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1.
Ann Endocrinol (Paris) ; 79 Suppl 1: S31-S39, 2018 Sep.
Artigo em Francês | MEDLINE | ID: mdl-30213303

RESUMO

Graves' thyroiditis is a frequent disease. It has a considerable impact on patient's life quality and health expenses. Thus, it is important to optimize the treatment and follow up. The identification of new factors predisposing to the disease and factors that may help to predict the severity or recurrence of the disease or the occurrence of graves' orbitopathy could optimize the management. Genetic predisposition has a major role in the development of Graves' disease. The new genes in addition to those already known to be involved in Graves' disease are under study. However, genetic predisposition alone cannot explain the occurrence of the disease. MicroRNAs are non-genetic factors that are significantly associated with different severities or relapses of Graves' disease as well as with the occurrence of graves' orbitopathy. These genetic and epigenetic factors together with known environmental factors can be used to predict the risk of relapse of Graves' disease or of the occurrence of orbital orbitopathy. This will lead to new promising therapeutic targets.


Assuntos
Doença de Graves/diagnóstico , Antígenos CD40/genética , Antígeno CTLA-4/genética , Meio Ambiente , Epigênese Genética , Predisposição Genética para Doença , Doença de Graves/etiologia , Doença de Graves/genética , Oftalmopatia de Graves , Antígenos HLA-DR/genética , Humanos , MicroRNAs , Prognóstico , Receptores da Tireotropina/genética , Recidiva , Tireoglobulina/genética
2.
Anticancer Res ; 38(5): 2793-2802, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29715101

RESUMO

BACKGROUND/AIM: Extra-thyroid expression of thyroid stimulating hormone (TSH) receptor (TSHR) has been reported in normal liver tissues, but never assessed in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Paired cancerous and non-cancerous HCC tissues were analyzed with TSHR expression assays. TSHR functional assessments and sequence analysis for the TSHR exon-10 were performed. RESULTS: TSHR overexpression was found in 150/197 (76.1%) HCCs. Higher TSHR expression was associated with unfavorable postoperative outcomes. Immunohistochemical analysis revealed predominantly nuclei/peri-nuclei localization of TSHR in cancerous tissues but cell membrane localization in non-cancerous parts. TSH stimulation on hepatoma cells resulted in increased cyclic adenosine monophosphate levels with altered cell sensitivity to cisplatin. Gene mutations leading to TSHR truncation were detected in 8/81 (9.9%) HCC tissues. CONCLUSION: Overexpression of TSHR was found in a great majority of HCC tissues and associated with unfavorable prognosis. Cell-based experiments and gene mutation analysis suggested that TSHR in HCCs was functional.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Receptores da Tireotropina/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Receptores da Tireotropina/biossíntese
3.
Eur J Endocrinol ; 178(6): 623-633, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29650690

RESUMO

OBJECTIVE: Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited. DESIGN AND METHODS: One hundred ten patients with primary CH were recruited in this study. All exons and exon-intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees. RESULTS: Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands. CONCLUSIONS: Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Hipotireoidismo Congênito/genética , China , Oxidases Duais/genética , Feminino , Fatores de Transcrição Forkhead/genética , Estudos de Associação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/genética , Humanos , Lactente , Recém-Nascido , Iodeto Peroxidase/genética , Masculino , Proteínas de Membrana/genética , Mutação , Fator de Transcrição PAX8/genética , Linhagem , Receptores da Tireotropina/genética , Análise de Sequência de DNA , Tireoglobulina/genética , Disgenesia da Tireoide/genética , Fator Nuclear 1 de Tireoide/genética , Fatores de Transcrição/genética
4.
Zhongguo Dang Dai Er Ke Za Zhi ; 20(3): 243-250, 2018 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-29530127

RESUMO

Congenital hypothyroidism (CH), which results from insufficient thyroid hormone biosynthesis, is one of the most common neonatal endocrine disorders. Thyroid dysgenesis and thyroid dyshormonogenesis are the two causes of CH and either one will lead to deficiencies of enzymes during thyroid hormone biosynthesis and insufficient thyroid hormone biosynthesis. Recently, researchers have performed extensive studies on genetics of CH. This paper reviews genes reported to be associated with CH in China.


