GERMLINE MUTATIONS IN THE THYROTROPIN RECEPTOR GENE CAUSE NON-AUTOIMMUNE AUTOSOMAL-DOMINANT HYPERTHYROIDISM

The thyrotropin receptor (TSHR), a member of the large family of G pro tein-coupled receptors, controls both the function and growth of thyro id 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 seven th (Cys672Tyr) transmembrane segments. When expressed by transfection in COS-7 cells, the mutated receptors display a higher constitutive ac tivation of adenylyl cyclase than wild type. This new disease entity i s the germline counterpart of hyperfunctioning thyroid adenomas, in wh ich different somatic mutations with similar functional characteristic s have been demonstrated.