Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 103
Filtrar
1.
Clin Genet ; 100(6): 713-721, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34564849

RESUMO

DUOX2 is the most frequently mutated gene in patients with congenital hypothyroidism (CH) in China. However, no reliable genotype-phenotype relationship has been found in patients with DUOX2 mutations. In this study, DUOX2 mutations were screened in 266 CH patients, and the enzymatic activity of 89 DUOX2 variants was determined in vitro. Furthermore, the DUOX2 residual activity in 76 CH patients caused by DUOX2 biallelic mutations was calculated. The thyroid-stimulating hormone (TSH) and free thyroxine (FT4) levels were found to be higher and lower in patients with DUOX2 residual activity ≤22%, respectively, compared to patients with residual enzymatic activity >22%. Moreover, we interpreted the pathogenicity of DUOX2 variants by applying the ACMG classification criteria with or without PS3/BS3 evidence. The results indicated that residual DUOX2 enzymatic activity was closely related to the clinical phenotypes of CH patients caused by DUOX2 biallelic mutations. These findings suggest that the residual enzymatic activity of 22% may be a cutoff value for estimating the severity of hypothyroidism in CH patients with biallelic DUOX2 mutations. Well-established functional studies are useful and necessary to evaluate the pathogenicity of DUOX2 variants, improving the accuracy and scope of genetic consultations.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34545167

RESUMO

Objective: Defects in the human solute carrier family 26 member 4 (SLC26A4) gene are reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC26A4 mutations in Chinese patients with CH and analyze the function of the mutations. Methods: 273 patients with primary CH were screened for 21 CH candidate genes mutations by targeted next-generation sequencing. All the exons and exon-intron boundaries of SLC26A4 were found and analyzed. The function of 6 missense mutation in SLC26A4 were further investigated in vitro. Results: Among 273 patients with CH, 7 distinct SLC26A4 heterozygous mutations (p.S49R, p.I363L, p.R409H, p.T485M, p.D661E, p.H723R, c.919-2A>G) were identified in 10 patients (3.66%, 10/273). In vitro experiments showed that mutation p.I363L, p.R409H,p.H723R affect the membrane location and ion transport of SLC26A4, ,while p.S49R did not.Mutation p.T485M and p.D661E only affect the ion transport, but has no effect on the membrane location. Conclusion: Our study indicated that the prevalence of SLC26A4 mutations was 3.66% in the Chinese patients with CH. Five mutations (p.I363L, p.R409H, p.T485M, p.D661E and p.H723R) impaired the membrane location or ion transport function of SLC26A4,which revealed important role of the Ile363,Arg409, Thr485, Asp661, His723 residues in function of SLC26A4. Because these mutations are heterozygous mutations, the pathogenesis of these patients cannot be explained, and the pathogenesis of these patients needs further study.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34374102

RESUMO

OBJECTIVE: Congenital hypothyroidism (CH) is known to be due to thyroid dyshormonogenesis (DH), which is mostly inherited in an autosomal recessive inheritance pattern or thyroid dysgenesis (TD), whose inheritance pattern is controversial and whose molecular etiology remains poorly understood. DESIGN AND METHODS: The variants in 37 candidate genes of CH, including 25 genes related to TD, were screened by targeted exon sequencing in 205 Chinese patients whose CH cannot be explained by biallelic variants in genes related to DH. The inheritance pattern of the genes was analyzed in family trios or quartets. RESULTS: Of the 205 patients, 83 patients carried at least one variant in 19 genes related to TD, and 59 of those 83 patients harbored more than two variants in distinct candidate genes for CH. Biallelic or de novo variants in the genes related to TD in Chinese patients are rare. We also found nine probands carried only one heterozygous variant in the genes related to TD that were inherited from a euthyroid either paternal or maternal parent. These findings did not support the monogenic inheritance pattern of the genes related to TD in CH patients. Notably, in family trio or quartet analysis, of 36 patients carrying more than two variants in distinct genes, 24 patients carried these variants inherited from both their parents, which indicated that the oligogenic inheritance pattern of the genes related to TD should be considered in CH. CONCLUSIONS: Our study expanded the variant spectrum of the genes related to TD in Chinese CH patients. It is rare that CH in Chinese patients could be explained by monogenic germline variants in genes related to TD. The hypothesis of an oligogenic origin of the CH should be considered.

