scholarly journals Hyperactivity and Learning Deficits in Transgenic Mice Bearing a Human Mutant Thyroid Hormone β1 Receptor Gene

1998 ◽  
Vol 5 (4) ◽  
pp. 289-301 ◽  
Author(s):  
Michael P. McDonald ◽  
Rosemary Wong ◽  
Gregory Goldstein ◽  
Bruce Weintraub ◽  
Sheue-yann Cheng ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Transgenic Mice ◽  
Sustained Attention ◽  
Receptor Gene ◽  
Operant Chamber ◽  
Elevated Serum ◽  
Vigilance Task ◽  
Serum Levels ◽  
Wild Type ◽  
Wild Type Littermate

Resistance to thyroid hormone (RTH) is a human syndrome mapped to the thyroid receptor β(TRβ) gene on chromosome 3, representing a mutation of the ligandbinding domain of the TRβ gene. The syndrome is characterized by reduced tissue responsiveness to thyroid hormone and elevated serum levels of thyroid hormones. A common behavioral phenotype associated with RTH is attention deficit hyperactivity disorder (ADHD). To test the hypothesis that RTH produces attention deficits and/or hyperactivity, transgenic mice expressing a mutant TRβ gene were generated. The present experiment tested RTH transgenic mice from the PV kindred on behavioral tasks relevant to the primary features of ADHD: hyperactivity, sustained attention (vigilance), learning, and impulsivity. Male transgenic mice showed elevated locomotor activity in an open field compared to male wild-type littermate controls. Both male and female transgenic mice exhibited impaired learning of an autoshaping task, compared to wild-type controls. On a vigilance task in an operant chamber, there were no differences between transgenics and controls on the proportion of hits, response latency, or duration of stimulus tolerated. On an operant go/no-go task measuring sustained attention and impulsivity, there were no differences between controls and transgenics. These results indicate that transgenic mice bearing a mutant human TRβ gene demonstrate several behavioral characteristics of ADHD and may serve a valuable heuristic role in elucidating possible candidate genes in converging pathways for other causes of ADHD.

scholarly journals Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin

2005 ◽  
Vol 202 (4) ◽  
pp. 541-549 ◽  
Author(s):  
Jane Yoo ◽  
Miyuki Omori ◽  
Dora Gyarmati ◽  
Baohua Zhou ◽  
Theingi Aye ◽  
...  
Keyword(s):  
Animal Model ◽  
Atopic Dermatitis ◽  
Transgenic Mice ◽  
Elevated Serum ◽  
Allergic Inflammation ◽  
Disease Process ◽  
Allergic Diseases ◽  
Serum Levels ◽  
Thymic Stromal Lymphopoietin ◽  
Common Disease

The cytokine thymic stromal lymphopoietin (TSLP) has recently been implicated in the pathogenesis of atopic dermatitis (AD) and other allergic diseases in humans. To further characterize its role in this disease process, transgenic mice were generated that express a keratinocyte-specific, tetracycline-inducible TSLP transgene. Skin-specific overexpression of TSLP resulted in an AD-like phenotype, with the development of eczematous lesions containing inflammatory dermal cellular infiltrates, a dramatic increase in Th2 CD4+ T cells expressing cutaneous homing receptors, and elevated serum levels of IgE. These transgenic mice demonstrate that TSLP can initiate a cascade of allergic inflammation in the skin and provide a valuable animal model for future study of this common disease.

scholarly journals Genotype-Phenotype Relationship in Patients with Mutations in Thyroid Hormone Transporter MCT8

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2184-2190 ◽  
Author(s):  
Jurgen Jansen ◽  
Edith C. H. Friesema ◽  
Monique H. A. Kester ◽  
Charles E. Schwartz ◽  
Theo J. Visser
Keyword(s):  
Plasma Membrane ◽  
Thyroid Hormone ◽  
Protein Expression ◽  
Elevated Serum ◽  
Monocarboxylate Transporter ◽  
Psychomotor Development ◽  
Substrate Affinity ◽  
Loss Of Function ◽  
Wild Type ◽  
Rt Pcr

