Thyroxine-Binding Globulin: Organization of the Gene and Variants

Refetoff, Samuel; Murata, Yoshiharu; Mori, Yuichi; Janßen, Onno E.; Takeda, Kyoko; Hayashi, Yoshitaka

doi:10.1159/000184775

Cited by 51 publications

(30 citation statements)

References 28 publications

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“…O transporte do T 3 é semelhante, apenas com uma proporção menor ligada à transtiretina. Uma pequena fração de T 4 e T 3 circulam ligados às lipoproteínas (75)(76)(77). Até a década de 60 a avaliação da função tireoidiana era feita pelo único teste disponível, utilizando-se a técnica do iodo ligado à proteína (PBI), uma estimativa indireta da concentração sérica de T 4 total (78).…”

Section: Dosagem De Iodotironinas (T 4 E T 3 ) E Fatores Interferenteunclassified

Fatores Interferentes na Interpretação de Dosagens Laboratoriais no Diagnóstico de Hiper e Hipotireoidismo

Graf

Carvalho

2002

Arq Bras Endocrinol Metab

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Laboratory Interfering Factors in the Diagnosis of Hyper and Hypothyroidism.Since the first reports in the medical literature describing the clinical presentation of hypo and hyperthyroidism, very little has changed on the semiologic scenario of these entities and even in their therapeutic approach. The changing trends refer much more to the tools used to diagnose thyroid disease. In parallel with these developments, we understand much better about the factors that interfere in the interpretation of thyroid function tests in the diagnosis of hyper and hypothyroidism. In this article, we analyzed the utility of serum TSH and thyroid hormone measurements, as well the pitfalls and interferences in its common daily use. (Arq Bras Endocrinol Metab 2002;46/1:51-64)

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Section: Dosagem De Iodotironinas (T 4 E T 3 ) E Fatores Interferenteunclassified

Fatores Interferentes na Interpretação de Dosagens Laboratoriais no Diagnóstico de Hiper e Hipotireoidismo

Graf

Carvalho

2002

Arq Bras Endocrinol Metab

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“…It is a small molecule formed by the linkage of two tyrosines, which are iodinated to give the alternative tri-or tetra-iodo forms of the hormone. Thyroxine is principally carried in the blood by thyroxine-binding globulin (TBG), which binds it with high affinity (K d ϭ 0.1 nM) in equilibrium with steady-state low levels of free thyroxine (1)(2)(3). Although TBG is not a protease inhibitor, it is otherwise a typical member of the serpin family of protease inhibitors.…”

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confidence: 99%

Structural mechanism for the carriage and release of thyroxine in the blood

Zhou

Wei

Read

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

117

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The hormones that most directly control tissue activities in health and disease are delivered by two noninhibitory members of the serpin family of protease inhibitors, thyroxine-binding globulin (TBG) and corticosteroid-binding globulin. The structure of TBG bound to tetra-iodo thyroxine, solved here at 2.8 Å, shows how the thyroxine is carried in a surface pocket on the molecule. This unexpected binding site is confirmed by mutations associated with a loss of hormone binding in both TBG and also homologously in corticosteroid-binding globulin. TBG strikingly differs from other serpins in having the upper half of its main ␤-sheet fully opened, so its reactive center peptide loop can readily move in and out of the sheet to give an equilibrated binding and release of thyroxine. The entry of the loop triggers a conformational change, with a linked contraction of the binding pocket and release of the bound thyroxine. The ready reversibility of this change is due to the unique presence in the reactive loop of TBG of a proline that impedes the full and irreversible entry of the loop that occurs in other serpins. Thus, TBG has adapted the serpin inhibitory mechanism to give a reversible flip-flop transition, from a high-affinity to a low-affinity form. The complexity and ready triggering of this conformational mechanism strongly indicates that TBG has evolved to allow a modulated and targeted delivery of thyroxine to the tissues.corticosteroid-binding globulin ͉ serpin ͉ thyroxine-binding globulin ͉ crystal structure T hyroxine is the major hormone controlling cellular development as well as the rate of body metabolism. It is a small molecule formed by the linkage of two tyrosines, which are iodinated to give the alternative tri-or tetra-iodo forms of the hormone. Thyroxine is principally carried in the blood by thyroxine-binding globulin (TBG), which binds it with high affinity (K d ϭ 0.1 nM) in equilibrium with steady-state low levels of free thyroxine (1-3). Although TBG is not a protease inhibitor, it is otherwise a typical member of the serpin family of protease inhibitors. The alignment of its sequence shows that it retains the same framework structure as the archetypal inhibitory members of the family, ␣ 1 -antitrypsin, antithrombin, and antichymotrypsin (4). It has similarly retained a typical reactive site loop, with a putative reactive center at the position denoted P1 and, with 17 residues before it, the hinge of the loop at P17 (see Fig. 1 and Table 1). In particular, TBG undergoes the profound and irreversible conformational change on cleavage of its reactive loop, which is characteristic of the serpins (5, 6). Such cleavage of the reactive loop of TBG by proteases does occur during sepsis to give a 3-fold reduction in its binding affinity (7-9). However, because only a minor proportion, Ͻ20%, of the circulating TBG is bound to thyroxine, even this relatively small decrease in affinity will result in an effective release of thyroxine (10), as demonstrably occurs at sites of inf lammation (11). Normally, ho...

