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Gene Review

SERPINA7  -  serpin peptidase inhibitor, clade A (alpha...

Homo sapiens

Synonyms: Serpin A7, T4-binding globulin, TBG, Thyroxine-binding globulin
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Disease relevance of SERPINA7

  • In 1987 a variant TBG was discovered in an infant born in Quebec, following an investigation prompted by the finding of low blood thyroxine (T4) level on screening for neonatal hypothyroidism [1].
  • If the FT4 level is equivocal in evaluating thyrotoxicosis in the presence of increased serum TBG values, then other clinical and laboratory parameters should be used [2].
  • The in vivo behavior of [125I]TBG was studied in six euthyroid subjects (controls) with normal serum levels of TBG as measured both by radioimmunoassay and by determination of maximal T4-binding capacity and in four male patients with untreated primary hyperthyroidism, three of whom had elevated serum TBG [3].
  • TBG t1/2 was 2.5 days in a patient with multiple myeloma and 3.6 days in two patients with thyrotoxicosis [4].
  • Total serum and urinary thyroxine (T4), triiodothyronine (T3), and thyroxine-binding globulin (TBG) as well as serum free T4, thyroid-stimulating hormone (TSH), and T3 resin uptake (T3RU) were measured in seven patients with the nephrotic syndrome [5].

Psychiatry related information on SERPINA7

  • The PTSD groups also showed a marked and sustained increase in T4-binding globulin levels, supporting the increased binding hypothesis [6].
  • To examine the possible effect of progesterone on circulating T4-binding globulin (TBG) in men, RIA measurements of plasma TBG and T4 levels were made before and after weekly administration of 500 mg medroxyprogesterone acetate, im, to men being treated for paraphilia (sexual deviation syndromes) [7].
  • Serum T4, free T4, T3, free T3, TSH, TBG and TBPA concentrations were significantly lower and rT3 levels were significantly higher in anorexia nervosa patients than in normal controls [8].
  • Levels of TBG in children, and lack of any correlation of low TBG levels with alcohol consumption or liver dysfunction, suggest that the low levels are not acquired in adult life [9].

High impact information on SERPINA7

  • Increased serum TBG concentrations result in a new thyroid hormone equilibrium characterized by an elevated serum thyroxine (T4) level and a reduced resin triiodothyronine (T3 uptake) level but a persistently normal serum-free T4 (FT4) level if the patient is euthyroid [2].
  • Thus, in patients with increased serum TBG levels, the calculated FT4 level is the critical serum determinant for laboratory assessment of thyroid function [2].
  • When a patient with an increased serum TBG concentration becomes thyrotoxic, the T4 level rises further and the resin T3 uptake increases from low into the normal range [2].
  • Changes in the T4 kinetics in these patients were compatible with euthyroidism and with the known alterations in the extrathyroidal T4 pool associated with the changes in serum TBG concentration [4].
  • Thyroxine-binding globulin (TBG) and partially desialylated or slow TBG (STBG) were purified from human serum by affinity chromatography [10].

Chemical compound and disease context of SERPINA7


Biological context of SERPINA7


Anatomical context of SERPINA7

  • For further analysis, vectors containing the coding regions of normal TBG (TBG-N) and TBG-CH were constructed, transcribed in vitro, and expressed in Xenopus oocytes [19].
  • On the other hand, mutational disruption of the putative hepatocyte nuclear factor-1 site (located 65 bp upstream of the TSS) completely abolished the promoter activity in all cell lines, indicating that this site is absolutely required for the transcription of the hTBG gene [17].
  • In contrast to individuals without this mutation, no TBG mRNA could be detected in fibroblasts of the propositus, expressing solely TBG-Jackson [20].
  • These data support the concept that cleavage of TBG by proteinases released in inflammation is a mechanism to deliver thyroid hormones to target tissues [21].
  • Translation of this RNA in rabbit reticulocyte lysate, followed by immunoprecipitation with anti-TBG serum, revealed a protein having the same electrophoretic mobility as deglycosylated TBG purified from human serum (Mr approximately 45,000) [22].

Associations of SERPINA7 with chemical compounds


Physical interactions of SERPINA7

  • DFT3 depended on the level of T4 in serum more than T3 concentration and was in inverse relationship with the maximal binding capacity of TBG [24].