4.
Genet Med ; 23(10): 1944-1951, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34194003

RESUMO

PURPOSE: Congenital hypothyroidism (CH) is a common congenital endocrine disorder in humans. CH-related diseases such as athyreosis, thyroid ectopy, and hypoplasia are primarily caused by dysgenic thyroid development. However, the underlying molecular mechanisms remain unknown. METHODS: To identify novel CH candidate genes, 192 CH patients were enrolled, and target sequencing of 21 known CH-related genes was performed. The remaining 98 CH patients carrying no known genes were subjected to exome sequencing (ES). The functions of the identified variants were confirmed using thyroid epithelial cells in vitro and in zebrafish model organisms in vivo. RESULTS: Four pathogenic GBP1 variations from three patients were identified. In zebrafish embryos, gbp1 knockdown caused defective thyroid primordium morphogenesis and hypothyroidism. The thyroid cells were stuck together and failed to dissociate from each other to form individual follicles in gbp1-deficient embryos. Furthermore, defects were restored with wild-type human GBP1 (hGBP1) messenger RNA (mRNA) except for mutated hGBP1 (p.H150Y, p.L187P) overexpression. GBP1 promoted ß-catenin translocation into the cytosol and suppressed the formation of cellular adhesion complexes. Suppression of cell-cell adhesion restored the thyroid primordium growth defect observed in gbp1-deficient zebrafish embryos. CONCLUSION: This study provides further understanding regarding thyroid development and shows that defective cellular remodeling could cause congenital hypothyroidism.


Assuntos
Hipotireoidismo Congênito , Proteínas de Ligação ao GTP , Disgenesia da Tireoide , Glândula Tireoide/crescimento & desenvolvimento , Animais , Hipotireoidismo Congênito/genética , Modelos Animais de Doenças , Proteínas de Ligação ao GTP/genética , Humanos , Morfogênese , Mutação , Regulação para Cima , Peixe-Zebra/genética
5.
J Clin Lab Anal ; 35(9): e23920, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34318534

RESUMO

BACKGROUND: Molecular testing for oncogenic mutations in fine-needle aspiration has showed high predictive value in identifying malignant lesions from thyroid nodules with indeterminate cytology. METHODS: To figure out an efficient and economical gene panel for most medical institutions in China, we designed a five-gene panel including BRAF/NRAS/KRAS/HRAS/TERT genes and conducted a retrospective study to evaluate the role of this five-gene diagnostic panel in differential diagnosis of thyroid nodules. RESULTS: A total of 665 patients with 695 thyroid nodules were investigated in the current study. The fine-needle aspiration biopsy and surgically separated thyroid tissue specimens were harvested to test BRAF, TERT, NRAS, KRAS, and HRAS mutations. We identified 261 mutations in 665 patients, including 177 V600E mutations in BRAF. Three hundred and sixty-nine patients who underwent thyroid surgery after completion of the initial clinical and cytological evaluation were enrolled in the final analysis. The diagnostic sensitivity, specificity, and accuracy of the combination of FNAB cytology and five-gene detection were 74.7%, 93.8%, and 84.8%, respectively. BRAF V600E and five-gene panel could recognize 46.4% and 53.6% of papillary thyroid carcinoma in the patients with cytologically indeterminate nodules. CONCLUSION: The five-gene panel can effectively improve the sensitivity, negative predictive value, and accuracy of fine-needle aspiration biopsy cytology, especially in the patients with cytologically indeterminate nodules.

6.
Endocrinology ; 162(8)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34019632

RESUMO

Congenital hypothyroidism (CH) is a highly prevalent but treatable neonatal endocrine disorder. Thyroid dyshormonogenesis is the main cause of congenital hypothyroidism in Chinese CH patients, and DUOX2 is the most frequent mutated gene involved in H2O2 production. In humans, the primary sources for H2O2 production are DUOX1 and DUOX2, while in zebrafish there is only a single orthologue for DUOX1 and DUOX2. In this study, duox mutant zebrafish were generated through knockdown duox by morpholino or knockout duox by CRISPR Cas9. The associated phenotypes were investigated and rescued by thyroxine (T4) treatment. Mutant zebrafish displayed hypothyroid phenotypes including growth retardation, goiter and, infertility. Homozygous mutants in adults also displayed extrathyroidal abnormal phenotypes, including lacking barbels, pigmentation defects, erythema in the opercular region, ragged fins, and delayed scales. All these abnormal phenotypes can be rescued by 10 nM T4 treatment. Strikingly, the fertility of zebrafish was dependent on thyroid hormone; T4 treatment should be continued and cannot be stopped over 2 weeks in hypothyroid zebrafish in order to achieve fertility. Thyroid hormones played a role in the developing and maturing of reproductive cells. Our work indicated that duox mutant zebrafish may provide a model for human congenital hypothyroidism.


