormal phenotype. Hum. Mol. Genet. 1994, 3: 1565–1568.

    Article  CAS  PubMed  Google Scholar 

  44. Cohen L.E., Wondisford F.E., Salvatoni A., Maghnie M., Brucker-Davis R., Weintraub B.D., Radovick S. A “hot spot” in the Pit-1 gene responsible for combined pituitary hormone deficiency: Clinical and molecular correlates. J. Clin. Endocrinol. Metab. 1995, 80: 679–684.

    CAS  PubMed  Google Scholar 

  45. de Zegher F., Parnasetti F., Vanhole C., Devlieger H., van den Berghe G., Martial L.A. The prenatal role of thyroid hormones evidenced by fetomaternal Pit-1 deficiency. J. Clin. Endocrinol. Metab. 1995, 80: 3127–3130.

    PubMed  Google Scholar 

  46. Irie Y., Tatsumi K., Ogawa M., Kamijo T., Preeyasombat C., Suprasongsin C., Amin N. A novel E250X mutation of the Pit-1 gene in a patient with combined pituitary hormone deficiency. Endocr. J. 1995, 42: 351–354.

    Article  CAS  PubMed  Google Scholar 

  47. Irie Y., Tatsumi K.-I., Kusuda K., Kawawaki H., Boyages S.C., Nose O., Ichiba Y., Katsumata N., Amino N. Screening for PIT-1 abnormality by PCR direct sequencing method. Thyroid 1995, 5: 207–210.

    CAS  PubMed  Google Scholar 

  48. Pfaffle R.W., Otten B., Eiholtzer U., Kim C., Blankenstein O. A genetic cause of familial and sporadic cases with combined pituitary hormone deficiencies for GH, PRL, and TSH. Horm. Res. 1995, 44: 9 (Abstract).

    Article  Google Scholar 

  49. Pellegrini-Bouiller I., Belicar P., Barlier A., Gunz G., Charvet J.-P., Jaquet P., Brue T., Vialettes B., Enjalbert A. A new mutation of the gene encoding the transcription factor Pit-1 is responsible for combined pituitary hormone deficiency. J. Clin. Endocrinol. Metab. 1996, 81: 2790–2796.

    CAS  PubMed  Google Scholar 

  50. Aarskog D., Eiken H.G., Bjerknes R., Myking O.L. Pituitary dwarfism in the R271 W Pit-1 gene mutation. Eur. J. Pediatr. 1997, 156: 829–834.

    Article  CAS  PubMed  Google Scholar 

  51. Brown M.R., Parks J.S., Adess M.E., Rich B.H., Rosenthal I.M., Voss T.C., VanderHeyden T.C., Hurley D.L. Central hypothyroidism reveals compound heterozygous mutations in the Pit-1 gene. Horm. Res. 1998, 49: 98–102.

    Article  CAS  PubMed  Google Scholar 

  52. Martinell A.M.R., Braga M., de Lacerda L., Raskin S., Graf H. Description of a Brazilian patient bearing the R271 W Pit-1 mutation. Thyroid 1998, 8: 299–304.

    Article  Google Scholar 

  53. Pernasetti P., Milner R.D.G., Al Ashwal A.A.Z., de Zegher F., Chavez V.M., Muller M., Martial J.A. Pro239Ser: A novel recessive mutation of the Pit-1 gene in seven Middle Eastern children with growth hormone, prolactin, and thyrotropin deficiency. J. Clin. Endocrinol. Metab. 1998, 83: 2079–2083.

    CAS  PubMed  Google Scholar 

  54. Ward L., Chavez M., Huot C., Lecocq P., Collu C., Décarie J.-C., Martial J.A., Van Vliet G. Severe congenital hypopituitarism with low prolactin levels and age-dependent anterior pituitary hypoplasia: A clue to a PIT-1 mutation. J. Pediatr. 1998, 132: 1036–1039.

    Article  CAS  PubMed  Google Scholar 

  55. Sornson M.W., Wu W., Dasen J.S., Flynn S., Norman D.J., O’Connell S.M., Gukovsky I., Carriere C., Ryan A.K., Miller A.P., Zuo L., Gleiberman A.S., Andersen B., Beamer W.G., Rosenfeld M.G. Pituitary lineage determination by the prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 1996, 384: 327–333.

    Article  CAS  PubMed  Google Scholar 

  56. Brown-Borg H.M., Borg K.E., Meliska C.J., Bartke A. Dwarf mice and the ageing process. Nature 1996, 384: 33 (Letter).

    Article  CAS  PubMed  Google Scholar 

  57. Cogan J.D., Wu W., Phillips J.A. III, Arnthold I.J., Fofanova O.V., Osorio M.G., Bircan I., Moreno A., Mendonca B.B. The PROP1 2-base pair deletion is a common cause of combined pituitary hormone deficiency. J. Clin. Endocrinol. Metab. 1998, 83: 3346–3349.

