The Leipzig Thyrotropin Receptor Mutation Database: Update 2012

Lüblinghoff, Julia; Nebel, Istvan-Tibor; Huth, Sandra; Jäschke, H; Schaarschmidt, Joerg; Eszlinger, Markus; Paschke, Ralf

doi:10.1159/000342918

Cited by 10 publications

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“…Cell culture reagents, ProLong Gold Antifade Reagent with DAPI, LysoTracker Red DND-99, ER- In silico prediction TSHR variants membrane expression and functionality was assessed through the TSH receptor mutation database (29). 55 variants were subjected to in silico predictions and assigned as damaging or not damaging as specified in Supplementary Methods.…”

Section: Chemicalsmentioning

confidence: 99%

“…TSHR post-translational modifications are required for correct trafficking, maturation, and activity (3,5,6). The N-linked glycosylation happening in the endoplasmic reticulum (ER) is fundamental (Fig.…”

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confidence: 99%

“…In trans-Golgi, TSHR finally acquires the complex-type carbohydrates (Fig. 1D) that characterize the mature form expressed on cell surface and undergoes tyrosine sulfation, fundamental for high-affinity binding and activation (6,8). On plasma membrane TSHR is cleaved by an unidentified enzyme with loss of a short sequence of variable size, peptide C (Figure 1E).…”

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confidence: 99%

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Thyrotropin Receptor p.N432D Retained Variant Is Degraded Through an Alternative Lysosomal/Autophagosomal Pathway and Can Be Functionally Rescued by Chemical Chaperones

Grassi

Lábadi

Vezzoli

et al. 2021

Thyroid

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Background. Loss of function mutations of thyrotropin receptor (TSHR) are one of the main causes of congenital hypothyroidism (CH). As for many disease-associated GPCRs, these mutations often affect the correct trafficking and maturation of the receptor, thus impairing the expression on the cell surface. Indeed, several retained GPCR mutants are able to effectively bind their ligands and to transduce signals when they are forced to the cell surface by degradation inhibition or by treatment with chaperones. Despite the large number of well-characterized retained TSHR mutants, no attempts have been made for rescue. Furthermore, little is known about TSHR degradation pathways. We hypothesize that, similarly to other GPCRs, TSHR retained mutants may be at least partially functional if their maturation and membrane expression is facilitated by chaperones or degradation inhibitors. Methods. We performed in silico predictions of the functionality of known TSHR variants and compared the results with available in vitro data. Western blot, confocal microscopy, ELISAs and dual luciferase assays Thyroid

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Section: Chemicalsmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Thyrotropin Receptor p.N432D Retained Variant Is Degraded Through an Alternative Lysosomal/Autophagosomal Pathway and Can Be Functionally Rescued by Chemical Chaperones

Grassi

Lábadi

Vezzoli

et al. 2021

Thyroid

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“…Инактивирующие наследуе-мые мутации являются причиной врожденной рези-стентности к ТТГ. На сегодняшний день описано 147 мутаций в TSHR, из них 51 инактивирующая [11].…”

Section: Introductionunclassified

Resistance to thyrotropin: familial case report

et al. 2016

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“…Activation of these G protein subtypes by constitutively activating TSHR mutations results in a higher ligand independent basal production of the second messenger cyclic adenosine monophosphate (cAMP) or inositol phosphate (IP) than observed for the wt TSHR. Presently more than 60 constitutively activating TSHR mutations with a broad range of constitutive in vitro activity levels are known (http://tsh-receptor-mutation-database.org [ 27 ] ). The clinical phenotype of hyperthyroidism was the initial reason for the identifi cation and subsequent functional in vitro characterization ( • ▶ Fig.…”

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Controversial Constitutive TSHR Activity: Patients, Physiology, and In Vitro Characterization

et al. 2014

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G protein-coupled receptors constitute a large family of transmembrane receptors, which activate cellular responses by signal transmission and regulation of second messenger metabolism after ligand binding. For several of these receptors it is known that they also signal ligand-independently. The G protein-coupled thyroid stimulating hormone receptor (TSHR) is characterized by a high level of constitutive activity in the wild type state. However, little is known yet concerning the physiological relevance of the constitutive wild type TSHR activity. Certainly, knowledge of the physiological relevance of constitutive wild type receptor activity is necessary to better understand thyroid physiology and it is a prerequisite for the development of better therapies for nonautoimmune hyperthyroidism and thyroid cancer. Based on a literature search regarding all published TSHR mutations, this review covers several mutations which are clearly associated with a hyperthyroidism-phenotype, but interestingly show a lack of constitutive activity determined by in vitro characterization. Possible reasons for the observed discrepancies between clinical phenotypes and in vitro characterization results for constitutive TSHR activity are reviewed. All current in vitro characterization methods for constitutive TSHR mutations are "preliminary attempts" and may well be revised by more comprehensive and even better approaches. However, a standardized approach for the determination of constitutive activity can help to identify TSHR mutations for which the investigation of additional signaling mechanisms would be most interesting to find explanations for the current clinical phenotype/in vitro discrepancies and thereby also define suitable methods to explore the physiological relevance of constitutive wild type TSHR activity.

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The Leipzig Thyrotropin Receptor Mutation Database: Update 2012

Cited by 10 publications

References 0 publications

Thyrotropin Receptor p.N432D Retained Variant Is Degraded Through an Alternative Lysosomal/Autophagosomal Pathway and Can Be Functionally Rescued by Chemical Chaperones

Thyrotropin Receptor p.N432D Retained Variant Is Degraded Through an Alternative Lysosomal/Autophagosomal Pathway and Can Be Functionally Rescued by Chemical Chaperones

Resistance to thyrotropin: familial case report

Controversial Constitutive TSHR Activity: Patients, Physiology, and In Vitro Characterization

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