Functional significance of the thyrotropin receptor germline polymorphism D727E

Sykiotis, Gerasimos P.; Neumann, Susanne; Georgopoulos, Neoklis A.; Sgourou, Argyro; Papachatzopoulou, Adamantia; Markou, Kostas B.; Kyriazopoulou, Venetsana; Paschke, Ralf; Vagenakis, Apostolos G.; Papavassiliou, Athanasios G.

doi:10.1016/s0006-291x(03)00071-8

Cited by 31 publications

(28 citation statements)

References 23 publications

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“…Functional studies have shown no differences in basal and TSHstimulated CRE-luciferase activities between D727E and wild-type TSHR (20,30,31). Interestingly, in vitro studies performed with a double mutant A593N/D727E showed higher constitutive activity than D727E, although the double mutant had 2.3-fold lower constitutive activity than the A593N mutant alone (31). This finding suggests that constitutive activities of mutant TSHR could be modified by the presence in the same TSHR gene allele of D727E or other nonsynonymous polymorphisms.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain

Palos-Paz

Perez-Guerra²,

Cameselle-Teijeiro³

et al. 2008

European Journal of Endocrinology

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Objective: Toxic thyroid adenoma (TA) is a common cause of hyperthyroidism. Mutations in the TSH receptor (TSHR) gene, and less frequently in the adenylate cyclase-stimulating G alpha protein (GNAS) gene, are well established causes of TA in Europe. However, genetic causes of TA remain unknown in a small percentage of cases. We report the first study to investigate mutations in TSHR, GNAS, protein kinase, cAMP-dependent, regulatory, type I alpha (PRKAR1A) and RAS genes, in a large series of TA from Galicia, an iodine-deficient region in NW Spain. Design and methods: Eighty-five TA samples were obtained surgically from 77 hyperthyroid patients, operated on for treatment of non-autoimmune toxic nodular goitre. After DNA extraction, all coding exons of TSHR, GNAS and PRKAR1A genes, and exons 2 and 3 of HRAS, KRAS and NRAS were amplified by PCR and sequenced. Previously unreported mutants were cloned in expression vectors and their basal constitutive activities were determined by quantification of cAMP response element (CRE)-luciferase activity in CO7 cells transfected with wild-type and mutant plasmids. Results: TSHR gene mutations were found in 52 (61.2%) samples, GNAS gene mutations in 4 (4.71%) samples and no PRKAR1A or RAS mutations were found. Only three previously unreported mutations were found, two affecting the TSHR, A623F and I635V, and one affecting the G-protein a-subunit (Gsa), L203P. All mutant proteins showed higher CRE-luciferase activity than their wild-type counterparts. Conclusions: TA in a hyperthyroid population living in Galicia, a Spanish iodine-deficient region, harbours elevated frequencies of TSHR and GNAS mutations activating the cAMP pathway. However, the genetic cause of TA was undetermined in 34% of the TA samples.European Journal of Endocrinology 159 623-631

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Section: Discussionmentioning

confidence: 99%

Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain

Palos-Paz

Perez-Guerra²,

Cameselle-Teijeiro³

et al. 2008

European Journal of Endocrinology

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“…TSH-suppressed DTC patients might have better conditions for an advantageous effect of a TSHR variant with an increased sensitivity because in a state of lower serum TSH concentration, a more sensitive TSHR could attribute to efficient local TSH effects. However, the functional significance of the TSHR-Asp727Glu allele has not yet been disentangled in all details (35,36,37). A TSHR-mediated mechanism was proposed to be involved in stimulation of D2 expression by TSH in rat astroglial cells, cultured rat brown adipose tissue, and human osteoblasts (7,8,15).…”

Section: Discussionmentioning

confidence: 99%

Fatigue and fatigue-related symptoms in patients treated for different causes of hypothyroidism

Louwerens

Appelhof

Verloop

et al. 2012

European Journal of Endocrinology

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Objective: Research on determinants of well-being in patients on thyroid hormone replacement therapy is warranted, as persistent fatigue-related complaints are common in this population. In this study, we evaluated the impact of different states of hypothyroidism on fatigue and fatigue-related symptoms. Furthermore, the relationship between fatigue and the TSH receptor (TSHR)-Asp727Glu polymorphism, a common genetic variant of the TSHR, was analyzed. Design: A cross-sectional study was performed in 278 patients (140 patients treated for differentiated thyroid carcinoma (DTC) and 138 with autoimmune hypothyroidism (AIH)) genotyped for the TSHR-Asp727Glu polymorphism. Methods: The multidimensional fatigue inventory (MFI-20) was used to assess fatigue, with higher MFI-20 scores indicating more fatigue-related complaints. MFI-20 scores were related to disease status and Asp727Glu polymorphism status. Results: AIH patients scored significantly higher than DTC patients on all five MFI-20 subscales (P!0.001), independent of clinical and thyroid hormone parameters. The frequency of the TSHR-Glu727 allele was 7.2%. Heterozygous DTC patients had more favorable MFI-20 scores than wild-type DTC patients on four of five subscales. The modest effect of the TSHR-Asp727Glu polymorphism on fatigue was found in DTC patients only. Conclusions: AIH patients had significantly higher levels of fatigue compared with DTC patients, which could not be attributed to clinical or thyroid hormone parameters. The modest effect of the TSHR-Asp727Glu polymorphism on fatigue in DTC patients should be confirmed in other cohorts.

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“…This could point toward a higher sensitivity of the variant versus the wild-type TSHR, since less TSH is needed to produce normal FT4 levels. Although there is one in vitro study showing that the TSHR-Glu727 variant results in an increased cAMP response of the receptor to TSH (11), others have not been able to replicate this (20,21). A different explanation would be that the Asp727Glu polymorphism is linked to another polymorphism elsewhere in the gene.…”

Section: Polymorphisms In the Tsh Receptormentioning

confidence: 99%

Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases

2006

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Serum thyroid parameters show substantial inter-individual variability, in which genetic variation is a major factor. Findings in patients with subclinical hyper-and hypothyroidism illustrate that even minor alterations in serum thyroid function tests can have important consequences for a variety of thyroid hormone-related clinical endpoints, such as atherosclerosis, bone mineral density, obesity, and heart rate. In the last few years, several studies described polymorphisms in thyroid hormone pathway genes that alter serum thyroid function tests. In this review, we discuss the genetic variation in the TSH receptor and iodothyronine deiodinases. We discuss the possible consequences of these studies for the individual patient and also the new insights in thyroid hormone action that can be obtained from these data.European Journal of Endocrinology 155 655-662

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Functional significance of the thyrotropin receptor germline polymorphism D727E

Cited by 31 publications

References 23 publications

Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain

Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain

Fatigue and fatigue-related symptoms in patients treated for different causes of hypothyroidism

Genetic variation in thyroid hormone pathway genes; polymorphisms in the TSH receptor and the iodothyronine deiodinases

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