Assuntos
Hipotireoidismo Congênito , Modelos Animais de Doenças , NADPH Oxidases/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Animais , Animais Geneticamente Modificados , Sistemas CRISPR-Cas , Feminino , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Masculino , Fenótipo , Tiroxina
7.
Aging (Albany NY) ; 13(9): 13087-13107, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971622

RESUMO

Mimecan encodes a secretory protein that is secreted into the human serum as two mature proteins with molecular masses of 25 and 12 kDa. We found 12-kDa mimecan to be a novel satiety hormone mediated by the upregulation of the expression of interleukin (IL)-1ß and IL-6 in the hypothalamus. Mimecan was found to be expressed in human pituitary corticotroph cells and was up-regulated by glucocorticoids, while the secretion of adrenocorticotropic hormone (ACTH) in pituitary corticotroph AtT-20 cells was induced by mimecan. However, the effects of mimecan in adrenal tissue on the hypothalamic-pituitary-adrenal (HPA) axis functions remain unknown. We demonstrated that the expression of mimecan in adrenal tissues is significantly downregulated by hypoglycemia and scalded stress. It was down-regulated by ACTH, but upregulated by glucocorticoids through in vivo and in vitro studies. We further found that 12-kDa mimecan fused protein increased the corticosterone secretion of adrenal cells in vivo and in vitro. Interestingly, compared to litter-mate mice, the diurnal rhythm of corticosterone secretion was disrupted under basal conditions, and the response to restraint stress was stronger in mimecan knockout mice. These findings suggest that mimecan stimulates corticosterone secretion in the adrenal tissues under basal conditions; however, the down-regulated expression of mimecan by increased ACTH secretion after stress in adrenal tissues might play a role in maintaining the homeostasis of an organism's responses to stress.


Assuntos
Expressão Gênica/fisiologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Estresse Fisiológico/fisiologia , Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico/sangue , Animais , Glucocorticoides/metabolismo , Hipotálamo/metabolismo , Camundongos , Camundongos Knockout , Hipófise/metabolismo
8.
Front Endocrinol (Lausanne) ; 12: 620117, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815280

RESUMO

Background and Objectives: Defects in the human sodium/iodide symporter (SLC5A5) gene have been reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify SLC5A5 mutations in Chinese patients with CH and to evaluate the function of the mutation. Methods: Two hundred and seventy-three patients with primary CH were screened for mutations in SLC5A5 using next-generation sequencing. We investigated the expression and cellular localization of the novel compound heterozygous mutation in SLC5A5. The functional activity of the mutants was further examined in vitro. Results: In 273 patients with CH, two previously undescribed pathogenic mutations p.Gly51AlafsTer45 (G51fs) and p.Gly421Arg (G421R) in a compound heterozygous state in SLC5A5 were identified in a pediatric patient. G51fs was located in the first intercellular loop connecting transmembrane segment I and II, whereas G421R was in the transmembrane segment (TMS) XI. G51fs and G421R resulted in a truncated NIS and reduced protein expression, respectively. In vitro experiments further showed that the normal function of iodine transport of sodium-iodide symporter (NIS) mutants was markedly impaired. Conclusion: The undescribed compound heterozygous mutation of SLC5A5 was discovered in a Chinese CH patient. The mutation led to significantly reduced NIS expression and impaired iodide transport function accompanied by the impaired location of the NIS on the plasma membrane. Our study thus provides further insights into the roles of SLC5A5 in CH pathogenesis.

