The Thyrotropin Receptor Mutation Database: Update 2003

Führer, Dagmar; Lachmund, Peter; Nebel, Istvan-Tibor; Paschke, Ralf

doi:10.1089/10507250360731514

Cited by 32 publications

(29 citation statements)

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“…Apart from the highly detailed locus-specific databases on GPCR variants that are reported in Table 1 [Fuhrer et al, 2003;Oetting, 2002;Pidasheva et al, 2004], the variety of online sources is evident from general databases that contain subsets of variants. Individual general databases contain rare disease-causing mutations [Cooper et al, 1998;Pearson et al, 1994], small genetic variants [HapMap Consortium, 2003;Sherry et al, 1999], CNVs [Iafrate et al, 2004], and other selections of variants [Yip et al, 2004].…”

Section: Introductionmentioning

confidence: 99%

GPCR NaVa database: natural variants in human G protein-coupled receptors

et al. 2007

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Communicated by Mauno VihinenThe superfamily of human G protein-coupled receptors (GPCRs) is large and regulates a plethora of important physiological processes by transducing extracellular signals over cell membranes. A diversity of natural variants occurs in these receptors, including rare mutations and common polymorphisms. These variants differ in their impact on DNA, ranging from single nucleotide polymorphisms (SNPs) to copy number variants, and in their impact on protein function. Natural variants furthermore vary in their effects on human phenotypes from neutral to disease-associated. As mutation data are highly dispersed over numerous sources, a single resource for variants would aid investigators of GPCRs. The GPCR NaVa database therefore integrates data on natural variants in human GPCRs from online databases, the scientific literature, and patents. Where available, variants contain information on their location in the DNA (and protein sequence), the involved nucleotides (and amino acids), the average frequency of each allele, reported disease associations, and references to public databases and the scientific literature. The GPCR NaVa database aims to facilitate studies into pharmacogenetics, genotype-phenotype, and structure-function relationships of GPCRs. The GPCR NaVa database is interlinked with the family-specific GPCRDB resource and is accessible as a stand-alone database through a user-friendly website at http://nava.

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Section: Introductionmentioning

confidence: 99%

GPCR NaVa database: natural variants in human G protein-coupled receptors

et al. 2007

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“…de/, innere/) (21). Three different constitutively activating mutations have been described in the 3rd ECL (32, 34, 48 -50) (TSH Receptor mutation Database II, http://www.uni-leipzig.de/, innere/).…”

Section: Discussionmentioning

confidence: 99%

“…Naturally occurring TSHR mutations, which have been identified as one of the molecular causes of hyperfunctioning thyroid adenomas, are mainly localized in the transmembrane domains as well as in the ECLs and ICLs (TSH Receptor mutation Database II, http:// www.uni-leipzig.de/, innere/) (21,22). These in vivo mutations give valuable indications for specific functional features, which are important for the analysis of intra-and intermolecular structure -function relationships.…”

Section: Introductionmentioning

confidence: 99%

Interactions between the extracellular domain and the extracellular loops as well as the 6th transmembrane domain are necessary for TSH receptor activation

Neumann

Claus²,

Paschke

2005

eur j endocrinol

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Objective: The molecular mechanisms of TSH receptor (TSHR) activation and intramolecular signal transduction are largely unknown. Deletion of the extracellular domain (ECD) of the TSHR results in increased constitutive activity, which suggests a self-inhibitory interaction between the ECD and the extracellular loops (ECLs) or the transmembrane domains (TMDs). To investigate these potential interactions and to pursue the idea that mutations in the ECD affect the constitutive activity of mutants in the ECLs or TMDs we generated double mutants between position 281 in the ECD and mutants in all three ECLs as well as the 6th TMD. Design: We combined mutation S281D, characterized by an impaired TSH-stimulated cAMP response, with the constitutively activating in vivo mutations I486F (1st ECL), I568T (2nd ECL), V656F (3rd ECL) and D633F (6th TMD). Further, we constructed double mutants containing the constitutively activating mutation S281N and one of the inactivating mutations D474E, T477I (1st ECL) and D633K (6th TMD). Results: The cAMP level of the double mutants with S281N and the inactive mutants in the 1st ECL was decreased below the level of the inactive single mutants, demonstrating that a constitutively activating mutation in the ECD cannot bypass disruption of signal transduction in the serpentine domain. In double mutants with S281D, basal and TSH-induced cAMP and inositol phosphate production of constitutively active mutants was reduced to the level of S281D. Conclusion: The dominance of S281D and the dependence of constitutively activating mutations in the ECLs on the functionally intact ECD strongly suggest that interactions between these receptor domains are required for TSHR activation and intramolecular signal transduction.European Journal of Endocrinology 152 625-634

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“…Several databases collate information and functional data on GPCRs: GPCR Database, http://www.gpcr.org/7tm (Horn et al, 1998); GRIS: Glycoprotein hormone Receptor Information System, http://gris.ulb.as.be (Van Durme et al, 2006); TSH Receptor mutation Database II, http://innere.uniklinikum-leipzig.de/tsh (Lachmund et al, 2004;Fuhrer et al, 2003); GPCR Natural Variants Database, http://nava.liacs.nl (Kazius et al, 2008). The unification and assignment of such information directly to the three-dimensional (3D) structure of GPCRs would facilitate the elucidation of causal relationships between sequence, structure, function and also malfunction.…”

Section: Introductionmentioning

confidence: 99%

An interactive web-tool for molecular analyses links naturally occurring mutation data with three-dimensional structures of the rhodopsin-like glycoprotein hormone receptors

et al. 2010

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ABSTRACT:The collection, description and molecular analysis of naturally occurring (pathogenic) mutations are important for understanding the functional mechanisms and malfunctions of biological units such as proteins. Numerous databases collate a huge amount of functional data or descriptions of mutations, but tools to analyse the molecular effects of genetic variations are as yet poorly provided. The goal of this work was therefore to develop a translational web-application that facilitates the interactive linkage of functional and structural data and which helps improve our understanding of the molecular basis of naturally occurring gain-or loss-of function mutations. Here we focus on the human glycoprotein hormone receptors (GPHRs), for which a huge number of mutations are known to cause diseases. We describe new options for interactive data analyses within three-dimensional structures, which enable the assignment of molecular relationships between structure and function. Strikingly, as the functional data are converted into relational percentage values, the system allows the comparison and classification of data from different GPHR subtypes and different experimental approaches. Our new application has been incorporated into a freely available database and website for the GPHRs (http://www.ssfa-gphr.de), but the principle development would also be applicable to other macromolecules.

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The Thyrotropin Receptor Mutation Database: Update 2003

Cited by 32 publications

References 10 publications

GPCR NaVa database: natural variants in human G protein-coupled receptors

GPCR NaVa database: natural variants in human G protein-coupled receptors

Interactions between the extracellular domain and the extracellular loops as well as the 6th transmembrane domain are necessary for TSH receptor activation

An interactive web-tool for molecular analyses links naturally occurring mutation data with three-dimensional structures of the rhodopsin-like glycoprotein hormone receptors

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