A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism

Alberti, Luisella; Proverbio, Maria Carla; Costagliola, Sabine; Weber, Giovanna; Beck‐Peccoz, Paolo; Chiumello, G; Persani, Luca

doi:10.1530/eje.0.1450249

Cited by 39 publications

(34 citation statements)

References 25 publications

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“…This effect was accompanied by a strong increase in the levels of cyclin D1 and histone H3 phosphorylation at Ser10, two cell proliferation markers ( Figure 3E). In addition, we compared the effects of transient EZH1 transfection in 2 FRT clones stably expressing the WT TSHR or an activating TSHR mutant (V597F) (20). In contrast to transfection of WT EZH1, which had only a moderate proliferative effect, transfection of the mutant EZH1 caused a strong increase of cell proliferation in both cell lines (Supplemental Figure 5).…”

Section: Resultsmentioning

confidence: 99%

Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

Calebiro¹,

Grassi²,

Eszlinger³

et al. 2016

Journal of Clinical Investigation

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Section: Resultsmentioning

confidence: 99%

Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

Calebiro¹,

Grassi²,

Eszlinger³

et al. 2016

Journal of Clinical Investigation

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“…Dietary iodine intake may also contribute to the wide range in age of onset of symptoms reported in families harbouring the same activating germline TSHR mutations (Alberti et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Biological activity of activating thyrotrophin receptor mutants: modulation by iodide

Al-Khafaji¹,

Wiltshire²,

Führer³

et al. 2005

Journal of Molecular Endocrinology

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Epidemiological studies have revealed a significantly higher incidence of toxic adenoma (TA) and toxic multi-nodular goitre (TMNG) in regions of iodine deficiency. Fifty to eighty percent of TA and TMNG are caused by activation of the cAMP pathway, mostly by mutations in the thyrotrophin receptor (TSHR).We aimed to investigate whether iodide could modulate the biological effects of activating TSHR mutations. We have applied an in vitro model of TA comprising FRTL-5 cells stably expressing activating TSHR. We have mimicked the in vivo situation by examining the effects of prolonged exposure to iodide on the proliferation and signal transduction etc. of these cells.We observed an iodide-induced 'inhibition of proliferation' which was significant from 10 mM in the presence of serum but from 1 mM in its absence. The inhibition of proliferation was significantly higher in the activating mutant expressing FRTL-5 compared with control Neo or wild-type TSHR, indicating that the effect was mediated via the cAMP cascade. The effect was neither due to hyper-tonicity nor was it the result of an increase in cell death either by apoptosis or necrosis. Prolonged exposure to iodide produces an increase in cells in the G2 and post-G2 phases, indicating that G2/M blockade contributes to the mechanism of inhibition.The mutant expressing FRTL-5 cells have increased proliferation when chronically exposed to TSH, and this is associated with a reduction in phosphorylated (p) CREB levels. This contrasts with the effect of iodide in which inhibition of proliferation is accompanied by an increase in pCREB.In conclusion, our studies indicate that the biological effects of activating TSHR mutations vary with the ambient iodide supply and could be masked in regions of high iodine intake.

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“…They are summarized in table 1[3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23]. Almost all mutations are located in the transmembrane domain of the TSH receptor protein which is encoded by exon 10.…”

Section: Discussionmentioning

confidence: 99%

Long-Term Carbimazole Treatment of Neonatal Nonautoimmune Hyperthyroidism due to a New Activating TSH Receptor Gene Mutation (Ala428Val)

et al. 2005

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Background: Hereditary nonautoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin receptor gene. Antithyroid treatment failed to control hyperthyroidism in most cases, so that primary thyroid ablation or ¹³¹I therapy is advocated as the preferred treatment of choice. Patient/Methods: We describe a case of neonatal nonautoimmune hyperthyroidism treated with carbimazole. Molecular analysis revealed a new heterozygous point mutation (A428V) in the TSH receptor (TSHR) gene. Result: Antithyroid treatment was successful in controlling hyperthyroidism for the first 5.9 years of age. Conclusion: We conclude that carbimazole therapy is effective in treating nonautoimmune hyperthyroidism. It may be an alternative to thyroidectomy or radioiodine treatment.

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A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism

Cited by 39 publications

References 25 publications

Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

Recurrent EZH1 mutations are a second hit in autonomous thyroid adenomas

Biological activity of activating thyrotrophin receptor mutants: modulation by iodide

Long-Term Carbimazole Treatment of Neonatal Nonautoimmune Hyperthyroidism due to a New Activating TSH Receptor Gene Mutation (Ala428Val)

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