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. 1996 Mar 1;97(5):1250–1256. doi: 10.1172/JCI118540

A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene.

G Medeiros-Neto 1, D T Herodotou 1, S Rajan 1, S Kommareddi 1, L de Lacerda 1, R Sandrini 1, M C Boguszewski 1, A N Hollenberg 1, S Radovick 1, F E Wondisford 1
PMCID: PMC507178  PMID: 8636437

Abstract

Mutation of a critical carboxy-terminal cysteine residue (C105V) in the thyrotropin-beta (TSH-beta) subunit gene was found in two related families with central hypothyroidism. Affected patients had low thyroid hormone levels and radioactive iodine uptake in the thyroid gland associated with measurable serum TSH. Thyrotropin-releasing hormone-stimulated TSH secretion did not increase thyroid hormone production in these patients as compared to their unaffected siblings, suggesting that the mutant TSH was biologically inactive in vivo. Recombinant TSH harboring this mutation was confirmed to be biologically inactive in an in vitro bioassay. Based on crystallographic structure of chorionic gonadotropin, a disulfide bond between C19 and C105 in the TSH-beta subunit is predicted to form the "buckle" of a "seat belt" that surrounds the common alpha subunit and maintains the conformation and bioactivity of the hormone. This natural mutation of the TSH-beta subunit confirms the importance of the seat belt in the family of pituitary and placental glycoprotein hormones.

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Selected References

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  1. Dacou-Voutetakis C., Feltquate D. M., Drakopoulou M., Kourides I. A., Dracopoli N. C. Familial hypothyroidism caused by a nonsense mutation in the thyroid-stimulating hormone beta-subunit gene. Am J Hum Genet. 1990 May;46(5):988–993. [PMC free article] [PubMed] [Google Scholar]
  2. Gross-Bellard M., Oudet P., Chambon P. Isolation of high-molecular-weight DNA from mammalian cells. Eur J Biochem. 1973 Jul 2;36(1):32–38. doi: 10.1111/j.1432-1033.1973.tb02881.x. [DOI] [PubMed] [Google Scholar]
  3. Hayashizaki Y., Hiraoka Y., Endo Y., Miyai K., Matsubara K. Thyroid-stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the beta-subunit. EMBO J. 1989 Aug;8(8):2291–2296. doi: 10.1002/j.1460-2075.1989.tb08355.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Inappropriate secretion of thyroid-stimulating hormone. Ann Intern Med. 1981 Sep;95(3):339–351. doi: 10.7326/0003-4819-95-3-339. [DOI] [PubMed] [Google Scholar]
  5. Kopp P., van Sande J., Parma J., Duprez L., Gerber H., Joss E., Jameson J. L., Dumont J. E., Vassart G. Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med. 1995 Jan 19;332(3):150–154. doi: 10.1056/NEJM199501193320304. [DOI] [PubMed] [Google Scholar]
  6. Kourides I. A., Weintraub B. D., Ridgway E. C., Maloof F. Pituitary secretion of free alpha and beta subunit of human thyrotropin in patients with thyroid disorders. J Clin Endocrinol Metab. 1975 May;40(5):872–885. doi: 10.1210/jcem-40-5-872. [DOI] [PubMed] [Google Scholar]
  7. 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 Jun 9;369(6480):455–461. doi: 10.1038/369455a0. [DOI] [PubMed] [Google Scholar]
  8. Matthews C. H., Borgato S., Beck-Peccoz P., Adams M., Tone Y., Gambino G., Casagrande S., Tedeschini G., Benedetti A., Chatterjee V. K. Primary amenorrhoea and infertility due to a mutation in the beta-subunit of follicle-stimulating hormone. Nat Genet. 1993 Sep;5(1):83–86. doi: 10.1038/ng0993-83. [DOI] [PubMed] [Google Scholar]
  9. Miyai K., Azukizawa M., Kumahara Y. Familial isolated thyrotropin deficiency with cretinism. N Engl J Med. 1971 Nov 4;285(19):1043–1048. doi: 10.1056/NEJM197111042851902. [DOI] [PubMed] [Google Scholar]
  10. Miyai K., Endo Y., Iijima Y., Kabutomori O., Hayashizaki Y. Serum free thyrotropin subunit in congenital isolated thyrotropin deficiency. Endocrinol Jpn. 1988 Jun;35(3):517–521. doi: 10.1507/endocrj1954.35.517. [DOI] [PubMed] [Google Scholar]
  11. Newton C. R., Graham A., Heptinstall L. E., Powell S. J., Summers C., Kalsheker N., Smith J. C., Markham A. F. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res. 1989 Apr 11;17(7):2503–2516. doi: 10.1093/nar/17.7.2503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. 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 Dec 15;189(2):851–855. doi: 10.1016/0006-291x(92)92281-2. [DOI] [PubMed] [Google Scholar]
  13. Pfäffle R. W., DiMattia G. E., Parks J. 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 Aug 21;257(5073):1118–1121. doi: 10.1126/science.257.5073.1118. [DOI] [PubMed] [Google Scholar]
  14. Pierce J. G., Parsons T. F. Glycoprotein hormones: structure and function. Annu Rev Biochem. 1981;50:465–495. doi: 10.1146/annurev.bi.50.070181.002341. [DOI] [PubMed] [Google Scholar]
  15. 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 Aug 21;257(5073):1115–1118. doi: 10.1126/science.257.5073.1115. [DOI] [PubMed] [Google Scholar]
  16. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  17. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Selden R. F., Howie K. B., Rowe M. E., Goodman H. M., Moore D. D. Human growth hormone as a reporter gene in regulation studies employing transient gene expression. Mol Cell Biol. 1986 Sep;6(9):3173–3179. doi: 10.1128/mcb.6.9.3173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sunthornthepvarakui T., Gottschalk M. E., Hayashi Y., Refetoff S. Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene. N Engl J Med. 1995 Jan 19;332(3):155–160. doi: 10.1056/NEJM199501193320305. [DOI] [PubMed] [Google Scholar]
  20. Tatsumi K., Miyai K., Notomi T., Kaibe K., Amino N., Mizuno Y., Kohno H. Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene. Nat Genet. 1992 Apr;1(1):56–58. doi: 10.1038/ng0492-56. [DOI] [PubMed] [Google Scholar]
  21. Weiss J., Axelrod L., Whitcomb R. W., Harris P. E., Crowley W. F., Jameson J. L. Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone. N Engl J Med. 1992 Jan 16;326(3):179–183. doi: 10.1056/NEJM199201163260306. [DOI] [PubMed] [Google Scholar]
  22. Wondisford F. E., Radovick S., Moates J. M., Usala S. J., Weintraub B. D. Isolation and characterization of the human thyrotropin beta-subunit gene. Differences in gene structure and promoter function from murine species. J Biol Chem. 1988 Sep 5;263(25):12538–12542. [PubMed] [Google Scholar]
  23. Wondisford F. E., Usala S. J., DeCherney G. S., Castren M., Radovick S., Gyves P. W., Trempe J. P., Kerfoot B. P., Nikodem V. M., Carter B. J. Cloning of the human thyrotropin beta-subunit gene and transient expression of biologically active human thyrotropin after gene transfection. Mol Endocrinol. 1988 Jan;2(1):32–39. doi: 10.1210/mend-2-1-32. [DOI] [PubMed] [Google Scholar]

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