Loss-of-function mutations in thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe X-linked psychomotor retardation and elevated serum T3 levels. Most patients, for example those with mutations V235M, S448X, insI189, or delF230, cannot stand, walk, or speak. Patients with mutations L434W, L568P, and S194F, however, walk independently and/or develop some dysarthric speech. To study the relationship between mutation and phenotype, we transfected JEG3 and COS1 cells with wild-type or mutant MCT8. Expression and function of the transporter were studied by analyzing T3 and T4 uptake, T3 metabolism (by cotransfected type 3 deiodinase), Western blotting, affinity labeling with N-bromoacetyl-T3, immunocytochemistry, and quantitative RT-PCR. Wild-type MCT8 increased T3 uptake and metabolism about 5-fold compared with empty vector controls. Mutants V235M, S448X, insI189, and delF230 did not significantly increase transport. However, S194F, L568P, and L434W showed about 20, 23, and 37% of wild-type activity. RT-PCR did not show significant differences in mRNA expression between wild-type and mutant MCT8. Immunocytochemistry detected the nonfunctional mutants V235M, insI189, and delF230 mostly in the cytoplasm, whereas mutants with residual function were expressed at the plasma membrane. Mutants S194F and L434W showed high protein expression but low affinity for N-bromoacetyl-T3; L568P was detected in low amounts but showed relatively high affinity. Mutations in MCT8 cause loss of function through reduced protein expression, impaired trafficking to the plasma membrane, or reduced substrate affinity. Mutants L434W, L568P, and S194F showed significant residual transport capacity, which may underlie the more advanced psychomotor development observed in patients with these mutations.

scholarly journals G1359A Variant of the Cannabinoid Receptor Gene (rs1049353) and Obesity-Related Traits and Related Endophenotypes: A Meta-Analysis

2018 ◽  
Vol 73 (1) ◽  
pp. 76-85 ◽  
Author(s):  
Mehdi Sadeghian ◽  
Sepideh Rahmani ◽  
Anahita Mansoori
Keyword(s):  
Dietary Intake ◽  
Web Of Science ◽  
Cannabinoid Receptor ◽  
Weighted Mean Difference ◽  
Meta Analysis ◽  
Receptor Gene ◽  
Serum Levels ◽  
Anthropometric Measurements ◽  
Fat Free Mass ◽  
Wild Type

Background: This study aimed to investigate the comparison of G1359A variant of cannabinoid receptor gene (rs1049353) with obesity-related traits including body mass index (BMI), fat mass (FM), fat-free mass (FFM), food-related traits, and leptin among healthy and non-healthy adults. Methods: We searched PubMed, Cochrane, Scopus, Web of Science, and EMBASE until December 2016 for observational studies assessing each of the anthropometric measurements, food-related traits, and leptin of 1359 G/A polymorphism of CNR1 gene. A total of 22 studies were included in the meta-analysis comparing mean and SD differences of the anthropometric measurements, leptin, and dietary intake between GA/AA and GG genotypes. Results: The results showed that subjects with GA/AA genotype had significantly lower BMI (weighted mean difference = –0.59 kg/m2, p < 0.001) compared to those with the GG genotype. Dietary intake of fat, carbohydrate, and protein as well as serum levels of leptin was not significantly different between GA/AA and GG genotypes. Conclusion: It was revealed that subjects with mutant polymorphism (GA/AA) of CNR1, compared to the wild-type group (GG), had lower BMI (although there was unexplained heterogeneity).

scholarly journals Targeted Disruption of the Type 1 Selenodeiodinase Gene (Dio1) Results in Marked Changes in Thyroid Hormone Economy in Mice

Endocrinology ◽  
2006 ◽  
Vol 147 (1) ◽  
pp. 580-589 ◽  
Author(s):  
Mark J. Schneider ◽  
Steven N. Fiering ◽  
B. Thai ◽  
Sing-yung Wu ◽  
Emily St. Germain ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Serum Levels ◽  
Normal Serum ◽  
Reproductive Capacity ◽  
Fecal Excretion ◽  
Wild Type ◽  
Targeted Disruption ◽  
Normal Thyroid Function ◽  
Serum T3

