Activating mutations of the thyrotropin receptor--unanswered questions

Abstract

The cloning of the TSH receptor (TSHr) in 1989-1990 was a seminal event in thyroidology. Much has been learned regarding the pathogenesis of a variety of thyroid diseases since that milestone. In recent months, it has become apparent that specific mutations of TSHr involving the transmembrane domain result in the expression of an altered receptor protein that possesses constitutive activity, i.e. increased signal transduction in the absence of its hormone ligand (l-3). These anomalous receptors are the apparent cause of some autonomously functioning thyroid nodules, where they appear as somatic mutations. More recently, germ line transmission of these mutations was found in families of patients with congenital, nonimmune hyperthyroidism (toxic thyroid hyperplasia, TTH) (4-6). In the current issue of JCEM (see page 0000), de Roux et al. describe an infant suffering from congenital, nonimmune hyperthyroidism (7). Following polymerase chain reaction (PCR) amplification of genomic DNA followed by direct sequence analysis, the authors showed that the infant expressed a TSH receptor gene containing a mutation within the second membrane-spanning segment of the transmembrane domain. Neither parent possessed the abnormal codon, indicating that the event was, in this case, a spontaneous mutation in the infant. When expressed in vitro, this mutant receptor demonstrated constitutive activity, similar to that described previously in other cases of congenital, nonimmune hyperthyroidism and autonomously functioning thyroid nodules (AFTN). The importance of the finding in this patient, other than the description of yet another mutation resulting in the phenotype, is that it is the first reported involving the second transmembrane segment, thereby expanding regions of the receptor harboring activating mutations. To date, all of the mutations found in patients with AFTN or TTH have been confined to exon 10, which codes for the entire transmembrane domain (TMD) of the receptor as well as the carboxyl terminal portion of the extracellular domain. As of the writing of this review, 13 distinct amino acid substitutions within the TMD that result in expression of a constitutively active TSH receptor and the phenotype of hyperthyroidism have been described. The locations of these mutations are well scattered across the TMD and involve the second, third, sixth, and seventh membrane-spanning segments as well as the first and second extracellular and the third intracellular loops (6, 7). Mutations within the large extracellular domain encoded by exons l-9 have also been described (8,9). However, none of these later alterations have