Assuntos
Hipotireoidismo Congênito/genética , Humanos , Iodeto Peroxidase/genética , Proteínas de Membrana/genética , Fator de Transcrição PAX8/genética , Receptores da Tireotropina/genética , Tireoglobulina/genética , Fatores de Transcrição/genética
5.
Diagn Cytopathol ; 46(5): 369-377, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29516685

RESUMO

BACKGROUND: Thyroid-stimulating hormone receptor (TSHR) gene mutations play a critical role in thyroid cell proliferation and function. They are found in 20%-82% of hyperfunctioning nodules, hyperfunctioning follicular thyroid cancers (FTC), and papillary thyroid cancers (PTC). The diagnostic importance of TSHR mutation testing in fine needle aspiration (FNA) specimens remains unstudied. METHODS: To examine the association of TSHR mutations with the functional status and surgical outcomes of thyroid nodules, we evaluated 703 consecutive thyroid FNA samples with indeterminate cytology for TSHR mutations using next-generation sequencing. Testing for EZH1 mutations was performed in selected cases. The molecular diagnostic testing was done as part of standard of care treatment, and did not require informed consent. RESULTS: TSHR mutations were detected in 31 (4.4%) nodules and were located in exons 281-640, with codon 486 being the most common. Allelic frequency ranged from 3% to 45%. Of 16 cases (12 benign, 3 FTC, 1 PTC) with surgical correlation, 15 had solitary TSHR mutations and 1 PTC had comutation with BRAF V600E. Hyperthyroidism was confirmed in all 3 FTC (2 overt, 1 subclinical). Of 5 nodules with solitary TSHR mutations detected at high allelic frequency, 3 (60%) were FTC. Those at low allelic frequency (3%-22%) were benign. EZH1 mutations were detected in 2 of 4 TSHR-mutant malignant nodules and neither of 2 benign nodules. CONCLUSION: We report that TSHR mutations occur in ∼5% thyroid nodules in a large consecutive series with indeterminate cytology. TSHR mutations may be associated with an increased cancer risk when present at high allelic frequency, even when the nodule is hyperfunctioning. Benign nodules were however most strongly correlated with TSHR mutations at low allelic frequency.


Assuntos
Transformação Celular Neoplásica/genética , Receptores da Tireotropina/genética , Nódulo da Glândula Tireoide/genética , Nódulo da Glândula Tireoide/patologia , Adulto , Idoso , Biópsia por Agulha Fina , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
6.
Bull Exp Biol Med ; 164(4): 430-433, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29500802

RESUMO

Sex differences in the expression of iodide transporter SLC5A5 and thyroid peroxidase in thyroid follicular epithelium and thyroid serum profile were assessed in pubertal rats exposed to endocrine disruptor DDT starting from the first postnatal day. It was found that exposure to DDT reduced expression of SLC5A5 in peripheral regions of thyroid lobes in males and in central regions in females. The most pronounced sex differences were observed in thyroid peroxidase expression that remained sensitive to thyroid stimulating hormone regulation in males and lost sensitivity to pituitary stimulation in females after exposure to disruptor, which determines more pronounced hypothyroidism in females.


Assuntos
DDT/farmacologia , Disruptores Endócrinos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotireoidismo/genética , Glândula Tireoide/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Feminino , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/metabolismo , Hipotireoidismo/patologia , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Masculino , Ratos , Ratos Wistar , Receptores da Tireotropina/genética , Receptores da Tireotropina/metabolismo , Fatores Sexuais , Maturidade Sexual , Simportadores/genética , Simportadores/metabolismo , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Tireotropina/genética , Tireotropina/metabolismo , Tiroxina/genética , Tiroxina/metabolismo , Tri-Iodotironina/genética , Tri-Iodotironina/metabolismo
7.
Biochem Biophys Res Commun ; 497(1): 39-45, 2018 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-29421660

RESUMO

The effect of thyroid-stimulating hormone receptor (TSHR) on hepatic lipid accumulation in vivo is not fully understood. Further, while TSHR in the thyroid has been studied extensively, whether and how the absence of TSHR in the liver affects systemic energy metabolism has not yet been reported. To examine these effects, we generated hepatic TSHR conditional knockout (LT-KO) mice using Cre/LoxP recombination technology. The liver-specific TSHR-knockout (LT-KO) mice exhibited not only lower hepatic triglyceride and cholesterol contents due to modified synthesis and catabolism of lipids in the liver, but also decreased serum lipids, especially serum LDL-C levels. Abnormalities of TSHR in the thyroid affect whole-body energy balance; however, measurements taken in metabolic chambers showed that the hepatic TSHR conditional deletion had no impact on systemic energy metabolism. Unlike its critical role in maintaining the normal growth and function of the thyroid gland, our results demonstrated that hepatic TSHR is involved in liver lipid metabolism and has little effect on energy metabolism.