Other interactions of SERPINA7

  • Treatment with both the patch and OC resulted in significant increases from baseline in SHBG, TBG and CBG [25].
  • An inverse linear correlation was found between TBG-DFT4 (alpha = 0.05) and DF T 3 (alpha = 0.002), TBPA-log DF T4 (alpha = 0.05) but not between TBG and TBPA [24].
  • However, there is little overall homology between TBG and transthyretin (prealbumin), the other major thyroxine-binding protein of human plasma [16].
  • To clarify the molecular basis of TBG-CD, we have cloned and sequenced the TBG gene of an affected male (CD5) of French Canadian origin [18].
  • TBG is member of the serpin family of proteins although it has no proteinase inhibitory activity [21].

Analytical, diagnostic and therapeutic context of SERPINA7

  • The human thyroxine-binding globulin (TBG) gene has been localized to X chromosome (Xq22.2) by in situ hybridization using a biotinylated gDNA probe [26].
  • This variant, TBG-San Diego (TBG-SD), also displays reduced heat stability but has a normal isoelectric focusing pattern [27].
  • In this report, a Japanese female patient (proband) with hyperthyroid state, whose lower TBG levels did not return to normal under the euthyroid state after treatment was examined [28].
  • The primary templates for sequencing were isolated from a human X-chromosome library (two positive plaques from 400,000 screened initially with a TBG cDNA probe) or were produced by PCR amplification using leucocyte genomic DNA as the amplification template [29].
  • The [125-I]TBG retained the electrophoretic and immunologic characteristics of unlabeled TBG but exhibited a partial loss of thyroxine-binding activity, as assessed by affinity chromatography [3].