The type 1 deiodinase (D1) is thought to be an important source of T3 in the euthyroid state. To explore the role of the D1 in thyroid hormone economy, a D1-deficient mouse (D1KO) was made by targeted disruption of the Dio1 gene. The general health and reproductive capacity of the D1KO mouse were seemingly unimpaired. In serum, levels of T4 and rT3 were elevated, whereas those of TSH and T3 were unchanged, as were several indices of peripheral thyroid status. It thus appears that the D1 is not essential for the maintenance of a normal serum T3 level in euthyroid mice. However, D1 deficiency resulted in marked changes in the metabolism and excretion of iodothyronines. Fecal excretion of endogenous iodothyronines was greatly increased. Furthermore, when compared with both wild-type and D2-deficient mice, fecal excretion of [125I]iodothyronines was greatly increased in D1KO mice during the 48 h after injection of [125I]T4 or [125I]T3, whereas urinary excretion of [125I]iodide was markedly diminished. From these data it was estimated that a majority of the iodide generated by the D1 was derived from substrates other than T4. Treatment with T3 resulted in a significantly higher serum T3 level and a greater degree of hyperthyroidism in D1KO mice than in wild-type mice. We conclude that, although the D1 is of questionable importance to the wellbeing of the euthyroid mouse, it may play a major role in limiting the detrimental effects of conditions that alter normal thyroid function, including hyperthyroidism and iodine deficiency.

Steatohepatitis develops rapidly in transgenic mice overexpressingAbcb11and fed a methionine-choline-deficient diet

2005 ◽  
Vol 288 (6) ◽  
pp. G1321-G1327 ◽  
Author(s):  
Shikha S. Sundaram ◽  
Peter F. Whitington ◽  
Richard M. Green
Keyword(s):  
Transgenic Mice ◽  
Fatty Acid Synthase ◽  
Regulatory Element ◽  
Elevated Serum ◽  
The United States ◽  
Hepatic Triglyceride ◽  
Wild Type ◽  
Serum Aminotransferase ◽  
Tnf Α ◽  
Cytochrome P 450

Nonalcoholic fatty liver disease is the most common reason for abnormal liver chemistries in the United States. The factors that lead from benign steatosis to nonalcoholic steatohepatitis are poorly understood. Transthyretin- Abcb11 (TTR- Abcb11) transgenic mice overexpress the bile salt transporter Abcb11 and hypersecrete biliary lipids. Thus the aim of this study is to employ feeding of the methionine-choline-deficient (MCD) diet to TTR- Abcb11 transgenic mice to further determine the mechanisms responsible for the development of steatohepatitis. FVB/NJ and TTR- Abcb11 mice were fed control or MCD diets for up to 30 days. Serum aminotransferase levels, serum and hepatic triglyceride content, cytokines, markers of oxidative stress, and expression of selective genes were examined. MCD diet-fed TTR- Abcb11, but not wild-type, mice have elevated serum aminotransferase levels when compared after 7 days. They also have significantly lower hepatic triglyceride levels at all time points studied. After 14 days on the MCD diet, TTR- Abcb11 mice have 3-fold increases in TNF-α mRNA and 3.9-fold increases in IL-6 mRNA compared with FVB/NJ mice. TTR- Abcb11 mice also had a greater increase in cytochrome P-450 2E1 expression. A greater decrease in sterol regulatory element binding protein-1c and fatty acid synthase mRNA expression was also seen in TTR- Abcb11 compared with wild-type mice fed an MCD diet. They also have enhanced TNF-α, IL-6, and cytochrome P-450 2E1 expression. We conclude that TTR- Abcb11 mice develop a more rapid hepatitis with less steatosis.

scholarly journals Excessive O -GlcNAcylation Causes Heart Failure and Sudden Death

Circulation ◽  
2021 ◽  
Vol 143 (17) ◽  
pp. 1687-1703
Author(s):  
Priya Umapathi ◽  
Olurotimi O. Mesubi ◽  
Partha S. Banerjee ◽  
Neha Abrol ◽  
Qinchuan Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Complex I ◽  
Metabolic Flux ◽  
Pressure Overload ◽  
Premature Death ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Functional Studies ◽  
Complex I Activity