Assuntos
Metabolismo Energético/fisiologia , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Receptores da Tireotropina/metabolismo , Glândula Tireoide/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores da Tireotropina/genética
8.
Cell Mol Life Sci ; 75(12): 2227-2239, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29290039

RESUMO

G-protein-coupled receptors (GPCRs) can constitute complexes with non-GPCR integral membrane proteins, while such interaction has not been demonstrated at a single molecule level so far. We here investigated the potential interaction between the thyrotropin receptor (TSHR) and the monocarboxylate transporter 8 (MCT8), a member of the major facilitator superfamily (MFS), using fluorescence cross-correlation spectroscopy (FCCS). Both the proteins are expressed endogenously on the basolateral plasma membrane of the thyrocytes and are involved in stimulation of thyroid hormone production and release. Indeed, we demonstrate strong interaction between both the proteins which causes a suppressed activation of Gq/11 by TSH-stimulated TSHR. Thus, we provide not only evidence for a novel interaction between the TSHR and MCT8, but could also prove this interaction on a single molecule level. Moreover, this interaction forces biased signaling at the TSHR. These results are of general interest for both the GPCR and the MFS research fields.


Assuntos
Transportadores de Ácidos Monocarboxílicos/metabolismo , Mapas de Interação de Proteínas , Receptores da Tireotropina/metabolismo , Animais , Células COS , Cercopithecus aethiops , Expressão Gênica , Células HEK293 , Humanos , Transportadores de Ácidos Monocarboxílicos/análise , Transportadores de Ácidos Monocarboxílicos/genética , Multimerização Proteica , Receptores da Tireotropina/análise , Receptores da Tireotropina/genética , Transdução de Sinais , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia
9.
Redox Biol ; 15: 418-434, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29353219

RESUMO

AIMS: Endothelial cells (ECs) constitute the defensive barrier of vasculature, which maintains the vascular homeostasis. Mitochondrial oxidative stress (mitoOS) in ECs significantly affects the initiation and progression of vascular diseases. The higher serum thyroid stimulating hormone (TSH) level is being recognized as a nonconventional risk factor responsible for the increased risk of cardiovascular diseases in subclinical hypothyroidism (SCH). However, effects and underlying mechanisms of elevated TSH on ECs are still ambiguous. We sought to investigate whether cyclophilin D (CypD), emerging as a crucial mediator in mitoOS, regulates effects of TSH on ECs. METHODS AND RESULTS: SCH patients with TSH > = 10mIU/L showed a positive correlation between serum TSH and endothelin-1 levels. When TSH levels declined to normal in these subjects after levothyroxine therapy, serum endothelin-1 levels were significantly reduced. Supplemented with exogenous thyroxine to keep normal thyroid hormones, thyroid-specific TSH receptor (TSHR)-knockout mice with injection of exogenous TSH exhibited elevated serum TSH levels, significant endothelial oxidative injuries and disturbed endothelium-dependent vasodilation. However, Tshr-/- mice resisted to TSH-impaired vasotonia. We further confirmed that elevated TSH triggered excessive mitochondrial permeability transition pore (mPTP) opening and mitochondrial oxidative damages in mouse aorta, as well as in cultured ECs. Genetic or pharmacological inhibition of CypD (the key regulator for mPTP opening) attenuated TSH-induced mitochondrial oxidative damages and further rescued endothelial functions. Finally, we confirmed that elevated TSH could activate CypD by enhancing CypD acetylation via inhibiting adenosine monophosphate-activated protein kinase/sirtuin-3 signaling pathway in ECs. CONCLUSIONS: These findings reveal that elevated TSH triggers mitochondrial perturbations in ECs and provide insights that blocking mitochondrial CypD enhances the defensive ability of ECs under TSH exposure.


Assuntos
Ciclofilinas/genética , Hipotireoidismo/tratamento farmacológico , Estresse Oxidativo/genética , Receptores da Tireotropina/genética , Tiroxina/administração & dosagem , Adulto , Idoso , Animais , Artérias/efeitos dos fármacos , Artérias/metabolismo , Artérias/patologia , Ciclofilinas/metabolismo , Células Endoteliais/metabolismo , Endotelina-1/sangue , Feminino , Humanos , Hipotireoidismo/genética , Hipotireoidismo/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Mitocôndrias/genética , Mitocôndrias/patologia , Proteínas de Transporte da Membrana Mitocondrial/genética , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Receptores da Tireotropina/metabolismo , Fatores de Risco , Tireotropina/sangue
10.
PLoS One ; 13(1): e0190987, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29320567