  1. Sequencing of the variant thyroxine-binding globulin (TBG)-Quebec reveals two nucleotide substitutions. Bertenshaw, R., Takeda, K., Refetoff, S. Am. J. Hum. Genet. (1991) [Pubmed]
  2. Remission of hyperthyroidims and oral contraceptive therapy. [Answer to question]. Selenkow, H.A. JAMA (1984) [Pubmed]
  3. Preparation of 125-I-labeled human thyroxine-binding alpha globulin and its turnover in normal and hypothyroid subjects. Cavalieri, R.R., McMahon, F.A., Castle, J.N. J. Clin. Invest. (1975) [Pubmed]
  4. Metabolism of thyroxine-binding globulin in man. Abnormal rate of synthesis in inherited thyroxine-binding globulin deficiency and excess. Refetoff, S., Fang, V.S., Marshall, J.S., Robin, N.I. J. Clin. Invest. (1976) [Pubmed]
  5. Thyroid function studies in the nephrotic syndrome. Afrasiabi, M.A., Vaziri, N.D., Gwinup, G., Mays, D.M., Barton, C.H., Ness, R.L., Valenta, L.J. Ann. Intern. Med. (1979) [Pubmed]
  6. Elevation of serum free triiodothyronine, total triiodothyronine, thyroxine-binding globulin, and total thyroxine levels in combat-related posttraumatic stress disorder. Mason, J., Southwick, S., Yehuda, R., Wang, S., Riney, S., Bremner, D., Johnson, D., Lubin, H., Blake, D., Zhou, G. Arch. Gen. Psychiatry (1994) [Pubmed]
  7. Progesterone has no effect on serum thyroxine-binding globulin concentration in men. Chen, J.J., Ladenson, P.W. J. Clin. Endocrinol. Metab. (1985) [Pubmed]
  8. Hypothalamic-pituitary-thyroidal dysfunctions in anorexia nervosa. Tamai, H., Mori, K., Matsubayashi, S., Kiyohara, K., Nakagawa, T., Okimura, M.C., Walter, R.M., Kumagai, L.F., Nagataki, S. Psychotherapy and psychosomatics. (1986) [Pubmed]
  9. Distribution and inheritance of low serum thyroxine-binding globulin levels in Australian Aborigines: a new genetic variation. Watson, F., Dick, M. Med. J. Aust. (1980) [Pubmed]
  10. Studies on human thyroxine-binding globulin (TBG). IX. Some physical, chemical, and biological properties of radioiodinated TBG and partially desialylated TBG. Refetoff, S., Fang, V.S., Marshall, J.S. J. Clin. Invest. (1975) [Pubmed]
  11. Specific methods to identify plasma binding abnormalities in euthyroid hyperthyroxinemia. Stockigt, J.R., Dyer, S.A., Mohr, V.S., White, E.L., Barlow, J.W. J. Clin. Endocrinol. Metab. (1986) [Pubmed]
  12. Dualistic effects of thyroid hormone on a human hepatoma cell line: inhibition of thyroxine-binding globulin synthesis and stimulation of alpha 1-acid glycoprotein synthesis. Kobayashi, M., Horiuchi, R., Hachisu, T., Takikawa, H. Endocrinology (1988) [Pubmed]
  13. Thyroid function in children with perinatal human immunodeficiency virus type 1 infection. Chiarelli, F., Galli, L., Verrotti, A., di Ricco, L., Vierucci, A., de Martino, M. Thyroid (2000) [Pubmed]
  14. Euthyroid hyperthyrotropinemia secondary to hyperestrogenemia in a male with congenital adrenal hyperplasia. Benvenga, S., Smedile, G., Lo Giudice, F., Alesci, S., Amato, A., Trimarchi, F. Horm. Metab. Res. (2000) [Pubmed]
  15. The effect of oral testosterone on serum TBG levels in alcoholic cirrhotic men. Becker, U., Gluud, C., Bennett, P. Liver (1988) [Pubmed]
  16. Complete amino acid sequence of human thyroxine-binding globulin deduced from cloned DNA: close homology to the serine antiproteases. Flink, I.L., Bailey, T.J., Gustafson, T.A., Markham, B.E., Morkin, E. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  17. Human thyroxine-binding globulin gene: complete sequence and transcriptional regulation. Hayashi, Y., Mori, Y., Janssen, O.E., Sunthornthepvarakul, T., Weiss, R.E., Takeda, K., Weinberg, M., Seo, H., Bell, G.I., Refetoff, S. Mol. Endocrinol. (1993) [Pubmed]
  18. Replacement of Leu227 by Pro in thyroxine-binding globulin (TBG) is associated with complete TBG deficiency in three of eight families with this inherited defect. Mori, Y., Takeda, K., Charbonneau, M., Refetoff, S. J. Clin. Endocrinol. Metab. (1990) [Pubmed]
  19. Molecular and structural characterization of the heat-resistant thyroxine-binding globulin-Chicago. Janssen, O.E., Chen, B., Büttner, C., Refetoff, S., Scriba, P.C. J. Biol. Chem. (1995) [Pubmed]
  20. Complete thyroxine-binding globulin (TBG) deficiency in two families without mutations in coding or promoter regions of the TBG genes: in vitro demonstration of exon skipping. Reutrakul, S., Dumitrescu, A., Macchia, P.E., Moll, G.W., Vierhapper, H., Refetoff, S. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  21. Linkage between the hormone binding site and the reactive center loop of thyroxine binding globulin. Suda, S.A., Gettins, P.G., Patston, P.A. Arch. Biochem. Biophys. (2000) [Pubmed]
  22. Characterization of nascent and secreted thyroxine-binding globulin in cultured human hepatoma (Hep G2) cells. Bartalena, L., Tata, J.R., Robbins, J. J. Biol. Chem. (1984) [Pubmed]
  23. Nucleotide deletion resulting in frameshift as a possible cause of complete thyroxine-binding globulin deficiency in six Japanese families. Yamamori, I., Mori, Y., Seo, H., Hirooka, Y., Imamura, S., Miura, Y., Matsui, N., Oiso, Y. J. Clin. Endocrinol. Metab. (1991) [Pubmed]
  24. Short and long term effects of radioiodine and antithyroid drugs on T4 binding proteins, free T4 and T3, during Graves' disease therapy. Jaffiol, C., Baldet, L., Robin, M., Papachristou, C., Lapinski, H., Mirouze, J. Horm. Metab. Res. (1977) [Pubmed]
  25. Effects of transdermal and oral contraceptives on estrogen-sensitive hepatic proteins. White, T., Ozel, B., Jain, J.K., Stanczyk, F.Z. Contraception. (2006) [Pubmed]
  26. Precise localization of the human thyroxine-binding globulin gene to chromosome Xq22.2 by fluorescence in situ hybridization. Mori, Y., Miura, Y., Oiso, Y., Hisao, S., Takazumi, K. Hum. Genet. (1995) [Pubmed]
  27. Sequencing of the variant thyroxine-binding globulin (TBG)-San Diego reveals two nucleotide substitutions. Bertenshaw, R., Sarne, D., Tornari, J., Weinberg, M., Refetoff, S. Biochim. Biophys. Acta (1992) [Pubmed]
  28. Thyroxine-binding globulin variant (TBG-Kumamoto): identification of a point mutation and genotype analysis of its family. Shirotani, T., Kishikawa, H., Wake, N., Miyamura, N., Hashimoto, Y., Motoyoshi, S., Yamaguchi, K., Shichiri, M. Endocrinol. Jpn. (1992) [Pubmed]
  29. The structure of the human thyroxine binding globulin (TBG) gene. Akbari, M.T., Kapadi, A., Farmer, M.J., Fitch, N.J., McCann, K.P., Kordestani, S., Flink, I.L., Sheppard, M.C., Ramsden, D.B. Biochim. Biophys. Acta (1993) [Pubmed]
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