R450H TSH receptor mutation in congenital hypothyroidism in Taiwanese children

Chang, Wei Chiao; Liao, Cheng Yu; Chen, Wei Chiao; Fan, Yung Ching; Chiu, Siou Jin; Kuo, Ho‐Chang; Woon, Peng Yeong; Chao, Mei

doi:10.1016/j.cca.2012.02.027

Cited by 24 publications

(15 citation statements)

References 11 publications

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“…TSHR gene mutations were reported to be one of the causes of thyroid dysgenesis. Fifteen different TSHR mutations were identified in our study, eight of them, including c.1349G>A [31], c.1574T>C [32], c.394G>C [33], c.1591C>T [34], c.915T>A [35], c.733G>A [32], c.1838A>G [36] and c.1270G>T [37] were reported related to CH.…”

Section: Discussionmentioning

confidence: 99%

Targeted next-generation sequencing of thirteen causative genes in Chinese patients with congenital hypothyroidism

Long

Zhou

et al. 2018

Endocr J

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To identify the spectrum and prevalence of thirteen causative genes mutations in congenital hypothyroidism (CH) patients, we collected blood samples and extracted genomic DNA of 106 CH patients, and designed a customized targeted next-generation sequencing panel containing 13 CH-causing genes to detect mutations. A total of 132 mutations were identified in 65.09% of patients (69/106) on the following nine genes: DUOX2, TG, TPO, TSHR, TTF1, TTF2, NKX2-5, PAX8 and GNAS. 69.70% (92/132) mutations related to thyroid dyshormonogenesis genes, including DUOX2 (n = 49), TG (n = 35), and TPO (n = 8). 21.21% (28/132) mutations related to thyroid dysgenesis genes, including TSHR (n = 19), TTF1 (n = 5), TTF2 (n = 1), PAX8 (n = 2), and NKX2-5 (n = 1). 9.09% (12/132) mutations related to GNAS, which was associated with thyrotropin resistance. No mutation of THRA, TSHB, IYD or SLC5A5 was detected. Among 69 mutations detected patients, 41 (59.42%) patients were two or more mutations detected, and mutations of 30 (43.48%) patients related to two or three genes. According to the pathomechanism of the mutant genes, 57.97% CH patients were classified as thyroid dyshormonogenesis. Overall, DUOX2, TG and TSHR mutations were the most common genetic defects in Chinese CH patients, and thyroid dyshormonogenesis could be the first genetic etiology of CH in Chinese. Besides, multiple mutations accounts for a part of genetic pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Targeted next-generation sequencing of thirteen causative genes in Chinese patients with congenital hypothyroidism

Long

Zhou

et al. 2018

Endocr J

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“…27 This mutation was also shown to be important in Taiwanese children with congenital hypothyroidism. 28 …”

Section: Tsh Receptor Mutationmentioning

confidence: 97%

A systematic review of genetic studies of thyroid disorders in Taiwan

Huang

Jap

2015

Journal of the Chinese Medical Association

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A systematic review of genetic studies of thyroid disorders in Taiwan identified studies of gene mutations involved in the synthesis and binding of thyroid hormone, as well as mutations of proto-oncogenes and tumor suppressor genes in thyroid cancer. Studies related to gene polymorphisms in patients with autoimmune thyroid disease (AITD) and thyroid cancer were also reviewed. The most prevalent mutations in the Han-Chinese population were c.2268insT in the thyroid peroxidase (TPO) gene and c.919-2A>G in the Pendred syndrome (PDS) gene. Additional mutations have also been revealed in the genes encoding TPO (n = 5), thyroglobulin (TG; n = 6), pendrin (n = 2), and thyroxine-binding globulin (TBG; n = 2), which were novel at the time they were reported. The prevalence of various somatic mutations in differentiated thyroid cancer was similar in Taiwan and Western countries, with the RAS kinase mutation and tyrosine receptor kinase (TRK) and rearranged during transfection (RET) proto-oncogenes being detected in lower frequencies and the B-type RAF kinase (BRAF) mutation accounting for the majority of cases. Recent microRNA analysis revealed an association between miR146b and the BRAF mutation, which was associated with poor prognosis of papillary thyroid carcinoma (PTC). Susceptibility to Graves' disease (GD) was linked to the human leukocyte antigen (HLA) region. The associated alleles were different in Han-Chinese and Caucasians; HLA-DPB1*0501, the major allele in Taiwan, has a low frequency in the West. By contrast, a high frequency of HLA-DRB1*0301 was detected in Caucasians but not Han-Chinese. In addition to the HLA region, cytotoxic T lymphocyte-associated molecule-4 (CTLA4) gene polymorphisms +49G>A and +6230G>A (CT60) were positively associated with GD. The GG genotype and G allele of single nucleotide polymorphism (SNP) +49G>A were also related to relapse of Graves' hyperthyroidism after antithyroid drug withdrawal. Differences in the genetic patterns between Han-Chinese and Caucasians for some thyroid disorders suggest the importance of variable genetic influences in different populations.

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“…The intracellular loop 1 (ICL1) contributes to G-protein binding but the amino acids have a different impact (111). Of particular interest is Arg450 at the transition between ICL1 and TMH2, where several cases of naturally occurring inactivating mutations were reported (244–247). Amino acid Arg450 may directly interact with Gα as suggested by our homology model, e.g., with Gln390 in the C-terminal α5-helix of Gαs (111).…”

Section: Signal Transduction By Structural Reorganization: the Tshr Amentioning

confidence: 99%

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

et al. 2017

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The thyroid-stimulating hormone receptor (TSHR) is a member of the glycoprotein hormone receptors, a sub-group of class A G-protein-coupled receptors (GPCRs). TSHR and its endogenous ligand thyrotropin (TSH) are of essential importance for growth and function of the thyroid gland and proper function of the TSH/TSHR system is pivotal for production and release of thyroid hormones. This receptor is also important with respect to pathophysiology, such as autoimmune (including ophthalmopathy) or non-autoimmune thyroid dysfunctions and cancer development. Pharmacological interventions directly targeting the TSHR should provide benefits to disease treatment compared to currently available therapies of dysfunctions associated with the TSHR or the thyroid gland. Upon TSHR activation, the molecular events conveying conformational changes from the extra- to the intracellular side of the cell across the membrane comprise reception, conversion, and amplification of the signal. These steps are highly dependent on structural features of this receptor and its intermolecular interaction partners, e.g., TSH, antibodies, small molecules, G-proteins, or arrestin. For better understanding of signal transduction, pathogenic mechanisms such as autoantibody action and mutational modifications or for developing new pharmacological strategies, it is essential to combine available structural data with functional information to generate homology models of the entire receptor. Although so far these insights are fragmental, in the past few decades essential contributions have been made to investigate in-depth the involved determinants, such as by structure determination via X-ray crystallography. This review summarizes available knowledge (as of December 2016) concerning the TSHR protein structure, associated functional aspects, and based on these insights we suggest several receptor complex models. Moreover, distinct TSHR properties will be highlighted in comparison to other class A GPCRs to understand the molecular activation mechanisms of this receptor comprehensively. Finally, limitations of current knowledge and lack of information are discussed highlighting the need for intensified efforts toward TSHR structure elucidation.

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R450H TSH receptor mutation in congenital hypothyroidism in Taiwanese children

Cited by 24 publications

References 11 publications

Targeted next-generation sequencing of thirteen causative genes in Chinese patients with congenital hypothyroidism

Targeted next-generation sequencing of thirteen causative genes in Chinese patients with congenital hypothyroidism

A systematic review of genetic studies of thyroid disorders in Taiwan

Structural–Functional Features of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work

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