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Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas

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Abstract

THE pituitary hormone thyrotropin stimulates the function, expression of differentiation and growth of thyrocytes by cyclic AMP-dependent mechanisms1–3. Tissue hyperplasia and hyperthyroidism are therefore expected to result when activation of the adenylyl cyclase–cAMP cascade is unregulated. This is observed in several situations4,5, including when somatic mutations impair the GTPase activity of the G protein Gsα (refs 6, 7). Such a mechanism is probably responsible for the development of a minority of monoclonal hyperfunctioning thyroid adenomas6,8,9. Here we identify somatic mutations in the carboxv-terminal portion of the third cytoplasmic loop of the thyrotropin receptor in three out of eleven hyperfunctioning thyroid adenomas. These mutations are restricted to tumour tissue and involve two different residues (aspartic acid at position 619 to glycine in two cases, and alanine at position 623 to isoleucine in one case). The mutant receptors confer constitutive activation of adenylyl cyclase when tested by transfection in COS cells. This shows that G-protein-coupled receptors are susceptible to constitutive activation by spontaneous somatic mutations10,11 and may thus behave as proto-oncogenes.

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Authors and Affiliations

  1. Institut de Recherche Interdisciplinaire, Faculty of Medicine, University of Brussels, Campus Erasme, 808 route de Lennik, 1070, Brussels, Belgium

    Jasmine Parma, Laurence Duprez, Jacqueline Van Sande, Pascale Cochaux, Christine Gervy, Jean Mockel, Jacques Dumont & Gilbert Vassart

  2. Service de Génétique Médicale, Faculty of Medicine, University of Brussels, Campus Erasme, 808 route de Lennik, 1070, Brussels, Belgium

    Pascale Cochaux & Gilbert Vassart

Authors
  1. Jasmine Parma
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  2. Laurence Duprez
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  3. Jacqueline Van Sande
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  4. Pascale Cochaux
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  5. Christine Gervy
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  6. Jean Mockel
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  7. Jacques Dumont
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  8. Gilbert Vassart
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Parma, J., Duprez, L., Sande, J. et al. Somatic mutations in the thyrotropin receptor gene cause hyperfunctioning thyroid adenomas. Nature 365, 649–651 (1993). https://doi.org/10.1038/365649a0

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