Nature Genetics
7, 396 - 401 (1994)
doi:10.1038/ng0794-396
Germline mutations in the thyrotropin receptor gene cause non−autoimmune autosomal dominant hyperthyroidismLaurence Duprez1, *, Jasmine Parma1, 6, *, Jacqueline Van Sande1, *, Anouk Allgeier1, Jacques Leclère2, Claire Schvartz3, Marie-Joëlle Delisle3, Marc Decoulx4, Jacques Orgiazzi5, Jacques Dumont1
& Gilbert Vassart1, 6, 7
1Institut de Recherche Interdisciplinaire, Faculty of Medicine, University of Brussels, Belgium
2Service d'Endocrinologie, Centre Hospitalier Universitaire, Nancy, France;
3Unité de Médecine Nucléaire et de Biophysique, Institut Jean Godinot, Reims, France
4Service de Clinique Médicale, Centre Hospitalier Régional et Universitaire de Lille, France
5Service de Médecine Interne, Centre Hospitaller de Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite Cedex
6Service de Génétique médicale, Université Libre de Bruxelles, Campus Erasme, 808 route de Lennik, 1070 Brussels, Belgium
7Correspondence should be addressed to G.V. The thyrotropin receptor (TSHR), a member of the large family of G protein−coupled receptors, controls both the function and growth of thyroid cells via stimulation of adenylyl cyclase. We report two different mutations in the TSHR gene of affected members of two large pedigrees with non−autoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia), that involve residues in the third (Val509Ala) and seventh (Cys672Tyr) transmembrane segments. When expressed by transfection in COS−7 cells, the mutated receptors display a higher constitutive activation of adenylyl cyclase than wild type. This new disease entity is the germline counterpart of hyperfunctioning thyroid adenomas, in which different somatic mutations with similar functional characteristics have been demonstrated.
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