Altered Signaling and Desensitization Responses in PTH1R Mutants Associated with Eiken Syndrome

The parathyroid hormone receptor type 1 (PTH1R) is a G protein-coupled receptor that plays key roles in regulating calcium homeostasis and skeletal development via binding the ligands, PTH and PTH-related protein (PTHrP), respectively. Eiken syndrome is a rare disease of delayed bone mineralization caused by homozygous PTH1R mutations. Of the three mutations identified so far, R485X, truncates the PTH1R C-terminal tail, while E35K and Y134S alter residues in the receptor's amino-terminal extracellular domain. Here, using a variety of cell-based assays, we show that R485X increases the receptor's basal rate of cAMP signaling and decreases its capacity to recruit beta-arrestin2 upon ligand stimulation. The E35K and Y134S mutations each weaken the binding of PTHrP leading to impaired beta-arrestin2 recruitment and desensitization of cAMP signaling response to PTHrP but not PTH. Our findings support a critical role for interaction with beta-arrestin in the mechanism by which the PTH1R regulates bone formation. Three mutations in parathyroid hormone receptor type 1 which are present in patients with Eiken syndrome are shown to influence cAMP signaling and beta-arrestin recruitment via gain-of-function effects.

Automated summary

Three mutations in the PTH1R gene have been identified in patients with Eiken syndrome, resulting in altered cAMP signaling and impaired recruitment of beta-arrestin2. These findings highlight the critical role of PTH1R-beta-arrestin interaction in regulating bone formation.