Oncogenic mutations in the thyrotropin receptor of autonomously functioning thyroid nodules in the Japanese population

Vanvooren, Vanessa; Uchino, Shigehiko; Duprez, Laurence; Costa, M. J.; Vandekerckhove, J; Parma, Jasmine; Vassart, Gilbert; Je, Dumont; Sande, Jacqueline Van; Noguchi, S

doi:10.1530/eje.0.1470287

Cited by 29 publications

(33 citation statements)

References 30 publications

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“…In Europe and Japan, one of the main mechanisms responsible for the hyperfunction and growth of thyroid autonomous adenomas is the constitutive activation of the cAMP-dependent mitogenic cascade, through mutations conferring constitutive activity of the TSH receptor (50-80%) or an activating mutation of G sa (8%) (Russo et al, 1995;Van Sande et al, 1995;Fuhrer et al, 1997;Tonacchera et al, 1999;Vanvooren et al, 2002). Similar mutations account for hyperfunctioning nodules in multinodular goiters (Tonacchera et al, 1999(Tonacchera et al, , 2000Krohn et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Wattel¹,

Mircescu²,

Venet³

et al. 2005

Oncogene

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The purpose of this study was to use the microarray technology to define expression profiles characteristic of thyroid autonomous adenomas and relate these findings to physiological mechanisms. Experiments were performed on a series of separated adenomas and their normal counterparts on Micromax cDNA microarrays covering 2400 genes (analysis I), and on a pool of adenomatous tissues and their corresponding normal counterparts using microarrays of 18 000 spots (analysis II). Results for genes present on the two arrays corroborated and several gene regulations previously determined by Northern blotting or microarrays in similar lesions were confirmed. Five overexpressed and 24 underexpressed genes were also confirmed by real-time RT-PCR in some of the samples used for microarray analysis, and in additional tumor specimens. Our results show: (1) a change in the cell populations of the tumor, with a marked decrease in lymphocytes and blood cells and an increase in endothelial cells. The latter increase would correspond to the establishment of a close relation between thyrocytes and endothelial cells and is related to increased N-cadherin expression. It explains the increased blood flow in the tumor; (2) a homogeneity of tumor samples correlating with their common physiopathological mechanism: the constitutive activation of the thyrotropin (TSH)/cAMP cascade; (3) a low proportion of regulated genes consistent with the concept of a minimal deviation tumor; (4) a higher expression of genes coding for specific functional proteins, consistent with the functional hyperactivity of the tumors; (5) an increase of phosphodiesterase gene expression which explains the relatively low cyclic AMP levels measured in these tumors; (6) an overexpression of antiapoptotic genes and underexpression of proapoptotic genes compatible with their low apoptosis rate; (7) an overexpression of N-cadherin and downregulation of caveolins, which casts doubt about the use of these expressions as markers for malignancy.Oncogene (2005) 24, 6902-6916.

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Section: Introductionmentioning

confidence: 99%

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Wattel¹,

Mircescu²,

Venet³

et al. 2005

Oncogene

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“…However, Kosugi et al analyzed the entire exon 10 of the TSHR gene and found the first activating mutation in the TSHR gene in a Japanese patient with AFTN [17]. Vanvooren et al consistently identified four mutations in the TSHR gene in 10 Japanese AFTN patients and thus suggested that activating mutations in the TSHR gene may not be rare in the Japanese population [18]. In contrast to the TSHR gene, the incidence of the mutations in Gsα is reportedly low in Europe as well as in Japan [18][19][20]22].…”

Section: Discussionmentioning

confidence: 99%

“…The polymerase chain reaction (PCR) was performed in a 25 µl reaction volume containing 100-200 ng of genomic DNA, 10 pmol of each upstream and downstream primer, 1.25 units of Taq polymerase (Takara, Otsu, Japan), 0.2 mM each dNTP, and 2 mM MgCl 2 . All the reactions were started by an initial denaturation at 95°C for 5 min (except for exon 9 of TSHR at 93°C for 2 min 30 sec and exon 10 of TSHR at 94°C for 2 min), followed by 35 cycles of denaturation at 94°C for 30 sec, annealing at 55°C for 30 sec (except for exon 9 of TSHR at 61°C for 30 sec) and extension at 72°C for 1 min [17,18,22]. Aliquots of PCR products were run in 1% agarose gel electrophoresis and visualized with ethidium bromide to verify their quality.…”