RESUMO

BACKGROUND: The association between dilated cardiomyopathy (DCM) and low thyroid hormone (TH) levels has been previously described. In these patients abnormal thyroid function is significantly related to impaired left ventricular (LV) function and increased risk of death. Although TH was originally thought to be produced exclusively by the thyroid gland, we recently reported TH biosynthesis in the human ischemic heart. OBJECTIVES: Based on these findings, we evaluated whether the genes required for TH production are also altered in patients with DCM. METHODS: Twenty-three LV tissue samples were obtained from patients with DCM (n = 13) undergoing heart transplantation and control donors (n = 10), and used for RNA sequencing analysis. The number of LV DCM samples was increased to 23 to determine total T4 and T3 tissue levels by ELISA. RESULTS: We found that all components of TH biosynthesis are expressed in human dilated heart tissue. Expression of genes encoding thyroperoxidase (-2.57-fold, P < 0.05) and dual oxidase 2 (2.64-fold, P < 0.01), the main enzymatic system of TH production, was significantly altered in patients with DCM and significantly associated with LV remodeling parameters. Thyroxine (T4) cardiac tissue levels were significantly increased (P < 0.01), whilst triiodothyronine (T3) levels were significantly diminished (P < 0.05) in the patients. CONCLUSIONS: Expression of TH biosynthesis machinery in the heart and total tissue levels of T4 and T3, are altered in patients with DCM. Given the relevance of TH in cardiac pathology, our results provide a basis for new gene-based therapeutic strategies for treating DCM.


Assuntos
Autoantígenos/genética , Cardiomiopatia Dilatada/genética , Oxidases Duais/genética , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Miocárdio/metabolismo , Receptores da Tireotropina/genética , Hormônios Tireóideos/biossíntese , Autoantígenos/metabolismo , Biomarcadores/metabolismo , Cardiomiopatia Dilatada/patologia , Estudos de Casos e Controles , Oxidases Duais/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Iodeto Peroxidase/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Receptores da Tireotropina/metabolismo , Remodelação Ventricular
11.
Endocr J ; 65(3): 317-323, 2018 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-29321381

RESUMO

Thyroid hormones play a vital role in the human body for growth and differentiation, regulation of energy metabolism, and physiological function. Hypothyroidism is a common endocrine disorder, which generally results from diminished normal circulating concentrations of serum thyroxine (fT4) and triiodothyronine (fT3). The primary choice in hypothyroidism treatment is oral administration of levothyroxine (L-T4), a synthetic T4 hormone, as approximately 100-125 µg/day. Generally, dose adjustment is made by trial and error approach. However, there are several factors which might influence bioavailability of L-T4 treatment. Genetic background could be an important factor in hypothyroid patients as well as age, gender, concurrent medications and patient compliance. The concentration of thyroid hormones in tissue is regulated by both deiodinases enzyme and thyroid hormone transporters. In the present study, it was aimed to evaluate the effects of genetic differences in the proteins and enzymes (DIO1, DIO2, TSHR, THR and UGT) which are efficient in thyroid hormone metabolism and bioavailability of L-T4 in Turkish population. According to our findings, rs225014 and rs225015 variants in DIO2, which catalyses the conversion of thyroxine (pro-hormone) to the active thyroid hormone, were associated with TSH levels. It should be given lower dose to the patients with rs225014 TT and rs225015 GG genotypes in order to provide proper treatment with higher effectivity and lower toxicity.


Assuntos
Hipotireoidismo/tratamento farmacológico , Hipotireoidismo/genética , Polimorfismo de Nucleotídeo Único , Tiroxina/farmacocinética , Disponibilidade Biológica , Proteínas de Ligação a DNA/genética , Feminino , Glucuronosiltransferase/genética , Humanos , Hipotireoidismo/sangue , Iodeto Peroxidase/genética , Masculino , Pessoa de Meia-Idade , Farmacogenética , Receptores dos Hormônios Tireóideos/genética , Receptores da Tireotropina/genética , Testes de Função Tireóidea , Hormônios Tireóideos/sangue , Tiroxina/uso terapêutico
12.
Eur J Endocrinol ; 178(2): 137-144, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29092890

