Variable Phenotype Associated with Ser505Asn-Activating Thyrotropin-Receptor Germline Mutation

Führer, Dagmar; Mix, Michael; Wonerow, Peter; Richter, I; Willgerodt, H; Paschke, Ralf

doi:10.1089/thy.1999.9.757

Cited by 36 publications

(37 citation statements)

References 13 publications

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“…No correlation with the phenotype of HTNs could be found for the different functional properties of somatic (Arturi et al 1998) or germline (Fuhrer et al 1999) TSHR mutations. Defects in feedback mechanisms such as GRK-induced desensitization of the TSHR receptor are possible explanations for these differences.…”

Section: Expression Of Grk 3 and Grk 4 Is Increased In Htnsmentioning

confidence: 99%

Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules

Voigt

Holzapfel²,

Meyer³

et al. 2004

Journal of Endocrinology

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G-protein-coupled receptor kinases (GRKs) are implicated in the pathophysiology of human diseases such as arterial hypertension, heart failure and rheumatoid arthritis. While G-protein-coupled receptor kinases 2 and 5 have been shown to be involved in the desensitization of the rat thyrotropin receptor (TSHR), their role in the pathophysiology of hyperfunctioning thyroid nodules (HTNs) is unknown. Therefore, we analyzed the expression pattern of the known GRKs in human thyroid tissue and investigated their function in the pathology of HTNs. The expression of different GRKs in human thyroid and HTNs was measured by Western blotting. The influence of GRK expression on TSHR function was analyzed by coexpression experiments in HEK 293 cells. We demonstrate that in addition to GRKs 2, 5 and 6, GRKs 3 and 4 are also expressed in the human thyroid. GRKs 2, 3, 5 and 6 are able to desensitize the TSHR in vitro. This GRKinduced desensitization is amplified by the additional over-expression of -arrestin 1 or 2. We did not find any mutations in the GRKs 2, 3 and 5 from 14 HTNs without TSHR mutations and G s mutations. The expression of GRKs 3 and 4 was increased in HTNs independently from the existence of TSHR mutations or G s mutations.In conclusion, the increased expression of GRK 3 in HTNs and the ability of GRK 3 to desensitize the TSHR in vitro, suggest a potential role for GRK 3 as a negative feedback regulator for the constitutively activated cAMP pathway in HTNs.

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Section: Expression Of Grk 3 and Grk 4 Is Increased In Htnsmentioning

confidence: 99%

Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules

Voigt

Holzapfel²,

Meyer³

et al. 2004

Journal of Endocrinology

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“…In spite of large variations of the time spans (months to 17 years) for transitions of autonomously functioning thyroid nodules (AFTNs) from subclinical to overt hyperthyroidism (Sandrock et al, 1993;Paschke and Ludgate, 1997), there is no genotype-phenotype correlation for constitutively activating TSHR mutations (Fuhrer et al, 1999), which can be found in 60% of all cases (Parma et al, 1993;Arturi et al, 1998). It is therefore very likely that unknown signaling events, apart from counter-regulatory mechanisms like arrestins (Voigt et al, 2000) or GRKs, contribute to the etiology of AFTNs and the clinical phenotype.…”

Section: Introductionmentioning

confidence: 99%

Gene expression analysis reveals evidence for inactivation of the TGF-β signaling cascade in autonomously functioning thyroid nodules

et al. 2004

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Molecular eventsthat lead to the development of autonomously functioning thyroid nodules (AFTNs) are somatic mutations of the thyrotropin receptor (TSHR) in approximately 60% of the nodules and less frequently, somatic mutations in the G s a protein. However, AFTNs without known mutations indicate that other causes remain to be identified. Moreover, the impact of constitutively activating TSHR mutations on the signal transduction network of the thyroid epithelial cell is unknown. We therefore investigated gene expression in 15 AFTNs and their surrounding tissue using Affymetrix GeneChips. Most prominently, data analysis revealed a changed pattern of gene expression in the TGF-b signaling cascade and 25 differentially regulated genes in AFTNs, including thyroid peroxidase, type I iodothyronine deiodinase and sialyltransferase (SIAT) 1. Strikingly coexpression of SIAT 1 and TSHR in COS-7 cells increased TSH binding and cell surface expression of the TSHR. Moreover, differences in gene expression patterns for AFTNs with and without TSHR mutations indicate specific alterations of signal transduction in AFTNs without TSHR mutations. These results suggest that AFTNs with TSHR mutations harbor further mechanisms of forward stimulation. Furthermore, they give important leads to elucidate the molecular etiology of AFTNs without TSHR mutations.

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“…Germline mutations in the TSHR have also been identified in familial non-autoimmune hyperthyroidism, in which it displays autosomal dominant inheritance, and in cases of sporadic neonatal thyrotoxicosis, which may become familial in time (18,19). The age of onset of symptoms can vary widely, even in the same family (20).…”

Section: Introductionmentioning

confidence: 99%

Demonstration of reduced in vivo surface expression of activating mutant thyrotrophin receptors in thyroid sections

Sequeira

Jasani²,

Führer³

et al. 2002

European Journal of Endocrinology

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Objective: Thyroid function and growth are controlled by TSH. Hyperthyroidism can be due to Graves' Disease (GD), in which thyroid-stimulating antibodies mimic TSH, or gain-of-function mutations in the TSH receptor (TSHR). These activating mutations have poor surface expression when assessed in non-thyroidal cells in vitro but nothing is known of their in vivo behaviour. Several TSHR antibodies have been produced but none has been applied to thyroid paraffin sections. This study aimed to develop a technique suitable for use on paraffin sections and apply it to investigate TSHR expression in thyroids harbouring activating TSHR germline mutations compared with normal and GD thyroids. Design and methods: Immunocytochemistry coupled with antigen retrieval, using a spectrum of antibodies to the TSHR, was applied to paraffin sections of GD thyroid tissue. Subsequently, TSHR immunoreactivity was examined in three normal thyroids, three patients with GD and three patients with familial hyperthyroidism, due to different gain-of-function TSHR germline mutations, using the optimised protocol. Results: Two antibodies, A10 and T3-495, to the extracellular domain (ECD) and membrane spanning region (MSR) of the TSHR respectively, produced specific basolateral staining of thyroid follicular cells. In normal and GD thyroids, basolateral staining with T3-495 was generally more intense than with A10, suggesting a possible surfeit of MSR over ECD. Graves' Disease thyroids have more abundant TSHR than normal glands. In contrast, thyroids harbouring gain-of-function mutations have the lowest expression in vivo, mirroring in vitro findings. Conclusions: The development of an immunocytochemical method applicable to paraffin sections has demonstrated that different molecular mechanisms causing hyperthyroidism result in the lowest (mutation) and highest (autoimmunity) levels of receptor at the thyrocyte surface.

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Variable Phenotype Associated with Ser505Asn-Activating Thyrotropin-Receptor Germline Mutation

Cited by 36 publications

References 13 publications

Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules

Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules

Gene expression analysis reveals evidence for inactivation of the TGF-β signaling cascade in autonomously functioning thyroid nodules

Demonstration of reduced in vivo surface expression of activating mutant thyrotrophin receptors in thyroid sections

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