Section: Sequencing Of the Tshr And Gsα Genesmentioning

confidence: 99%

“…TSH binds to its receptor (TSHR) and activates the α-subunit of the stimulatory G protein (Gsα), leading to adenylate cyclase (AC) activation and subsequently cyclic AMP (cAMP) production. In autonomously functioning thyroid nodule (AFTN), which is characterized by autonomous, TSH-independent hypersecretion of thyroid hormones, gain-of-function mutations have been identified in TSHR and Gsα genes [17][18][19][20]. These mutations result in the constitutive activation of the AC-cAMP pathway, leading to cellular hyperfunction and proliferation.…”

mentioning

confidence: 99%

“…Here we report a case with AFTN who suffered from attacks of TPP. In addition, we analyzed mutations in exons 9 and 10 of the TSHR gene and exons 8 and 9 of Gsα gene, which are frequently detected in AFTN from European countries [18][19][20], as well as mutations in CACNA1S and KCNE3, which are identified as the cause of FHPP [5,6,8].…”

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Autonomously Functioning Thyroid Nodule Associated with Thyrotoxic Periodic Paralysis

et al. 2008

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Abstract. Thyrotoxic periodic paralysis (TPP) is mainly associated with Graves' disease but rarely with autonomously functioning thyroid nodule (AFTN). We herein report a case of AFTN associated with TPP in which the latter resolved after 131 I therapy for the former. We analyzed the genes encoding thyrotropin receptor (TSHR), the α-subunit of the stimulatory G protein (Gsα), calcium channel CACNA1S and potassium channel KCNE3, and found that the patient does not carry the known mutations in these genes. Whereas the pathogenesis of TPP and AFTN remains to be understood, the present case suggests that ion channel defects responsible for familial hypokalemic periodic paralysis may not be associated with TPP, and that mutations in TSHR and Gsα genes may be less frequent in AFTN patients in the Japanese population.

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United detection GNAS and TSHR mutations in subclinical toxic multinodular goiter

Liu

Yang

Wang

et al. 2009

Eur Arch Otorhinolaryngol

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The aim of the study was to investigate whether the mutations of the GNAS gene and thyroid-stimulating hormone receptor (TSHR) gene were a potential molecular biological mechanism for subclinical toxic multinodular goiter (sTMG) and to evaluate the association of these mutations with the clinicopathological features of these disorders.Forty-four patients with sTMG and 20 controls(multinodular goiter) from Heilongjiang province of China who underwent subtotal thyroidectomy were recruited. Genes' mutations were analyzed by direct DNA sequencing of the polymerase chain reaction-amplified the parts of exons. In sTMG group, three mutations at GNAS gene were identified in seven patients (15.9%). Six mutations at TSHR gene were identified in 14 patients (31.8%). Mutation positivity of TSHR gene had statistically significant by comparison of two groups. In sTMG group, the mutation positivity of patients with serum TSH level below 0.1 microU/ml and above 0.01 microU/ml is obviously different (P < 0.05) at TSHR gene. However, these statistically significant differences were both not being seen at GNAS gene, and patients with nodules before universal salt iodization (USI)and after USI (P > 0.05). Mutation positivity of TSHR gene has a relation with sTMG. It is more probable that serum TSH level play an important role in mutagenesis.

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Oncogenic mutations in the thyrotropin receptor of autonomously functioning thyroid nodules in the Japanese population

Cited by 29 publications

References 30 publications

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology

Autonomously Functioning Thyroid Nodule Associated with Thyrotoxic Periodic Paralysis

United detection GNAS and TSHR mutations in subclinical toxic multinodular goiter

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