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The First Activating TSH Receptor Mutation in Transmembrane Domain 1 Identified in a Family with Nonautoimmune Hyperthyroidism

Otto Heubner Centrum für Kinderheilkunde und Jugendmedizin, Pädiatrische Endokrinologie; Charité Campus Virchow Klinikum, Humboldt Universität zu Berlin (H.B., A.G.), 13353 Berlin, Germany; Institut für Pharmakologie, Universitätsklinikum Benjamin Franklin, Freie Universität Berlin (T.S.), 14195 Berlin, Germany; Division of Endocrinology, Department of Pediatrics, Ohio State University (J.G.), Columbus, Ohio 43205; and Institut für Pharmakologie und Toxikologie, Fachbereich Humanmedizin, Philipps Universität Marburg (C.H., T.G.), 35033 Marburg, Germany

Address all correspondence and requests for reprints to: Dr. Annette Grüters, Otto Heubner Centrum für Kinderheilkunde und Jugendmedizin Pädiatrische Endorinologie, Charité Campus Virchow Klinikum, Humboldt Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: annette.grueters{at}charite.de

Abstract

Sporadic and familial nonautoimmune hyperthyroidism are very rarely occurring diseases. Within the last years constitutively activating TSH receptor mutations were identified as one possible pathomechanism. Except for S281N in the extracellular N-terminal domain, all other germline mutations are located in the transmembrane domains 2, 3, 5, 6, and 7 of the TSH receptor, whereas no mutation was reported in transmembrane domains 1 and 4 to date. Here we report the first family with a constitutively active TSHR mutation in transmembrane domain 1 resulting in a substitution of the conserved Gly⁴³¹ for Ser. This mutation was found in the investigated patient, his father, and the paternal grandmother. As known from other familial cases of nonautoimmune hyperthyroidism, the age of onset of the disease was variable, ranging from early childhood in the patient and his father to adolescence in the grandmother. Functional characterization of this mutation showed a constitutive activation of the G_s/adenylyl cyclase system. Moreover, this germline mutation also activates the G_q/11/phospholipase C pathway. The importance of Gly⁴³¹ for receptor quiescence is supported further by introduction of other mutations at this position, all leading to constitutive receptor activity. Our data show now that constitutively activating mutations can be found in the entire transmembrane domain region of the TSH receptor, indicating the important role of all parts of the transmembrane domain region for maintaining the inactive receptor conformation.

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