Compound hemizygous variants in SERPINA7 gene cause thyroxine-binding globulin deficiency.
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ABSTRACT: Sub-heading
Compound hemizygous variants in SERPINA7 gene.Background
Thyroxine-binding globulin (TBG) is encoded by SERPINA7 (OMIM. 314200) which is located on Xq22.3. SERPINA7 variants caused TBG deficiency which does not require treatment, but the decreased thyroxine may be misdiagnosed as hypothyroidism. We discovered some variants of TBG caused by alterations that differ from previously reported.Materials and methods
In this study, we enrolled 32 subjects from 10 families and sequenced the SERPINA7 genes of TBG-deficient subjects. Then, variants were analyzed to assess their effect on TBG expression and secretion. Bioinformatics database, protein structure, and dynamics simulation were used to evaluate the deleterious effects. Finally, we identified 2 novel and 4 known variants, and found 26 of 30 subjects carried the p.L303F. The DynaMut predictions indicated the variants (p.E91K, p.I92T, p.R294C, and p.L303F) exhibited decreased stability.Conclusion
Analyses revealed the p.L303F change the protein stability and flexibility, and it had an impact on the function of TBG, but when coexisted with other variants it might change the conformational structure of the protein and aggravate the damage to the protein. We speculated that the existence of a higher number of variants resulted in lower TBG secretion.
SUBMITTER: Fang Y
PROVIDER: S-EPMC8077092 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC6887617 | biostudies-literature
Project description:BackgroundThyroxine-binding globulin (TBG) is the major thyroid hormone transport protein in serum. Located on the long arm of the X chromosome, TBG (SERPINA7) gene mutations most commonly produce inherited partial TBG deficiency (TBG-PD).ObjectiveWe report a novel TBG variant associated with TBG-PD identified in 2 different families of Ashkenazi origin residing in greater Chicago.MethodsFamily 1: The proband was 12.6 years old when she presented for delayed puberty and was placed on L-T4. Although her serum TSH normalized, her serum T4 remained low. Affected family members had low total T4 and T3, but a normal free T4 index, even when serum TSH concentrations were normal. Family 2: A 71-year-old male presented with a history of a nonfunctioning pituitary adenoma and normal pituitary axes except for low total T4 and T3. His brother had a similar thyroid phenotype.ResultsFollowing direct DNA sequencing, both index patients were found to carry a missense mutation in the TBG gene (c.751T>G) producing p.V215G. The proposita of family 1 was heterozygous and the proband in family 2 was hemizygous for the mutation. Isoelectric focusing showed no alteration in the TBG isoforms and in vitro expression demonstrated a TBG with reduced affinity for T4.ConclusionsWe report a novel mutation in the TBG gene in 2 unrelated families that produces a molecule with reduced affinity for T4 resulting in low serum T4. However, the physical properties of the mutant molecule remained unaltered as determined by isoelectric focusing.
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Project description:Thyroxine-binding globulin (TBG), the major carrier of thyroid hormones in human and murine sera, is in the rat a developmentally regulated protein, showing a large surge during post-natal growth followed by virtual disappearance in adults. Here we study as a function of age, from the 19-day embryo to 60 days after birth, the structural and binding characteristics of rat TBG microheterogeneity. Serum obtained throughout development, when pre-incubated with 125I-thyroxine (T4), was shown by isoelectric focusing (IEF; pH range 4-5) to contain six labelled isoforms of TBG, with isoelectric points between 4.25 and 4.55. These isoforms differ in their sialic acid content. The relative labelling densities of the isoforms show age-related changes: in neonates, the bulk of T4 is bound to the most alkaline (least sialylated) TBG isoforms; then, with advancing age, it shifts to the most acidic isoforms. To understand whether this progressive transfer of ligand reflects developmental changes in the relative abundance of isoforms, we submitted sera from rats of different ages to crossed immunoelectrofocusing analysis. We demonstrate that the relative proportions of the TBG isoforms remain fairly constant, independent of the level of total TBG. The most acidic forms always represented the majority (approximately 50%), with the most alkaline ones only representing 15% of total TBG. Experiments based on IEF of charcoal-treated sera, supplemented or not with lipidic serum extracts, further demonstrate that the paradoxical low labelling seen in the neonates for the most abundant highly sialylated isoforms is due to inhibition of their binding abilities by liposoluble components, which are particularly concentrated in the sera at the earlier post-natal ages. These studies represent the first analysis of concentration versus binding functions of rat TBG isoforms in the physiological conditions of normal ontogeny. Our results point to an important influence for the serum environment on the binding properties of TBG isoforms. The physiological significance of such interactions remains to be clarified.