9.
FEBS Open Bio ; 11(5): 1417-1427, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33735512

RESUMO

Thyroid dysgenesis (TD) is a major cause of primary congenital hypothyroidism; however, the molecular mechanism underlying this process is unclear. Current knowledge regarding the morphogenesis of the thyroid gland and vascular anomalies affecting thyroid development is limited. To monitor the early stages of thyroid gland development, we generated double transgenic zebrafish embryos Tg(tg:mCherry/flk1:EGFP). We described the volume of the thyroid from 2 days postfertilization (dpf) to 5 dpf using 3D reconstruction images. We treated zebrafish embryos with the fibroblast growth factor (FGF) inhibitor PD166866 to better understand the impact of vascular defects on thyroid development and the effects of drug administration at specific time periods on different stages of thyroid development. The 3D reconstruction data revealed that the thyroid glands underwent significant transformation at critical time points. PD166866 treatment from 48 to 72 hours postfertilization (hpf) and from 72 to 96 hpf did not cause obvious reductions in thyroid volume but did result in observable abnormalities in thyroid morphology. The treatment also affected thyroid volume from 36 to 48 hpf, thus indicating that there are time-point-specific effects of drug administration during thyroid development. Three-dimensional image reconstruction provides a comprehensive picture of thyroid anatomy and can be used to complement anatomical fluorescence information. The effects of an FGF pathway inhibitor on thyroid development were determined to be time-point-dependent.

10.
Mol Cell Endocrinol ; 528: 111223, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33667596

RESUMO

The transcription factor GLIS3 is an important factor in hormone biosynthesis and thyroid development, and mutations in GLIS3 are relatively rare. Deletions of more than one of the 11 exons of GLIS3 occur in most patients with various extrathyroidal abnormalities and congenital hypothyroidism (CH), and only 18 missense variants of GLIS3 related to thyroid disease have been reported. The aim of this study was to report the family history and molecular basis of patients with CH who carry GLIS3 variants. Three hundred and fifty-three non-consanguineous infants with CH were recruited and subjected to targeted exome sequencing of CH-related genes. The transcriptional activity and cellular localization of the variants in GLIS3 were investigated in vitro. We identified 20 heterozygous GLIS3 exonic missense variants, including eight novel sites, in 19 patients with CH. One patient carried compound heterozygous GLIS3 variants (p.His34Arg and p.Pro835Leu). None of the variants affected the nuclear localization. However, three variants (p.His34Arg, p.Pro835Leu, and p.Ser893Phe) located in the N-terminal and C-terminal regions of the GLIS3 protein downregulated the transcriptional activation of several genes required for thyroid hormone (TH) biosynthesis. This study of patients with CH extends the current knowledge surrounding the spectrum of GLIS3 variants and the mechanisms by which they cause TH biosynthesis defects.

11.
Eur J Endocrinol ; 183(6): 607-617, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33105104

RESUMO

Objective: Thyrotoxic periodic paralysis (TPP) is a rare and potentially fatal complication of hyperthyroidism. By meta-analysis of genome-wide association studies, we aim to discover novel susceptibility loci and understand the pathogenesis of TPP. Methods: This meta-analysis comprised 319 TPP cases and 3516 healthy controls from three independent cohorts (two from Hong Kong; one from Shanghai). Genetic variants in each cohort were separately genotyped, imputed and analyzed for association with TPP. Fixed-effect meta-analysis was performed to combine the data. Using the three independent genome-wide significant variants, a weighted genetic risk score (GRS) was developed. Results: Of 7 077 246 variants tested for association with TPP, 260 variants reached genome-wide significance and were represented by independent variants from four distinct genomic loci, but a risk locus for Graves' disease at 6p21.33-p21.22 was excluded from subsequent analyses. Two novel loci near TRIM2 (4q31.3; rs6827197: OR = 4.075; P = 3.46 × 10-9) and AC140912.1 (16q22.3; rs6420387: OR = 1.861; P = 2.66 × 10-8) were identified. Together with previously reported KCNJ2 (17q24.3; rs312743: OR = 2.564; P = 1.15 × 10-21), the three susceptibility variants explained 4.36% of the genetic liability. Expression quantitative trait loci analyses showed the variants altered expression of TRIM2 in nerve and KCNJ2 in skeletal muscle. The weighted GRS had an area under curve of 0.827 and 0.682 in the derivation and validation cohorts in Hong Kong. Conclusions: We identified two novel TPP risk loci near TRIM2 and AC140912.1. While rare mutations in TRIM2 and KCNJ2 were implicated in monogenic disorders characterized by muscle paralysis, our study suggested common variants near these genes might dysregulate gene expression and lead to milder phenotypes.


