Thyroxine-binding globulin (TBG) is a globulin that binds thyroid hormones in circulation. It is one of three transport proteins (along with transthyretin and serum albumin) responsible for carrying the thyroid hormones thyroxine (T4) and triiodothyronine (T3) in the bloodstream. Of these three proteins, TBG has the highest affinity for T4 and T3 but is present in the lowest concentration. Despite its low concentration, TBG carries the majority of T4 in the blood plasma. Due to the very low concentration of T4 and T3 in the blood, TBG is rarely more than 25% saturated with its ligand. Unlike transthyretin and albumin, TBG has a single binding site for T4/T3. TBG is synthesized primarily in the liver as a 54-kDa protein. In terms of genomics, TBG is a serpin; however, it has no inhibitory function like many other members of this class of proteins.
Role in diagnosis
Thyroxine-binding globulin tests are sometimes used to find the cause of raised or lowered levels of thyroid hormone. This is done by measuring resin binding to labeled thyroid hormone, which happens only when the labeled thyroid hormone is free.
The patient's serum is mixed with the labeled thyroid hormone; next, the resin is added to the whole mixture to measure the amount of free labeled thyroid hormone. So, for instance, if the patient is truly hypothyroid, and TBG levels are normal, then there are many sites open for binding on the TBG, since the total thyroid hormone level is low. Therefore, when the labeled hormone is added, it will bind mostly to the TBG, leaving little of it left for binding to the resin. In contrast, however, if the patient is truly hyperthyroid, and TBG levels are normal, the patient's endogenous hormone will saturate the TBG binding sites more, leaving less room for the labeled hormone, which allows greater binding to the resin.
In the situations described above, TBG testing is not very useful. However, if total thyroid hormone levels point to hypothyroidism or hyperthyroidism in the absence of accompanying symptoms, the utility of TBG testing becomes more evident, since TBG production can be modified by other factors such as estrogen levels, corticosteroid levels, or liver failure. If, for example, the TBG level is high, which can occur when estrogen levels are high, the TBG will bind more thyroid hormone, decreasing the free hormone available in the blood, which leads to stimulation of TSH, and the production of more thyroid hormone. In this case, the total thyroid hormone level will be high. And so, when labeled hormone is added, since TBG is so high, once equilibrium between the binding of endogenous thyroid hormone and the labeled hormone is achieved, less free labeled hormone will be available for uptake into the resin. On the converse, in the presence of corticosteroids, which lower TBG levels, the total thyroid hormone (bound and free) in the blood will be low. Thus, when the labeled hormone is added, since so little TBG is available in the blood, after equilibrium is achieved, only a small portion of it will bind, leaving plenty available for uptake by the resin
- Cheng SY (1978). "Partial amino acid sequence of human thyroxine-binding globulin. Further evidence for a single polypeptide chain". Biochem. Biophys. Res. Commun. 79 (4): 1212–8. PMID 414747. doi:10.1016/0006-291X(77)91135-4.
- Shirotani T, Kishikawa H, Wake N, et al. (1993). "Thyroxine-binding globulin variant (TBG-Kumamoto): identification of a point mutation and genotype analysis of its family". Endocrinol. Jpn. 39 (6): 577–84. PMID 1294376. doi:10.1507/endocrj1954.39.577.
- Bertenshaw R, Sarne D, Tornari J, et al. (1992). "Sequencing of the variant thyroxine-binding globulin (TBG)-San Diego reveals two nucleotide substitutions". Biochim. Biophys. Acta. 1139 (4): 307–10. PMID 1515456. doi:10.1016/0925-4439(92)90105-v.
- Bertenshaw R, Takeda K, Refetoff S (1991). "Sequencing of the variant thyroxine-binding globulin (TBG)-Quebec reveals two nucleotide substitutions". Am. J. Hum. Genet. 48 (4): 741–4. PMC . PMID 1901689.
- Imamura S, Mori Y, Murata Y, et al. (1991). "Molecular cloning and primary structure of rat thyroxine-binding globulin". Biochemistry. 30 (22): 5406–11. PMID 1903654. doi:10.1021/bi00236a012.
- Janssen OE, Takeda K, Refetoff S (1991). "Sequence of the variant thyroxine-binding globulin (TBG) in a Montreal family with partial TBG deficiency". Hum. Genet. 87 (2): 119–22. PMID 1906047. doi:10.1007/BF00204164.
