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Thyrotropin receptor mutations in hyperfunctioning thyroid adenomas: new mutants, new second messenger and new frequency

Activation of the cAMP pathway by TSH stimulates both cell proliferation and differentiation of thyrocytes. TSH is known to bind to a seven transmembrane receptor, coupled to heterotrimeric G proteins. Adenylate cyclase activity is increased by TSH through activation of Gs. But the human TSH receptor also activates the phospholipase C-diacylglycerol-inositol phosphate cascade. Hyperfunctioning thyroid adenomas are monoclonal and their growth and functional activity are TSH-independent. Therefore, somatic activating mutations in genes encoding proteins of the TSH signaling pathway (mainly the cAMP-regulatory cascade) were expected in these tumors. GaS activating mutations leading to TSH-independent constitutive adenylate cyclase activity were the first to be described. More recently, activating point mutations of TSH receptor were reported. The mutations studied initially cause constitutive activation of the cAMP-regulatory cascade only, without stimulation of the inositol phosphate-diacylglycerol one. The effect of TSH receptor and Gas mutations is dominant. TSH receptor activating mutations have been found