RESUMO

OBJECTIVE: Biallelic TSHR mutations cause congenital hypothyroidism (CH). Serum TSH levels of monoallelic mutation carriers range from normal to mildly elevated, and thus the size of its effect remains unclear. The objectives were to examine the association between monoallelic TSHR mutations and positivity at newborn screening (NBS) for CH, and to test whether the association was modified by another genetic factor. SUBJECTS AND METHODS: We enrolled 395 patients that had a positive result in NBS and sequenced TSHR. Monoallelic TSHR mutation carriers were further sequenced for DUOX2. Molecular functions of the mutations were verified in vitro. The frequency of the mutations in the study subjects was compared with a theoretical value in the Japanese general population. Odds ratio (OR) for NBS positivity associated with the mutation was calculated. Using Bayes' theorem, we estimated a posterior probability of NBS positivity given the mutation. RESULTS: Twenty-six monoallelic TSHR mutation carriers were found. Four out of the 26 also had a monoallelic DUOX2 mutation (double heterozygotes). The frequencies of monoallelic TSHR mutation carriers (6.6%) and double heterozygotes (1.0%) were significantly higher than those in the general population (0.58% and 0.0087%, respectively). OR for NBS positivity of having a monoallelic TSHR mutation or being a double heterozygote was 12.0 or 117.9, respectively. Posterior probability of NBS positivity was 0.38% in monoallelic TSHR mutation carriers and 3.8% in double heterozygotes. CONCLUSIONS: Monoallelic TSHR mutations are significantly associated with NBS positivity, and the association is further strengthened by the coexistence of monoallelic DUOX2 mutations.


Assuntos
Hipotireoidismo Congênito/genética , Oxidases Duais/genética , Receptores da Tireotropina/genética , Grupo com Ancestrais do Continente Asiático/genética , Teorema de Bayes , Feminino , Heterozigoto , Humanos , Técnicas In Vitro , Recém-Nascido , Japão , Masculino , Mutação , Triagem Neonatal , Razão de Chances , Análise de Sequência de DNA
13.
Acta Med Indones ; 49(3): 195-204, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29093229

RESUMO

BACKGROUND: graves' disease (GD) is the most common condition of thyrotoxicosis. The management of GD is initiated with the administration of antithyroid drugs; however, it requires a long time to achieve remission. In reality more than 50% of patients who had remission may be at risk for relapse after the drug is stopped. This study aimed to evaluate the role of clinical factors such as smoking habit, degree of ophtalmopathy, degree of thyroid enlargement; genetic factors such as CTLA-4 gene on nucleotide 49 at codon 17 of exon 1, CTLA-4 gene of promotor -318, TSHR gene polymorphism rs2268458 of intron 1; and immunological factors such as regulatory T cells (Treg) and thyroid receptor antibody (TRAb); that affecting the relapse of patients with Graves' disease in Indonesia. METHODS: this was a case-control study, that compared 72 subjects who had relapse and 72 subjects without relapse at 12 months after cessation of antithyroid treatment, who met the inclusion criteria. Genetic polymorphism examination was performed using PCR-RFLP. The number of regulatory T cells was counted using flow cytometry analysis and ELISA was used to measure TRAb. The logistic regression was used since the dependent variables were categorical variables. RESULTS: the analysis of this study demonstrated that there was a correlation between relapse of disease and family factors (p=0.008), age at diagnosis (p=0.021), 2nd degree of Graves' ophthalmopathy (p=0.001), enlarged thyroid gland, which exceeded the lateral edge of the sternocleidomastoid muscles (p=0.040), duration of remission period (p=0.029), GG genotype of CTLA-4 gene on the nucleotide 49 at codon 17 of exon 1 (p=0.016), CC genotype of TSHR gene on the rs2268458 of intron 1 (p=0.003), the number of regulatory T cells (p=0.001) and TRAb levels (p=0.002). CONCLUSION: genetic polymorphisms of CTLA-4 gene on the nucleotide 49 at codon 17 of exon 1, TSHR gene SNP rs2268458 of intron 1, number of regulatory T cells and TRAb levels play a role as risk factors for relapse in patients with Graves' disease.


Assuntos
Antígeno CTLA-4/genética , Doença de Graves/genética , Imunoglobulinas Glândula Tireoide-Estimulantes/sangue , Receptores da Tireotropina/genética , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Antitireóideos/uso terapêutico , Antígeno CTLA-4/imunologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Doença de Graves/tratamento farmacológico , Doença de Graves/imunologia , Humanos , Indonésia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Recidiva , Fatores de Risco
14.
Iran J Immunol ; 14(3): 223-230, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28919585

