PTH1R Mutants Found in Patients with Primary Failure of Tooth Eruption Disrupt G-Protein Signaling

Please always quote using this URN: urn:nbn:de:bvb:20-opus-147967
  • Aim Primary failure of tooth eruption (PFE) is causally linked to heterozygous mutations of the parathyroid hormone receptor (PTH1R) gene. The mutants described so far lead to exchange of amino acids or truncation of the protein that may result in structural changes of the expressed PTH1R. However, functional effects of these mutations have not been investigated yet. Materials and Methods In HEK293 cells, PTH1R wild type was co-transfected with selected PTH1R mutants identified in patients with PFE. The effects on activation ofAim Primary failure of tooth eruption (PFE) is causally linked to heterozygous mutations of the parathyroid hormone receptor (PTH1R) gene. The mutants described so far lead to exchange of amino acids or truncation of the protein that may result in structural changes of the expressed PTH1R. However, functional effects of these mutations have not been investigated yet. Materials and Methods In HEK293 cells, PTH1R wild type was co-transfected with selected PTH1R mutants identified in patients with PFE. The effects on activation of PTH-regulated intracellular signaling pathways were analyzed by ELISA and Western immunoblotting. Differential effects of wild type and mutated PTH1R on TRESK ion channel regulation were analyzed by electrophysiological recordings in Xenopus laevis oocytes. Results In HEK293 cells, activation of PTH1R wild type increases cAMP and in response activates cAMP-stimulated protein kinase as detected by phosphorylation of the vasodilator stimulated phosphoprotein (VASP). In contrast, the PTH1R mutants are functionally inactive and mutant PTH1R/Gly452Glu has a dominant negative effect on the signaling of PTH1R wild type. Confocal imaging revealed that wild type PTH1R is expressed on the cell surface, whereas PTH1R/Gly452Glu mutant is mostly retained inside the cell. Furthermore, in contrast to wild type PTH1R which substantially augmented K+ currents of TRESK channels, coupling of mutated PTH1R to TRESK channels was completely abolished. Conclusions PTH1R mutations affect intracellular PTH-regulated signaling in vitro. In patients with primary failure of tooth eruption defective signaling of PTH1R mutations is suggested to occur in dento-alveolar cells and thus may lead to impaired tooth movement.show moreshow less

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Author: Hariharan Subramanian, Frank Döring, Sina Kollert, Natalia Rukoyatkina, Julia Sturm, Stepan Gambaryan, Angelika Stellzig-Eisenhauer, Philipp Meyer-Marcotty, Martin Eigenthaler, Erhard Wischmeyer
URN:urn:nbn:de:bvb:20-opus-147967
Document Type:Journal article
Faculties:Medizinische Fakultät / Institut für Klinische Biochemie und Pathobiochemie
Medizinische Fakultät / Physiologisches Institut
Medizinische Fakultät / Poliklinik für Kieferorthopädie
Language:English
Parent Title (English):PLoS One
Year of Completion:2016
Volume:11
Issue:11
Pagenumber:e0167033
Source:PLoS ONE 11(11): e0167033. https://doi.org/10.1371/journal.pone.0167033
DOI:https://doi.org/10.1371/journal.pone.0167033
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 617 Chirurgie und verwandte medizinische Fachrichtungen
Tag:calcium signaling; intracellular receptors; mutation; phosphorylation; teeth; tooth eruption; transfection; xenopus oocytes
Release Date:2017/06/08
Collections:Open-Access-Publikationsfonds / Förderzeitraum 2016
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung