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

• Immunoprecipitation of [125I]T4 by antibody to prealbumin, precipitation of [125I]T4 by polyethylene glycol 6000 19%, and in vitro resin uptake of T3 were specific for prealbumin-associated hyperthyroxinemia, autoantibody binding of T4, and T4-binding globulin excess, respectively [11].
• In conclusion, thyroid hormone has dualistic effects on the secretory proteins synthesized by a human hepatoblastoma cell line: physiological concentrations of thyroid hormones decrease the synthesis of TBG, but increase the synthesis of AGP [12].
• RESULTS: TT3, TT4, FT4, and TG were significantly reduced and rT3, TBG, and TSH increased in children with HIV-1 infection when compared with controls [13].
• A 10-year-old boy with congenital adrenal hyperplasia and associated hyperplastic testicular adrenal rests had high serum concentrations of 17-OH progesterone (17-OHP), estradiol (E2), testosterone (T), and basal and TRH-stimulated TSH and PRL, but normal thyroid hormones (T3, T4, FT3, FT4) and thyroxine-binding globulin (TBG) [14].
• Using a multivariate test, it is demonstrated that testosterone treatment significantly reduced TBG concentrations in cirrhotic men with preserved liver function, like normal men, but not in patients with moderate liver dysfunction [15].

Biological context of SERPINA7

• To complete the protein sequence, the cDNA clone was used to identify a genomic clone coding for TBG in a human X chromosome library [16].
• Unexpectedly, the nucleotide sequence of TBG is closely homologous to those encoding the plasma serine antiproteases alpha 1-antichymotrypsin and alpha 1-antitrypsin [16].
• The analysis of genomic clones revealed that the hTBG gene consists of five exons and that its exon-intron organization is similar to that of other members of the serine protease inhibitor family [17].
• To this purpose, we isolated from liver a complete hTBG cDNA clone containing the 5'-untranslated region and localized the transcription start site (TSS) [17].
• The T4-binding globulin (TBG) gene is a single copy located on the X-chromosome [18].

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

• Thyroxine-binding globulin (TBG) is a liver glycoprotein that transports thyroid hormone in serum [1].
• Accordingly, stabilization of the TBG molecule by replacement of tyrosine with phenylalanine in position 309 causes the increased heat stability of TBG-CH [19].
• The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, down-regulated the promoter activity by more than 80% and completely inhibited hTBG synthesis, whereas thyroid hormone, glucocorticoid, estrogen, and nicotinic acid had little, if any, effect [17].
• T4-binding globulin (TBG) is a glycoprotein of hepatic origin which transports thyroid hormone in serum [17].
• Compared with common-type TBG, the mutated polypeptide results in 1) 22 different amino acids on its carboxy-terminus, 2) a 22-amino acid truncation, and 3) the absence of a potential N-linked glycosylation site [23].

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].

References