Background: Heart failure is a leading cause of death worldwide and is associated with the rising prevalence of obesity, hypertension, and diabetes. O -GlcNAcylation (the attachment of O -linked β-N-acetylglucosamine [ O -GlcNAc] moieties to cytoplasmic, nuclear, and mitochondrial proteins) is a posttranslational modification of intracellular proteins and serves as a metabolic rheostat for cellular stress. Total levels of O -GlcNAcylation are determined by nutrient and metabolic flux, in addition to the net activity of 2 enzymes: O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA). Failing myocardium is marked by increased O -GlcNAcylation, but whether excessive O -GlcNAcylation contributes to cardiomyopathy and heart failure is unknown. Methods: We developed 2 new transgenic mouse models with myocardial overexpression of OGT and OGA to control O -GlcNAcylation independent of pathologic stress. Results: We found that OGT transgenic hearts showed increased O -GlcNAcylation and developed severe dilated cardiomyopathy, ventricular arrhythmias, and premature death. In contrast, OGA transgenic hearts had lower O -GlcNAcylation but identical cardiac function to wild-type littermate controls. OGA transgenic hearts were resistant to pathologic stress induced by pressure overload with attenuated myocardial O -GlcNAcylation levels after stress and decreased pathologic hypertrophy compared with wild-type controls. Interbreeding OGT with OGA transgenic mice rescued cardiomyopathy and premature death, despite persistent elevation of myocardial OGT. Transcriptomic and functional studies revealed disrupted mitochondrial energetics with impairment of complex I activity in hearts from OGT transgenic mice. Complex I activity was rescued by OGA transgenic interbreeding, suggesting an important role for mitochondrial complex I in O -GlcNAc–mediated cardiac pathology. Conclusions: Our data provide evidence that excessive O -GlcNAcylation causes cardiomyopathy, at least in part, attributable to defective energetics. Enhanced OGA activity is well tolerated and attenuation of O -GlcNAcylation is beneficial against pressure overload–induced pathologic remodeling and heart failure. These findings suggest that attenuation of excessive O -GlcNAcylation may represent a novel therapeutic approach for cardiomyopathy.

scholarly journals Elevated serum levels of free triiodothyronine in adolescent boys with gynaecomastia compared with controls

2014 ◽  
Vol 171 (2) ◽  
pp. 193-198 ◽  
Author(s):  
Mikkel G Mieritz ◽  
Kaspar Sorensen ◽  
Lise Aksglaede ◽  
Annette Mouritsen ◽  
Casper P Hagen ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Elevated Serum ◽  
Serum Levels ◽  
Adolescent Boys ◽  
Free Triiodothyronine ◽  
Pubertal Stage ◽  
Cross Sectional ◽  
Healthy Adolescent ◽  
Serum Free ◽  
Thyroid Hormone Levels

ObjectivePubertal gynaecomastia is a frequent phenomenon occurring in 20–40% of otherwise healthy adolescent boys. Little is known about the aetiology of pubertal gynaecomastia. Markedly elevated thyroid hormone levels in adults with hyperthyroidism are associated with gynaecomastia.DesignA cross-sectional examination of 444 healthy boys with and without pubertal gynaecomastia.MethodsWe evaluated TSH, triiodothyronine (T3), thyroxine (T4), free T4 and free T3 in a cohort of healthy boys with and without pubertal gynaecomastia.ResultsBoys with gynaecomastia had significantly higher serum free T3, even after correction for age, BMI and pubertal stage. After inclusion of IGF1 in the model the differences disappeared. TSH, T4, free T4 and T3 did not differ between the groups.ConclusionsWe speculate that the GH/IGF1 axis and thyroid hormones interact and influence the development of pubertal gynaecomastia.

scholarly journals The Mutant Thyroid Hormone Receptor Beta R320P Causes Syndrome of Resistance to Thyroid Hormone

2018 ◽  
Vol 2018 ◽  
pp. 1-3 ◽  
Author(s):  
Tetsuya Kimura ◽  
Yoshitaka Hayashi ◽  
Yuka Tsukamoto ◽  
Yasuyuki Okamoto
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormone Receptor ◽  
Elevated Serum ◽  
Index Patient ◽  
Serum Levels ◽  
Heterozygous Mutation ◽  
Hormone Resistance ◽  
Thyroid Hormone Resistance ◽  
First Case ◽  
Thyroid Hormone Resistance Syndrome