Assuntos
Predisposição Genética para Doença/genética , Proteínas Nucleares/genética , Paralisias Periódicas Familiares/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Tireotoxicose/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Hong Kong , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
12.
Thyroid ; 30(12): 1820-1830, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32746755

RESUMO

Background: We aimed to examine the association of urinary iodine concentration with Hashimoto's thyroiditis (HT) risk, and particularly, to investigate whether the HT-related genetic variations might modify the effects of urinary iodine on HT in the Chinese Han population. Methods: We conducted a case-control study with 1723 Chinese (731 cases, 992 controls). The associations between urinary iodine concentration and HT risk were analyzed using logistic regression models. The effects of interactions between the genetic risk scores (GRSs) and urinary iodine on HT risk were assessed by including the respective interaction terms in the models. We also applied restricted cubic spline regression to estimate the possible nonlinear relationship. The multinomial logistic regression models were performed to determine the associations of urinary iodine with euthyroid-HT and hypothyroidism-HT. Results: After controlling for potential confounders, the odds of HT increased with increasing quartiles of urinary iodine concentration: adjusted odds ratios (ORs) and 95% confidence intervals [CIs] were 1.45 [1.06-1.99], 1.66 [1.17-2.34], and 2.07 [1.38-3.10] for the quartiles 2, 3, and 4, respectively, compared with the first quartile (p for trend <0.001). Multivariable restricted cubic spline regression analysis further demonstrated that there was a near-linear association between urinary iodine concentration and HT risk (p-overall <0.001; p-nonlinear = 0.074). However, we did not find significant interactions between urinary iodine and GRSs on the risk of HT (all p for interaction >0.05). Interestingly, we found that each increment of urinary iodine was associated with a more than twofold increase in the odds of hypothyroidism-HT (adjusted OR = 2.64 [CI = 1.73-4.05]), but not with euthyroid-HT (p > 0.05). Conclusions: Higher urinary iodine concentration was associated with increased risk of HT, and this association was near linear, indicating that increased urinary iodine has a continuous and graded impact on HT risk. Moreover, the iodine-HT association was not modified by genetic predisposition to HT. Interestingly, urinary iodine concentration was significantly associated with increased risk of hypothyroidism.

14.
Biomed Res Int ; 2020: 1789514, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32596280

RESUMO

Background: A deficiency in steroid 5α-reductase type 2 is an autosomal recessive disorder. Affected individuals manifested ambiguous genitalia, which is caused by decreased dihydrotestosterone (DHT) synthesis in the fetus. Methods: We analyzed 25 patients with 5α-reductase deficiency in China. Seventeen of the 25 patients (68%) were initially raised as females. Sixteen patients changed their social gender from female to male after puberty. Results: Eighteen mutations were identified in these patients. p.Gly203Ser and p.Gln6∗ were found to be the most prevalent mutations. On the basis of the genotype of these patients, we divided them into different groups. There was no significant difference in hormone levels and external masculinization score (EMS) in patients with or without these prevalent mutations. Twelve common single-nucleotide polymorphisms (SNPs) near the p.Gln6∗ mutation were chosen for haplotype analysis. Three haplotypes were observed in 6 patients who had the p.Gln6∗ mutation (12 alleles). Conclusion: We analyzed mutations of the SRD5A2 gene in Chinese patients with 5α-reductase deficiency. Although hotspot mutations exist, no founder effect of prevalent mutations in the SRD5A2 gene was detected in the Chinese population.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , Transtorno 46,XY do Desenvolvimento Sexual/genética , Hipospadia/genética , Proteínas de Membrana/genética , Erros Inatos do Metabolismo de Esteroides/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/sangue , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Criança , Pré-Escolar , China , Di-Hidrotestosterona/sangue , Transtorno 46,XY do Desenvolvimento Sexual/sangue , Transtorno 46,XY do Desenvolvimento Sexual/epidemiologia , Feminino , Haplótipos/genética , Humanos , Hipospadia/sangue , Hipospadia/epidemiologia , Lactente , Recém-Nascido , Masculino , Mutação/genética , Erros Inatos do Metabolismo de Esteroides/sangue , Erros Inatos do Metabolismo de Esteroides/epidemiologia , Adulto Jovem
15.
J Clin Endocrinol Metab ; 105(7)2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32246145