RESUMO

BACKGROUND: Graves' disease (GD), a highly rampant autoimmune disorder of the thyroid gland, is responsible for 60-80% of the clinical cases of hyperthyroidism. Over the past decades, genetic association studies have identified several GD susceptibility loci in CTLA-4, TSHR and major histocompatibility complex regions. The information on the association between the human leukocyte antigens (HLA) and GD among Iranians is scarce. OBJECTIVE: To identify HLA polymorphisms that might confer susceptibility or protect against GD. METHODS: Eighty unrelated patients with a confirmed diagnosis of GD were included in the case group. The control group consisted of 180 unrelated healthy individuals with normal thyroid function tests. The polymerase chain reaction with sequence specific primers (PCR-SSP) method was used for HLA typing. RESULTS: Frequencies of HLA-A*68 (15.6% vs. 4.2%, p=0.004) and B*08 (8.8% vs. 2.5, p=0.030) were significantly higher in patients with GD compared with healthy controls. No patients with GD had HLA-A*33, whereas it was found in 7.0% of the controls (p=0.011). HLA-DQB1*0201 was significantly less frequent among patients with GD (15.6% vs. 26.8%, p=0.040). Additionally, patients with GD were significantly less bound to have HLA-DQA1*0201 (6.2% vs. 15.1%, p=0.045). Concerning allelic distributions, no noticeable difference was found between GD patients with and without Graves' ophthalmopathy (p>0.05 in all cases). CONCLUSION: In the Iranian population, HLA-A*68 and -B*08 confer susceptibility to GD, whereas HLA-A*33, -DQB1*0201, and -DQA1*0201 appear to have protective roles.


Assuntos
Oftalmopatia de Graves/genética , Antígenos HLA-A/genética , Antígeno HLA-B8/genética , Cadeias alfa de HLA-DQ/genética , Cadeias beta de HLA-DQ/genética , Glândula Tireoide/metabolismo , Adulto , Antígeno CTLA-4/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Receptores da Tireotropina/genética , Glândula Tireoide/patologia
15.
J Biol Chem ; 292(37): 15434-15444, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28743746

RESUMO

The thyroid gland secretes primarily tetraiodothyronine (T4), and some triiodothyronine (T3). Under normal physiological circumstances, only one-fifth of circulating T3 is directly released by the thyroid, but in states of hyperactivation of thyroid-stimulating hormone receptors (TSHRs), patients develop a syndrome of relative T3 toxicosis. Thyroidal T4 production results from iodination of thyroglobulin (TG) at residues Tyr5 and Tyr130, whereas thyroidal T3 production may originate in several different ways. In this study, the data demonstrate that within the carboxyl-terminal portion of mouse TG, T3 is formed de novo independently of deiodination from T4 We found that upon iodination in vitro, de novo T3 formation in TG was decreased in mice lacking TSHRs. Conversely, de novo T3 that can be formed upon iodination of TG secreted from PCCL3 (rat thyrocyte) cells was augmented from cells previously exposed to increased TSH, a TSHR agonist, a cAMP analog, or a TSHR-stimulating antibody. We present data suggesting that TSH-stimulated TG phosphorylation contributes to enhanced de novo T3 formation. These effects were reversed within a few days after removal of the hyperstimulating conditions. Indeed, direct exposure of PCCL3 cells to human serum from two patients with Graves' disease, but not control sera, led to secretion of TG with an increased intrinsic ability to form T3 upon in vitro iodination. Furthermore, TG secreted from human thyrocyte cultures hyperstimulated with TSH also showed an increased intrinsic ability to form T3 Our data support the hypothesis that TG processing in the secretory pathway of TSHR-hyperstimulated thyrocytes alters the structure of the iodination substrate in a way that enhances de novo T3 formation, contributing to the relative T3 toxicosis of Graves' disease.


Assuntos
Processamento de Proteína Pós-Traducional , Receptores da Tireotropina/agonistas , Transdução de Sinais , Tireoglobulina/metabolismo , Células Epiteliais da Tireoide/metabolismo , Tireotropina/metabolismo , Tri-Iodotironina/biossíntese , Animais , Proteínas de Ligação ao Cálcio/agonistas , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Caseína Quinase I/genética , Caseína Quinase I/metabolismo , Linhagem Celular , Células Cultivadas , Proteínas da Matriz Extracelular/agonistas , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Doença de Graves/sangue , Doença de Graves/metabolismo , Doença de Graves/patologia , Halogenação , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Receptores da Tireotropina/genética , Receptores da Tireotropina/metabolismo , Células Epiteliais da Tireoide/citologia , Células Epiteliais da Tireoide/patologia , Tirosina/metabolismo , Regulação para Cima
16.
Best Pract Res Clin Endocrinol Metab ; 31(2): 183-194, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28648507