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“…Moreover, no significant differences were found considering fT 3 , fT 4 and fT 3 /fT 4 , suggesting a comparable activity of the other genes involved in the thyroid function set-point [16,17,18,19,20,21,22,23,24,25,26]. …”

Section: Discussionmentioning

confidence: 99%

“…Individual differences in LT 4 requirements could be justified by the presence of genetic variants, such as single nucleotide polymorphisms (SNPs), in the genes involved in the determination of thyroid hormone levels. Several genes of the HPT axis have been analyzed in relation to the thyroid function set-point: thyroid-stimulating hormone receptor [16], iodothyronine deiodinase 1 [17,18], iodothyronine deiodinase 2 [17,18,19,20,21], iodothyronine deiodinase 3 [22], monocarboxylate transporter 8 [23], monocarboxylate transporter 10 [24], several members of the organic anion transporting polypeptide family [24], thyroxine-binding globulin [25] and thyroid hormone receptors α and β [22,26]. …”

Section: Introductionmentioning

confidence: 99%

TheTRHRGene Is Associated with Hypothalamo-Pituitary Sensitivity to Levothyroxine

et al. 2014

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Background: Thyroidectomized patients need variable doses of levothyroxine (LT₄) to obtain target thyroid-stimulating hormone (TSH) levels. Individual feedback set-points have been hypothesized and the influence of several genes in the regulation of the pituitary-thyroid axis has been demonstrated. Objectives: We hypothesized that genetic variants of the TRHR gene could be associated with a different hypothalamo-pituitary sensitivity to thyroid hormone feedback. Methods: We retrospectively analyzed 84 thyroidectomized patients with no residual thyroid function and undetectable thyroglobulin levels. Patients were evaluated under LT₄ resulting in TSH levels detectable but <0.5 μIU/ml. The two SNPs rs3134105 and rs3110040 were identified as informative markers of the TRHR gene. Genotyping was performed using high-resolution melting technology. Genotype distribution was compared between the patients and 99 euthyroid controls. Results: The selected SNPs were in linkage disequilibrium and only rs3134105 was further considered. A significant difference between the three possible genotypes for rs3134105 was found for TSH (p = 0.04) and free thyroxine (fT₄)/TSH ratio (p = 0.02). Moreover, despite similar serum concentrations of free triiodothyronine (fT₃) and fT₄, carriers of at least one A allele of rs3134105 had significantly lower serum TSH levels (p = 0.01) as well as higher fT₃/TSH (p = 0.01) and fT₄/TSH ratios (p < 0.01). Conclusions: We demonstrated an association between serum TSH levels and discrete alleles of the TRHR gene in totally thyroidectomized patients under LT₄ therapy. Therefore, the TRHR gene seems to be a determinant of hypothalamo-pituitary sensitivity to LT₄.

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Thyroxine-Binding Globulin: Organization of the Gene and Variants

Cited by 51 publications

References 28 publications

Fatores Interferentes na Interpretação de Dosagens Laboratoriais no Diagnóstico de Hiper e Hipotireoidismo

Fatores Interferentes na Interpretação de Dosagens Laboratoriais no Diagnóstico de Hiper e Hipotireoidismo

Structural mechanism for the carriage and release of thyroxine in the blood

TheTRHRGene Is Associated with Hypothalamo-Pituitary Sensitivity to Levothyroxine

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