RESUMO

CONTEXT: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are the 2 main autoimmune thyroid diseases that have both similarities and differences. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these closely related diseases. OBJECTS: To identify the susceptibility genes for HT in the Chinese cohort and compare susceptibility genes between GD and HT. DESIGN: In the current study, 18 SNPs from 18 established GD risk loci were selected and then genotyped in 2682 patients with HT, 4980 patients with GD, and 3892 controls. The association analysis between HT and controls and heterogeneity analysis between HT and GD were performed on SPSS, with the logistic regression analysis adjusted for sex and age. RESULTS: We identified 11 susceptibility loci for HT in the Chinese Han population, with 4 loci, including the rs1265883 in SLAMF6 locus, rs1024161 in CTLA4, rs1521 in HLA-B, and rs5912838 in GPR174/ ITM2A at X chromosome, reaching genome-wide significance of 5 × 10-8. Five loci were reported to be associated with HT for the first time. We also identified 6 susceptibility loci with heterogeneity between GD and HT. Out of them, 4 loci were associated with GD but not with HT, including HLA-DPB1, CD40, TSHR, and TG; the association of HLA-B with GD was stronger than that with HT, but the association of SLAMF6 was reversed. CONCLUSION: Our findings suggested that the pathogenesis of HT and GD was different.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Doença de Graves/genética , Doença de Hashimoto/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Antígeno CTLA-4/genética , China , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Antígenos HLA-B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Acoplados a Proteínas G/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/genética
16.
Mol Genet Genomic Med ; 8(7): e1249, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32342657

RESUMO

BACKGROUND: With several susceptibility single nucleotide polymorphisms identified by case-control association studies, Graves' disease is one of the most common forms of autoimmune thyroid disease. In this study, we aimed to determine whether any observed differences in genetic associations are influenced by sex in Chinese Han populations. METHODS: A total of 8,835 patients with Graves' disease and 9,936 sex-matched healthy controls were enrolled in the study. Confirmed by a two-staged association analysis, sex-specific analyses among 20 Graves' disease susceptibility loci were conducted. RESULTS: A significant sex-gene interaction was detected primarily at rs5912838 on Xq21.1 between the GPR174 and ITM2A genes, whereby male Graves' disease patients possessed a significantly higher frequency of risk alleles than their female counterparts. Interestingly, compared to women, male patients with Graves' disease had a higher cumulative genetic risk and higher persistent thyroid stimulating hormone receptor antibody-positive rate after receiving antithyroid drug therapy for at least 1 year. CONCLUSION: The findings of this study suggest the existence of one potential sex-specific Graves' disease variant on Xq21.1. This could increase our understanding of the pivotal mechanism behind Graves' disease and ultimately aid in identifying possible therapeutic targets.


Assuntos
Cromossomos Humanos X/genética , Doença de Graves/genética , Polimorfismo de Nucleotídeo Único , China , Epistasia Genética , Feminino , Frequência do Gene , Humanos , Masculino , Proteínas de Membrana/genética , Receptores Acoplados a Proteínas G/genética , Fatores Sexuais
17.
Mol Cell Endocrinol ; 506: 110761, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32088313

RESUMO

Inborn defects in thyroid hormone biosynthesis contribute to nearly half of congenital hypothyroidism (CH) cases in China. The thyroid peroxidase (TPO) mutation is one of the most frequent mutations that results in thyroid dyshormonogenesis. In this study, 35 non-synonymous mutations in 15 TPO sites, including 6 novel mutations, were identified in 230 Chinese patients with CH. The enzyme activity of the mutations in TPO was investigated in vitro, and patients with less than 15% residual enzyme activity showed severe CH, such as markedly increased thyroid-stimulating hormone (TSH) at diagnosis (>100 µIU/mL) and pronounced goiter, and required a higher dose of L-thyroxine to maintain the euthyroid. However, CH patients with greater than 16% TPO activity showed mild CH, a typical childhood socially without L-thyroxine treatment before 3 years of age, and the appearance of a macroscopic goiter at childhood. The findings indicated that the residual enzymatic activity of TPO was correlated with clinical phenotypes of CH patients with TPO biallelic mutations.


Assuntos
Autoantígenos/genética , Hipotireoidismo Congênito/diagnóstico , Hipotireoidismo Congênito/genética , Iodeto Peroxidase/genética , Proteínas de Ligação ao Ferro/genética , Adolescente , Adulto , Criança , Pré-Escolar , China/epidemiologia , Hipotireoidismo Congênito/tratamento farmacológico , Hipotireoidismo Congênito/epidemiologia , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Testes Genéticos/métodos , Células HEK293 , Terapia de Reposição Hormonal , Humanos , Lactente , Recém-Nascido , Padrões de Herança/genética , Masculino , Mutação , Triagem Neonatal/métodos , Linhagem , Polimorfismo de Nucleotídeo Único , Tiroxina/uso terapêutico , Adulto Jovem
18.
Ann Transl Med ; 7(18): 434, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31700870