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Project description:BackgroundMajor depressive disorder (MDD), common mental disorder, lacks objective diagnostic and prognosis biomarkers. The objective of this study was to perform proteomic analysis to identify proteins with changed expression levels after antidepressant treatment and investigate differences in protein expression between MDD patients and healthy individuals.MethodsA total of 111 proteins obtained from literature review were subjected to multiple reaction monitoring (MRM)-based protein quantitation. Finally, seven proteins were quantified for plasma specimens of 10 healthy controls and 78 MDD patients (those at baseline and at 6 weeks after antidepressant treatment of either selective serotonin reuptake inhibitors (SSRIs) or mirtazapine).ResultsAmong 78 MDD patients, 35 patients were treated with SSRIs and 43 patients were treated with mirtazapine. Nineteen (54.3%) and 16 (37.2%) patients responded to SSRIs and mirtazapine, respectively. Comparing MDD patients with healthy individuals, alteration of transthyretin was observed in MDD (P = 0.026). A few differences were observed in protein levels related to SSRIs treatment, although they were not statistically significant. Plasma thyroxine-binding globulin (TBG) was different between before and after mirtazapine treatment only in responders (P = 0.007).ConclusionsIn proteomic analysis of plasma specimens from MDD patients, transthyretin and TBG levels were altered in MDD and changed after antidepressant treatment.
| S-EPMC7811235 | biostudies-literature
Project description:IntroductionNewborn screening (NBS) for congenital hypothyroidism (CH) in the Netherlands consists of thyroxine (T4), thyroid-stimulating hormone (TSH), and T4-binding globulin (TBG) measurements to detect thyroidal CH and central CH (CH-C). CH-C is detected by T4 or a calculated T4/TBG ratio, which serves as an indirect measure of free T4. TSH and TBG are only measured in the lowest 20 and 5% of daily T4 values, respectively. A recent evaluation of the Dutch NBS for CH showed that the T4 and T4/TBG ratio contribute to the detection of CH-C but also lead to a low positive predictive value (PPV). Dried blood spot (DBS) reference intervals (RIs) are currently unknown and may contribute to improvement of our NBS algorithm.Materials and methodsRIs of T4, TSH, TBG, and the T4/TBG ratio were determined according to Clinical & Laboratory Standards Institute guidelines in heel puncture cards from routine NBS in both sexes and at the common NBS sampling ages. Scatter plots were used to compare the healthy reference population to previously published data of CH-C patients and false positives.ResultsAnalyses of 1,670 heel puncture cards showed small differences between subgroups and led to the formulation of total sample DBS RIs for T4 (56-118 nmol/L), TSH (<2.6 mIU/L), TBG (116-271 nmol/L), and the T4/TBG ratio (>20). 46% of false-positive referrals based on T4 alone had a TBG below the RI, indicating preventable referral due to partial TBG deficiency. One case of CH-C also had partial TBG deficiency (TBG 59 and T4 12 nmol/L blood).Discussion/conclusionEstablished DBS RIs provided possibilities to improve the PPV of the Dutch CH NBS algorithm. We conclude that by taking partial TBG deficiency into account, approximately half of T4 false-positive referrals may be prevented while maintaining NBS sensitivity at the current level.
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Project description:We confirm our finding of a major development-regulated thyroxine-binding globulin (TBG) in the serum of the euthyroid mouse and investigate a number of its binding, structural and regulatory properties. Between 16 days foetal and 60 days postnatal life, the thyroxine (T4)- and tri-iodothyronine (T3)-binding activities of the sera show a striking ontogenic pattern: the binding is 2-3 times higher in foetuses than in mothers, then further increases after birth, reaching between 3 and 5 days maximum values which are 7-8 times higher than the adult ones. This pattern is not correlated with the ontogenesis of the acknowledged specific (transthyretin, TTR) and non-specific (albumin, alpha 1-foetoprotein) thyroid-hormone carriers of the mouse sera. PAGE studies demonstrate that the protein responsible for the elevated binding of the perinatal period is an alpha 1-globulin, with a migration similar to that of human and rat TBGs. Scatchard analysis is consistent with the notions that the T4-binding sites of TBG have high association constants, about two orders of magnitude above the T4 sites of TTR (10(9) M-1 as against 10(7) M-1) and low capacities (37 and 4 nmol/g of serum proteins in pups and adults respectively). Isoelectric focusing (i.e.f.) demonstrates that mouse TBG is a microheterogeneous protein separable, as a function of the pH gradient, in up to 10-12 isoforms, Marked shifts of the relative abundance of isoforms in the course of development are evidenced. The modulation of the TBG binding activity by non-esterified fatty acids (NEFA) and the control of its synthesis by the thyroid status are also reported. Mono- and poly-unsaturated NEFAs are strong inhibitors of the TBG, although they affect TTR less readily. On the other hand, the biosynthesis and/or secretion of TBG, but not of TTR, is under thyroid-hormone control, experimental hypothyroidism inducing a marked increase of the serum TBG. The TBG of mouse behaves as a highly significant parameter of development, pointing to a likely important function of the protein in the process of maturation. Our finding of major TBGs in both euthyroid rats and mice suggests that TBG is more widely spread than was thought until now, but difficult to detect in certain species outside definite maturation stages.
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