Functional Characterization of the 258 A/G (D2-ORFa-Gly3Asp) Human Type-2 Deiodinase Polymorphism: A Naturally Occurring Variant Increases the Enzymatic Activity by Removing a Putative Repressor Site in the 5′ UTR of the Gene

Coppotelli, Giuseppe; Summers, Aaron; Chidakel, Aaron; Ross, Jaime M.; Celi, Francesco S.

doi:10.1089/thy.2006.16.625

Cited by 28 publications

(17 citation statements)

References 29 publications

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“…The risk of MCI was decreased in male carriers of the Asp allele (OR ＝ 0.471, P < 0.05). Examination of the relationship between different genotypes of ORFa-Gly3Asp and TH revealed that the serum level of T 3 in male carriers of the Asp allele was higher than that of Gly carriers, which was consistent with the results of Coppotelli et al (2006). Thus, the Gly3Asp mutation in males may increase the serum level of T 3 , decrease the incidence of MCI, and act as a protective factor.…”

Section: Discussionsupporting

confidence: 77%

Type II deiodinase polymorphisms and serum thyroid hormone levels in patients with mild cognitive impairment

Luo¹,

Xh²,

T³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. We investigated type II deiodinase (DIO 2 ) polymorphisms and serum thyroid hormone levels in subjects with mild cognitive impairment (MCI) in a Uygur population. We studied the DIO 2 Thr92Ala (rs225014) and ORFa-Gly3Asp (rs12885300) polymorphisms of 129 unrelated MCI cases and 131 matched controls. All subjects were genotyped using SNaPshot SNP genotyping assays. Serum thyroid hormone levels were measured by radioimmunoassay. Levels of serum triiodothyronine and thyroxine in the MCI group were significantly lower than those in the control group. Genotype and allele frequencies in the DIO 2 gene between the MCI and control groups were not significantly different. There was no association in genotype and allele frequencies of Thr92Ala between genders in both groups. ORFa-Gly3Asp genotype and allele frequencies were significantly different in patients and controls by gender. The Asp allele was less frequent among male MCI patients compared to controls (odds ratio = 0.471, 95% confidence interval = 0.261-0.848). However, female Asp carriers were more frequent among MCI patients than among controls (odds ratio = 2.842, 95% confidence interval = 1.326-6.09). Serum levels of triiodothyronine and thyroxine 5408 M. Luo et al. ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 5407-5416 (2015) were lower in individuals of the Ala/Ala genotype than in those with the Thr/Thr or Thr/Ala genotype. Serum levels of triiodothyronine were lower in male Gly/Gly carriers than in Gly/Asp or Asp/Asp carriers. Decreased serum levels of triiodothyronine and thyroxine may influence the incidence of MCI in the Uygur population. DIO 2 gene polymorphisms may play a role in the incidence of MCI in male patients.

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Section: Discussionsupporting

confidence: 77%

Type II deiodinase polymorphisms and serum thyroid hormone levels in patients with mild cognitive impairment

Luo¹,

Xh²,

T³

et al. 2015

Genet. Mol. Res.

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“…Cells were homogenized in 0.25 M sucrose, 0.02 M Tris/HCl (pH 7.0), and 1 mM EDTA. After centrifugation at 1000 ϫ g, the supernatant was collected and stored at -80 C. De-iodinase activity was measured according to previously described methods (42,43). Each reaction was performed in the presence of 5 mM propylthiouracil (Sigma), an inhibitor of de-iodinase type 1.…”