RESUMO

Background: This study aimed to determine independent risk loci of Graves' disease (GD) in the thyroglobulin (TG) region. Methods: In this two-staged association study, a total of 9,757 patients with GD and 10,626 sex-matched controls were recruited from Chinese Han population. Illumina Human660-Quad BeadChips in the discovery stage and TaqMan SNP Genotyping Assays in the replication stage were used for genotyping. Trend test and logistic regression analysis were performed in this association study. Results: In the discovery stage, rs2294025 and rs7005834 were the most highly associated susceptibility loci with GD in TG. In the replication phase, 7 SNPs, including rs2294025 and rs7005834, were selected for fine-mapping. Finally, we confirmed that rs2294025 and rs7005834 were the independent risk loci of GD in the combined populations. At the same time, there was no significant difference between the risk allele frequencies of rs2294025 and rs7005834 in different clinical phenotypes of GD. Conclusions: The fine mapping study of thyroglobulin identified two independent SNPs (rs2294025 and rs7005834) for GD susceptibility. However, no significant differences for rs2294025 and rs7005834 were observed, between the different clinical phenotypes of GD, including gender, Graves' ophthalmopathy (GO), and serum levels of thyrotropin receptor antibody, thyroid peroxidase antibody, and thyroglobulin antibody. These results provide a deeper understanding of the association mechanism of thyroglobulin and GD risk.

19.
Clin Chim Acta ; 497: 147-152, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31356790

RESUMO

BACKGROUND: Defects in the human thyroid stimulating hormone receptor (TSHR) gene are reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify mutations in Chinese patients with CH and analyze the relationships between TSHR phenotypes and clinical phenotypes. METHODS: 220 patients with primary CH were screened for TSHR mutations by performing next-generation sequencing. All the exons and exon-intron boundaries of TSHR were analyzed. The function of 8 mutants in TSHR were further investigated in vitro. RESULTS: Among 220 patients with CH, 15 distinct TSHR mutations were identified in 13 patients (5.91%, 13/220, including our previous reported 110 patients, carried with 10 mutations in 8 patients). We found five distinct mutations in the additional cohort of 110 CH patients and identified 7 mutations (including a novel mutation, p.S567R) were loss-of-function mutations. CONCLUSION: Our study indicated that the prevalence of TSHR mutations was 5.91% among studied Chinese patients with CH. One novel TSHR variant was found and four genetic alterations revealed important role of the Ile216, Ala275, Asn372, Ser567 residues in signaling.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Hipotireoidismo Congênito/genética , Análise Mutacional de DNA , Mutação , Receptores da Tireotropina/genética , Adulto , China , DNA/genética , Feminino , Células HEK293 , Humanos , Masculino , Fenótipo
20.
Mol Cell Endocrinol ; 494: 110492, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31255731

RESUMO

Approximately 20% of Graves' disease (GD) patients may result eventually in hypothyroidism in their natural course. Uterus globulin-associated protein 1 (UGRP1) was associated with GD in our previous study. Here we investigated the role of UGRP1 in the development of autoimmune thyroid disease (AITD). The results showed that UGRP1 was expressed in the thyrocytes of most Hashimoto's thyroiditis (HT) patients and a proportion of GD patients (293 HT and 198 GD). The pathologic features of UGRP1-positive thyrocytes resembled "Hürthle cells", and were surrounded by infiltrated leukocytes. The positivity rate of TPOAb in UGRP1-positive GD patients was much higher than that in -negative GD patients. Moreover, UGRP1 was co-expressed with Fas and HLA-DR in the thyrocytes of AITD patients. We also found IL-1ß but not Th1 or Th2 cytokines was able to upregulate the expression of UGRP1. Our findings indicated that UGRP1 may be a novel marker in thyrocytes to predict GD patients who develop hypothyroidism.


Assuntos
Progressão da Doença , Doença de Graves/metabolismo , Doença de Graves/patologia , Hipotireoidismo/metabolismo , Hipotireoidismo/patologia , Secretoglobinas/metabolismo , Biomarcadores/metabolismo , Antígenos HLA-DR/metabolismo , Humanos , Interleucina-1beta/metabolismo , Secretoglobinas/genética , Células Epiteliais da Tireoide/metabolismo , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Regulação para Cima/genética , Receptor fas/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...