A 31-year-old Japanese male patient with a history of atrial fibrillation showed elevated serum levels of free thyroxine and triiodothyronine and a normal level of thyrotropin. The same abnormal hormone pattern was also found in his son. These data indicated that the index patient and the son have thyroid hormone resistance syndrome. Exon sequencing using DNA from these two patients revealed that both patients harbored a heterozygous mutation in the THRB gene: G1244C in exon 9, which results in R320P substitution. Therefore, thyroid hormone resistance syndrome caused by THRB mutation (RTHβ) was diagnosed. The mutation of the 320th arginine to proline has not been found to date. In conclusion, herein, we have described the first case of RTHβ that is associated with R320P mutation.

scholarly journals The N-Glycans Determine the Differential Blood Clearance and Hepatic Uptake of Human Immunoglobulin (Ig)a1 and Iga2 Isotypes

2000 ◽  
Vol 191 (12) ◽  
pp. 2171-2182 ◽  
Author(s):  
Abdalla Rifai ◽  
Kim Fadden ◽  
Sherie L. Morrison ◽  
Koteswara R. Chintalacharuvu
Keyword(s):  
Elevated Serum ◽  
Serum Levels ◽  
Hepatic Uptake ◽  
Human Immunoglobulin ◽  
Wild Type ◽  
Major Pathway ◽  
Serum Iga ◽  
Pharmacokinetic Properties ◽  
Rapid Clearance ◽  
Deficient Mice

Human immunoglobulin (Ig)A exists in blood as two isotypes, IgA1 and IgA2, with IgA2 present as three allotypes: IgA2m(1), IgA2m(2), and IgA2m(n). We now demonstrate that recombinant, chimeric IgA1 and IgA2 differ in their pharmacokinetic properties. The major pathway for the clearance of all IgA2 allotypes is the liver. Liver-mediated uptake is through the asialoglycoprotein receptor (ASGR), since clearance can be blocked by injection of excess galactose-Ficoll ligand and suppressed in ASGR-deficient mice. In contrast, only a small percentage of IgA1 is cleared through this pathway. The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1. IgA1 and IgA2 that are not rapidly eliminated by the ASGR are both removed through an undefined ASGR-independent pathway with half-lives of 14 and 10 h, respectively. The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2. In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.

scholarly journals Neuroprotection of reduced thyroid hormone with increased estrogen and progestogen in postpartum depression

2019 ◽  
Vol 39 (9) ◽  
Author(s):  
Dan Li ◽  
Yangyao Li ◽  
Yun Chen ◽  
Haiyan Li ◽  
Yuqi She ◽  
...  
Keyword(s):  
Body Weight ◽  
Thyroid Hormone ◽  
Postpartum Depression ◽  
Cell Structure ◽  
Elevated Serum ◽  
Serum Levels ◽  
Thyroid Stimulating Hormone ◽  
The Body ◽  
Free Triiodothyronine ◽  
Promising Therapeutic Approach

Abstract Background: Postpartum depression (PPD) is a common serious mental health problem. Recent studies have demonstrated that hormone therapy serves as a promising therapeutic approach in managing PPD. The present study aims at exploring the role of thyroid hormone (TH), estrogen and progestogen in patients with PPD. Methods: Initially, PPD patients were enrolled and a PPD mouse model was established. The serum levels of estradiol (E2), progesterone (P), triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were subsequently measured. Next, in order to identify the effects of TH, estrogen and progestogen on PPD progression, mice were administrated with E2, P, contraceptives (CA), Euthyrox and methimazole (MMI). Besides, the body weight, activities, basolateral amygdala (BLA) neuron cell structure and the related gene expression of mice were analyzed. Results: The PPD patients and the mice showed elevated serum levels of T3, T4, FT3 and FT4 along with diminished E2, P and TSH levels. In the mice administered with a combination of E2, P, and MMI, decreased TH and increased estrogen and progestogen were detected, which resulted in increased body weight, normal activities, and BLA neuron cell structure. Moreover, brain-derived neurotrophic factor (BDNF) and cAMP-responsive element-binding protein (CREB) were both up-regulated in PPD mice administrated with a combination of E2, P, and MMI, which was accompanied by decreased TH and elevated estrogen and progestogen. Conclusion: Taken together, reduced TH combined with enhanced estrogen and progestogen confers neuroprotection in PPD, highlighting a potential target in prevention and treatment of PPD.

Sign in / Sign up

Export Citation Format

Share Document