Section: Molecular Modeling and Dockingmentioning

confidence: 99%

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Neumann¹,

Huang

Titus

et al. 2009

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

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113

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Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer.7TMR ͉ G protein-coupled receptor ͉ low-molecular-weight ligands ͉ radioiodide uptake ͉ TSH receptor S mall-molecule agonists and antagonists for 7-transmembrane-spanning receptors (7TMRs; G protein-coupled receptors) make up approximately 40% of the drugs in clinical use (1). The natural ligands for the 7TMRs for which drugs have been discovered are themselves primarily small molecules, such as norepinephrine, adenosine, and acetylcholine. Smallmolecule ligands for the subclass of 7TMRs for which the natural ligands are 30-kDa heterodimeric glycoprotein hormones have recently begun to be described, but none have been approved for use in humans. For example, small-molecule agonists (2-5) and an antagonist (6) for the luteinizing hormone/chorionic gonadotropin receptor (LHCGR), and small-molecule agonists (7-9) and antagonists (10-12) for the FSH receptor (FSHR) have been reported. The thyrotropin (thyroid-stimulating hormone, TSH) receptor (TSHR) is the third member of the glycoprotein hormone receptor subfamily. We recently reported smallmolecule agonists (13) and an antagonist (14) for human TSHR; however, the agonists were of low affinity and were shown to activate TSHRs only in a model cell system in which human TSHRs were ectopically over-expressed.The physiologic role of TSHRs in the hypothalamic-pituitarythyroid axis is well known. TSH, which is produced in the thyrotrophs of the anterior pituitary gland, is secreted into the circulation in response to TSH-releasing hormone stimulation and in turn stimulates the function of the thyroid follicular cells (i.e., thyrocytes) leading, in particular, to increases in size ...

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“…Previous studies have demonstrated that polymorphisms in the deiodinase genes might interfere in the phenotypic expression of these enzymes (6,10). Interestingly, a study described a single-nucleotide polymorphism in D2, in which a threonine (Thr) changes to alanine (Ala) at codon 92 (D2 Thr92Ala) was associated with w20% lower glucose disposal rate in nondiabetic subjects (11).…”

Section: Introductionmentioning

confidence: 99%

Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case–control study and meta-analysis

Dora¹,

Machado²,

Rheinheimer³

et al. 2010

European Journal of Endocrinology

122

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Objective: The type 2 deiodinase (D2) is a key enzyme for intracellular triiodothyronine (T 3 ) generation. A single-nucleotide polymorphism in D2 (Thr92Ala) has been associated with increased insulin resistance in nondiabetic and type 2 diabetes (DM2) subjects. Our aim was to evaluate whether the D2 Thr92Ala polymorphism is associated with increased risk for DM2. Design and methods: A case-control study with 1057 DM2 and 516 nondiabetic subjects was performed. All participants underwent genotyping of the D2 Thr92Ala polymorphism. Additionally, systematic review and meta-analysis of the literature for genetic association studies of D2 Thr92Ala polymorphism and DM2 were performed in Medline, Embase, LiLacs, and SciELO, and major meeting databases using the terms 'rs225014' odds ratio (OR) 'thr92ala' OR 'T92A' OR 'dio2 a/g'. Results: In the case-control study, the frequencies of D2 Ala92Ala homozygous were 16.4% (nZ173) versus 12.0% (nZ62) in DM2 versus controls respectively resulting in an adjusted OR of 1.41 (95% confidence intervals (CI) 1.03-1.94, PZ0.03). The literature search identified three studies that analyzed the association of the D2 Thr92Ala polymorphism with DM2, with the following effect estimates: Mentuccia (OR 1.40 (95% CI 0.78-2.51)), Grarup (OR 1.09 (95% CI 0.92-1.29)), and Maia (OR 1.22 (95% CI 0.78-1.92)). The pooled effect of the four studies resulted in an OR 1.18 (95% CI 1.03-1.36, PZ0.02). Conclusions: Our results indicate that in a case-control study, the homozygosity for D2 Thr92Ala polymorphism is associated with increased risk for DM2. These results were confirmed by a metaanalysis including 11 033 individuals, and support a role for intracellular T 3 concentration in skeletal muscle on DM2 pathogenesis.

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Functional Characterization of the 258 A/G (D2-ORFa-Gly3Asp) Human Type-2 Deiodinase Polymorphism: A Naturally Occurring Variant Increases the Enzymatic Activity by Removing a Putative Repressor Site in the 5′ UTR of the Gene

Abstract: These data suggest that the increase in gene transcription induced by the 258A polymorphism could be mediated by reduction in the binding ability of a putative nuclear repressor.

Cited by 28 publications

References 29 publications

Type II deiodinase polymorphisms and serum thyroid hormone levels in patients with mild cognitive impairment

Type II deiodinase polymorphisms and serum thyroid hormone levels in patients with mild cognitive impairment

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice

Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case–control study and meta-analysis

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