- Yamamori I, Mori Y, Seo H, et al. (1991). "Nucleotide deletion resulting in frameshift as a possible cause of complete thyroxine-binding globulin deficiency in six Japanese families". J. Clin. Endocrinol. Metab. 73 (2): 262–7. PMID 1906892. doi:10.1210/jcem-73-2-262.
- Li P, Janssen OE, Takeda K, et al. (1991). "Complete thyroxine-binding globulin (TBG) deficiency caused by a single nucleotide deletion in the TBG gene". Metab. Clin. Exp. 40 (11): 1231–4. PMID 1943753. doi:10.1016/0026-0495(91)90221-h.
- Waltz MR, Pullman TN, Takeda K, et al. (1990). "Molecular basis for the properties of the thyroxine-binding globulin-slow variant in American blacks". J. Endocrinol. Invest. 13 (4): 343–9. PMID 2115061. doi:10.1007/bf03349576.
- Mori Y, Takeda K, Charbonneau M, Refetoff S (1990). "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". J. Clin. Endocrinol. Metab. 70 (3): 804–9. PMID 2155256. doi:10.1210/jcem-70-3-804.
- Takeda K, Mori Y, Sobieszczyk S, et al. (1989). "Sequence of the variant thyroxine-binding globulin of Australian aborigines. Only one of two amino acid replacements is responsible for its altered properties". J. Clin. Invest. 83 (4): 1344–8. PMC . PMID 2495303. doi:10.1172/JCI114021.
- Mori Y, Seino S, Takeda K, et al. (1989). "A mutation causing reduced biological activity and stability of thyroxine-binding globulin probably as a result of abnormal glycosylation of the molecule". Mol. Endocrinol. 3 (3): 575–9. PMID 2501669. doi:10.1210/mend-3-3-575.
- Flink IL, Bailey TJ, Gustafson TA, et al. (1986). "Complete amino acid sequence of human thyroxine-binding globulin deduced from cloned DNA: close homology to the serine antiproteases". Proc. Natl. Acad. Sci. U.S.A. 83 (20): 7708–12. PMC . PMID 3094014. doi:10.1073/pnas.83.20.7708.
- Janssen OE, Chen B, Büttner C, et al. (1996). "Molecular and structural characterization of the heat-resistant thyroxine-binding globulin-Chicago". J. Biol. Chem. 270 (47): 28234–8. PMID 7499319. doi:10.1074/jbc.270.47.28234.
- Mori Y, Miura Y, Oiso Y, et al. (1995). "Precise localization of the human thyroxine-binding globulin gene to chromosome Xq22.2 by fluorescence in situ hybridization". Hum. Genet. 96 (4): 481–2. PMID 7557975. doi:10.1007/BF00191811.
- Miura Y, Mori Y, Yamamori I, et al. (1994). "Sequence of a variant thyroxine-binding globulin (TBG) in a family with partial TBG deficiency in Japanese (TBG-PDJ)". Endocr. J. 40 (1): 127–32. PMID 7951486. doi:10.1507/endocrj.40.127.
- Hayashi Y, Mori Y, Janssen OE, et al. (1993). "Human thyroxine-binding globulin gene: complete sequence and transcriptional regulation". Mol. Endocrinol. 7 (8): 1049–60. PMID 8232304. doi:10.1210/me.7.8.1049.
- Akbari MT, Kapadi A, Farmer MJ, et al. (1994). "The structure of the human thyroxine binding globulin (TBG) gene". Biochim. Biophys. Acta. 1216 (3): 446–54. PMID 8268226. doi:10.1016/0167-4781(93)90013-4.
- Mori Y, Miura Y, Takeuchi H, et al. (1996). "Gene amplification as a cause of inherited thyroxine-binding globulin excess in two Japanese families". J. Clin. Endocrinol. Metab. 80 (12): 3758–62. PMID 8530630. doi:10.1210/jc.80.12.3758.
- Carvalho GA, Weiss RE, Vladutiu AO, Refetoff S (1998). "Complete deficiency of thyroxine-binding globulin (TBG-CD Buffalo) caused by a new nonsense mutation in the thyroxine-binding globulin gene". Thyroid. 8 (2): 161–5. PMID 9510125. doi:10.1089/thy.1998.8.161.