    CAS  PubMed  Google Scholar 

  58. Fluck C., Deladoey J., Rutishauser K., Eble A., Marti U., Wu W., Mullis P.E. Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg to Cys at codon 120 (R120C). J. Clin. Endocrinol. Metab. 1998, 83: 3727–3734.

    CAS  PubMed  Google Scholar 

  59. Deladoey J., Fluck C., Buyukgebiz A., Kuhlmann B.V., Eblé A., Hiondmarsh P.C., Wu W., Mullis P.E. “Hot spot” in the PROP1 gene responsible for combined pituitary hormone deficiency. J. Clin. Endocrinol. Metab. 1999, 84: 1645–1650.

    CAS  PubMed  Google Scholar 

  60. Shupnik M.A., Ridgway E.C., Chin W.W. Molecular biology of thyrotropin. Endocr. Rev. 1989, 10: 459–475.

    Article  CAS  PubMed  Google Scholar 

  61. Hayashizaki Y., Hiraoka Y., Endo Y., Matsubara K. Thyroid-stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGIC region of the β-subunit. EMBO J. 1989, 8: 2291–2296.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Persani L. Hypothalamic thyrotropin-releasing hormone and thyrotropin biological activity. Thyroid 1998, 8: 941–946.

    Article  CAS  PubMed  Google Scholar 

  63. Beck-Peccoz P., Amr S., Menezes Ferreira M.M., Faglia G., Weintraub B.D. Decreased receptor binding of biologically inactive thyrotropin in central hypothyroidism. Effect of treatment with thyrotropin-releasing hormone. N. Engl. J. Med. 1985, 312: 1085–1090.

    Article  CAS  PubMed  Google Scholar 

  64. Wondisford F.E., Radovick S., Moates J.M., Usala S.J., Weintraub B.D. Isolation and characterization of the human thyrotropin β-subunit gene: Differences in gene structure and promoter function from murine species. J. Biol. Chem. 1988, 263: 12538–12542.

    CAS  PubMed  Google Scholar 

  65. Dracopoli N.C., Meisler M.H. Mapping the human amylase gene cluster on the proximal short arm of chromosome 1 using a highly informative (CA)n repeat. Genomics 1990, 7: 97–102.

    Article  CAS  PubMed  Google Scholar 

  66. Steinfelder H.J., Radovick S., Wondisford F.E. Hormonal regulation of the thyrotropin β-subunit gene by phosphorylation of the pituitary-specific transcription factor Pit-1. Proc. Natl. Acad. Sci. USA. 1992, 89: 5942–5945.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Miyai K., Azukizawa M., Kumahara Y. Familial isolated thyrotropin deficiency with cretinism. N. Engl. J. Med. 1971, 285: 1043–1048.

    Article  CAS  PubMed  Google Scholar 

  68. Dacou-Voutetakis C., Feltquate D.M., Drakopoulou M., Kouridis I.A., Dracopoli N.C. Familial hypothyroidism caused by a nonsense mutation in the thyroid-stimulating hormone β-subunit gene. Am. J. Hum. Genet. 1990, 46: 988–993.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Hayashizaki Y., Hiraoka Y., Tatsumi K., Hashimoto T., Furuyama L, Miyai K., Nishijo K., Matsuura M., Kohno H., Labbe A., Matsubara K. Deoxyribonucleic acid analyses of five families with familial inherited thyroid-stimulating hormone deficiency. J. Clin. Endocrino. Metab. 1990, 71: 792–796.

    Article  CAS  Google Scholar 

  70. Medeiros-Neto G., Herodotou D.T., Rajan S., Kornmareddi S., de Lacerda L., Sandrini R., Boguszewski M.C., Hollenberg A.N., Radovick S., Wondisford F.E. A circulating, biologically inactive thyrotropin caused by a mutation in the beta-subunit gene. J. Clin. Invest. 1996, 97: 1250–1256.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Decker B.M., Pfaffle R.N., Pohlenz J., Andler W. Congenital central hypothyroidism due to a homozygous mutation in the thyrotropin β-subunit gene follows an autosomal recessive inheritance. J. Clin. Endocrinol. Metab. 1998, 83: 1762–1765.

    Google Scholar 

  72. Lapthorn A.J., Harris D.C., Littlejohn A., Lustbader J.W., Canfield R.E., Machin K.J., Morgan F.J., Isaacs N.W. Crystal structure of human chorionic gonadotropin. Nature 1994, 369: 455–461.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Endocrinology, University of Ancona, Torrette Hospital, Ancona, Italy

    Robert Collu M.D., FRCPC

Authors
  1. Robert Collu M.D., FRCPC
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Collu, R. Genetic aspects of central hypothyroidism. J Endocrinol Invest 23, 125–134 (2000). https://doi.org/10.1007/BF03343692

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03343692

Key-words

Search

Navigation