dc.contributor.author
Kalveram, Laura
dc.contributor.author
Kleinau, Gunnar
dc.contributor.author
Szymańska, Kamila
dc.contributor.author
Scheerer, Patrick
dc.contributor.author
Rivero-Müller, Adolfo
dc.contributor.author
Grüters-Kieslich, Annette
dc.contributor.author
Biebermann, Heike
dc.date.accessioned
2020-01-21T11:48:34Z
dc.date.available
2020-01-21T11:48:34Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/26476
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-26236
dc.description.abstract
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.
en
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
central congenital hypothyroidism
en
dc.subject
G-protein coupled receptors
en
dc.subject
thyroid-stimulating hormone
en
dc.subject.ddc
600 Technik, Medizin, angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
dc.title
The Pathogenic TSH β-Subunit Variant C105Vfs114X Causes a Modified Signaling Profile at TSHR
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
5564
dcterms.bibliographicCitation.doi
10.3390/ijms20225564
dcterms.bibliographicCitation.journaltitle
International Journal of Molecular Sciences
dcterms.bibliographicCitation.number
22
dcterms.bibliographicCitation.originalpublishername
MDPI AG
dcterms.bibliographicCitation.volume
20
refubium.affiliation
Charité - Universitätsmedizin Berlin
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.bibliographicCitation.pmid
31703413
dcterms.isPartOf.eissn
1422-0067