دورية أكاديمية
The Pathogenic TSH β-Subunit Variant C105Vfs114X Causes a Modified Signaling Profile at TSHR
| العنوان: | The Pathogenic TSH β-Subunit Variant C105Vfs114X Causes a Modified Signaling Profile at TSHR |
|---|---|
| المؤلفون: | Laura Kalveram, Gunnar Kleinau, Kamila Szymańska, Patrick Scheerer, Adolfo Rivero-Müller, Annette Grüters-Kieslich, Heike Biebermann |
| المصدر: | International Journal of Molecular Sciences, Vol 20, Iss 22, p 5564 (2019) |
| بيانات النشر: | MDPI AG, 2019. |
| سنة النشر: | 2019 |
| المجموعة: | LCC:Biology (General) LCC:Chemistry |
| مصطلحات موضوعية: | central congenital hypothyroidism, g-protein coupled receptors, thyroid-stimulating hormone, tshr, Biology (General), QH301-705.5, Chemistry, QD1-999 |
| الوصف: | (1) Background: Central congenital hypothyroidism (CCH) is a rare endocrine disorder that can be caused by mutations in the β-subunit of thyrotropin (TSHB). The TSHB mutation C105Vfs114X leads to isolated thyroid-stimulating-hormone-(TSH)-deficiency and results in a severe phenotype. The aim of this study was to gain more insight into the underlying molecular mechanism and the functional effects of this mutation based on two assumptions: a) the three-dimensional (3D) structure of TSH should be modified with the C105V substitution, and/or b) whether the C-terminal modifications lead to signaling differences. (2) Methods: wild-type (WT) and different mutants of hTSH were generated in human embryonic kidney 293 cells (HEK293 cells) and TSH preparations were used to stimulate thyrotropin receptor (TSHR) stably transfected into follicular thyroid cancer cells (FTC133-TSHR cells) and transiently transfected into HEK293 cells. Functional characterization was performed by determination of Gs, mitogen activated protein kinase (MAPK) and Gq/11 activation. (3) Results: The patient mutation C105Vfs114X and further designed TSH mutants diminished cyclic adenosine monophosphate (cAMP) signaling activity. Surprisingly, MAPK signaling for all mutants was comparable to WT, while none of the mutants induced PLC activation. (4) Conclusion: We characterized the patient mutation C105Vfs114X concerning different signaling pathways. We identified a strong decrease of cAMP signaling induction and speculate that this could, in combination with diverse signaling regarding the other pathways, accounting for the patient’s severe phenotype. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1422-0067 |
| العلاقة: | https://www.mdpi.com/1422-0067/20/22/5564Test; https://doaj.org/toc/1422-0067Test |
| DOI: | 10.3390/ijms20225564 |
| الوصول الحر: | https://doaj.org/article/98e240326f184b89b34f78bde5d32406Test |
| رقم الانضمام: | edsdoj.98e240326f184b89b34f78bde5d32406 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14220067 |
|---|---|
| DOI: | 10.3390/ijms20225564 |