We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Lack of in vitro constitutive activity for four previously reported TSH receptor mutations identified in patients with nonautoimmune hyperthyroidism and hot thyroid carcinomas H. Jaeschke et al. TSHR mutations in thyroid disease.
- Authors
Jaeschke, Holger; Mueller, Sandra; Eszlinger, Markus; Paschke, Ralf
- Abstract
Constitutively activating mutations (CAMs) of the TSHR are the major cause for nonautoimmune hyperthyroidism. Re-examination of constitutive activity previously determined in CHO cell lines recently demonstrated the caveats for the in vitro determination of constitutive TSHR activity, which leads to false positive conclusions regarding the molecular origin of hyperthyroidism or hot thyroid carcinomas. Mutations L677V and T620I identified in hot thyroid carcinomas were previously characterized in CHO and in 3T3-Vill cell lines, respectively, stably expressing the mutant without determination of TSHR expression. F666L identified in a patient with hot thyroid nodules, I691F in a family with nonautoimmune hyperthyroidism and F631I identified in a hot thyroid carcinoma were not characterized for their in vitro function. Therefore, we decided to (re)evaluate the in vitro function of these five TSHR variants by determination of cell surface expression, and intracellular cAMP and inositol phosphate levels and performed additionally linear regression analyses to determine basal activity independently from the mutant's cell surface expression in COS-7 and HEK cells. Only one (F631I) of the five investigated TSHR variants displayed constitutive activity for Gs signalling and showed correlation with the clinical phenotype. The previous false classification of T620I and L677V as CAMs is most likely related to the fact that both mutations were characterized in cell lines stably expressing the mutated receptor construct without assessing the respective receptor number per cell. Other molecular aetiologies for the nonautoimmune hyperthyroidism and/or hot thyroid carcinomas in these three patients and one family should be elucidated.
- Subjects
HYPERTHYROIDISM; THYROID diseases; THYROID cancer; INOSITOL phosphates; PHENOTYPES; GENOTYPE-environment interaction; ETIOLOGY of diseases
- Publication
Clinical Endocrinology, 2010, Vol 73, Issue 6, p815
- ISSN
0300-0664
- Publication type
Article
- DOI
10.1111/j.1365-2265.2010.03872.x