RESUMO

Resistance to thyrotropin (RTSH) is broadly defined as reduced sensitivity of thyroid follicle cells to stimulation by biologically active TSH due to genetic defects. Affected individuals have elevated serum TSH in the absence of goiter, with the severity ranging from nongoitrous isolated hyperthyrotropinemia to severe congenital hypothyroidism with thyroid hypoplasia. Conceptually, defects leading to RTSH impair both aspects of TSH-mediated action, namely thyroid hormone synthesis and gland growth. These include inactivating mutations in the genes encoding the TSH receptor and the PAX8 transcription factor. A common third cause has been genetically mapped to a locus on chromosome 15, but the underlying pathophysiology has not yet been elucidated. This review provides a succinct overview of currently defined causes of nonsyndromic RTSH, their differential diagnoses (autoimmune; partial iodine organification defects; syndromic forms of RTSH) and implications for the clinical approach to patients with RTSH.


Assuntos
Hipotireoidismo Congênito/complicações , Resistência a Medicamentos , Disgenesia da Tireoide/complicações , Tireotropina/fisiologia , Hipotireoidismo Congênito/genética , Humanos , Mutação , Receptores da Tireotropina/genética , Síndrome , Disgenesia da Tireoide/genética , Hormônios Tireóideos/metabolismo , Tireotropina/genética
17.
Best Pract Res Clin Endocrinol Metab ; 31(2): 265-275, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28648513

RESUMO

Hyperthyroidism is a clinical state that results from high thyroid hormone levels which has multiple etiologies, manifestations, and potential therapies. Excluding the autoimmune Graves disease, autonomic adenomas account for the most import cause of non-autoimmune hyperthyroidism. Activating germline mutations of the TSH receptor are rare etiologies for hyperthyroidism. They can be inherited in an autosomal dominant manner (familial or hereditary, FNAH), or may occur sporadically as a de novo condition, also called: persistent sporadic congenital non-autoimmune hyperthyroidism (PSNAH). These three conditions: autonomic adenoma, FNAH and PSNAH constitute the inheritable and sporadic non-autoimmune hyperthyroidism. Particularities in epidemiology, etiology, molecular and clinical aspects of these three entities will be discussed in this review in order to guide to an accurate diagnosis allowing among others genetic counseling and presymptomatic diagnosis for the affected families. The optimal treatment based on the right diagnosis will avoid consequences of a persistent or relapsing hyperthyroidism.


Assuntos
Hipertireoidismo/genética , Bases de Dados Genéticas , Aconselhamento Genético , Mutação em Linhagem Germinativa , Humanos , Hipertireoidismo/diagnóstico , Hipertireoidismo/epidemiologia , Padrões de Herança , Mutação , Receptores da Tireotropina/genética , Doenças da Glândula Tireoide/complicações , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/epidemiologia , Doenças da Glândula Tireoide/genética
18.
Clin Endocrinol (Oxf) ; 87(5): 587-596, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28561265

RESUMO

OBJECTIVE: Mutations in TSH receptor (TSHR) are associated with TSH resistance, a genetic defect characterized by a heterogeneous phenotype ranging from severe hypothyroidism to subclinical hypothyroidism (SCH). We assessed the clinical and hormonal pattern of TSHR variants in a series of pediatric patients, and the long-term outcome of growth, biochemical measurements of metabolism, and neuropsychological functions in TSHR mutations carriers. DESIGN: Observational, retrospective study. PATIENTS: Thirty four children (age 7 days to 11 years) and 18 adult carriers of TSHR variants. MEASUREMENTS: The TSHR gene was sequenced by PCR-amplified direct sequencing in 111 pediatric patients with slight to moderate elevation of TSH and normal FT4 levels. The study focused on the: auxological and biochemical parameters, thyroid ultrasound, bone age, bone mineral density (BMD), and intellectual outcome (IQ) were collected during the long follow-up (1-15 years). RESULTS: Seventeen different TSHR variants (eight novel) were identified in 34 of the 111 pediatric patients, with a high prevalence of familial cases (27/34). Neonatal screening for congenital hypothyroidism was positive in half of the TSHR carriers. Growth, IQ, BMD, and biochemical parameters were normal in all subjects. Twenty patients received L-T4 replacement therapy, in all cases before genetic analysis. After re-evaluation, six patients resumed L-T4 therapy: they were compound heterozygous, or single heterozygous and with associated conditions at risk of thyroid impairment (SGA). No adults presented clinical features consistent with impaired thyroid function. CONCLUSIONS: Children carriers of TSHR variants, regardless of L-T4 treatment, show regular growth and neuropsychological development, with no evident biochemical and US alterations.


Assuntos
Hipotireoidismo/genética , Mutação , Receptores da Tireotropina/genética , Adulto , Criança , Pré-Escolar , Terapia de Reposição Hormonal/métodos , Humanos , Hipotireoidismo/tratamento farmacológico , Lactente , Recém-Nascido , Estudos Longitudinais , Receptores dos Hormônios Tireóideos/sangue , Estudos Retrospectivos , Resultado do Tratamento
19.
Clin Chim Acta ; 470: 36-41, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28455095

RESUMO

BACKGROUND: The abnormal expression of certain transcription factors (NKX2.1, FOXE1, NKX2.5, and PAX8) and thyroid stimulating hormone receptor (TSHR) genes has been associated with athyreosis, which is a form of thyroid dysgenesis (TD). We aimed to identify candidate gene mutations in CH patients with athyreosis and to establish the genotype-phenotype correlations in a Chinese population. METHODS: The exons and flanking sequences of NKX2.1, FOXE1, NKX2.5, PAX8, and TSHR were screened by next-generation sequencing and further confirmed by direct Sanger sequencing. The mutation frequencies were calculated and compared against databases. The relationship between genotype and phenotype was also determined. RESULTS: Seven variants were detected in TSHR-p.P52T, p.G132R, p.M164K, p.R450H, p.C700E, p.A522V, and p.R528S. The p. G132R, p. M164K and p. R528S variants were first identified in public databases. Five variants (p.G44D, p.G360V, p.R401Q, p.L418I, and p.E453Q) were found in NKX2.1 and one variant (p.P243T) was detected in FOXE1. In addition, one variant (p.N291I) was found in NKX2.5 and two variants (p.A355V and c.-26G>A) were detected in PAX8. CONCLUSIONS: Our study indicated that TSHR mutations have phenotypic variability and has further expanded the mutation spectrum of TSHR. We also revealed that the rate of NKX2.1, FOXE1, NKX2.5, and PAX8 mutations were low in patients with CH and athyreosis, in contrast to the higher rate of TSHR mutations.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Hipotireoidismo Congênito/genética , Análise Mutacional de DNA , Sequenciamento de Nucleotídeos em Larga Escala , Receptores da Tireotropina/genética , Disgenesia da Tireoide/genética , Fatores de Transcrição/genética , Sequência de Bases , Criança , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/genética , Genótipo , Proteína Homeobox Nkx-2.5/genética , Humanos , Masculino , Fator de Transcrição PAX8/genética , Fenótipo , Glândula Tireoide/metabolismo , Fator Nuclear 1 de Tireoide/genética
20.
Mol Biol Evol ; 34(8): 1981-1990, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28444234

RESUMO

Ancient DNA provides an opportunity to infer the drivers of natural selection by linking allele frequency changes to temporal shifts in environment or cultural practices. However, analyses have often been hampered by uneven sampling and uncertainties in sample dating, as well as being confounded by demographic processes. Here, we present a Bayesian statistical framework for quantifying the timing and strength of selection using ancient DNA that explicitly addresses these challenges. We applied this method to time series data for two loci: TSHR and BCDO2, both hypothesised to have undergone strong and recent selection in domestic chickens. The derived variant in TSHR, associated with reduced aggression to conspecifics and faster onset of egg laying, shows strong selection beginning around 1,100 years ago, coincident with archaeological evidence for intensified chicken production and documented changes in egg and chicken consumption. To our knowledge, this is the first example of preindustrial domesticate trait selection in response to a historically attested cultural shift in food preference. For BCDO2, we find support for selection, but demonstrate that the recent rise in allele frequency could also have been driven by gene flow from imported Asian chickens during more recent breed formations. Our findings highlight that traits found ubiquitously in modern domestic species may not necessarily have originated during the early stages of domestication. In addition, our results demonstrate the importance of precise estimation of allele frequency trajectories through time for understanding the drivers of selection.


Assuntos
Galinhas/genética , Seleção Genética/genética , Análise de Sequência de DNA/métodos , Alelos , Criação de Animais Domésticos , Animais , Animais Domésticos/genética , Teorema de Bayes , Cruzamento , DNA Antigo/análise , DNA Mitocondrial/genética , Dioxigenases/genética , Frequência do Gene/genética , Aves Domésticas/genética , Receptores da Tireotropina/genética
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