BACKGROUND: Primary failure of eruption (PFE) is a rare disorder characterized by a posterior open bite. While mutations in the parathyroid hormone 1 receptor (PTH1R) gene have been demonstrated to cause PFE, the underlying mechanisms remain largely unknown. METHODS: Whole exome sequencing was conducted to identify PTH1R variants in a PFE family. MG63 cells that stably expressed the corresponding mutant PTH1R were established using lentiviruses. Next, osteogenesis was assessed by measuring cell alkaline phosphatase activity, conducting alizarin red staining, and evaluating osteoblast-specific gene expression. Then, computational analysis of binding affinity and RNA sequencing were carried out. Lastly, rescue experiments were performed to validate the mechanism underlying the pathogenesis of PFE. RESULTS: A novel PTH1R missense mutation (c.904G >
A, p.E302K) was identified in a Chinese family affected by PFE. Moreover, the E302K mutation inhibited the expression of osteogenic-specific genes and proteins in MG63 cells. Computational analysis revealed the E302K mutation decreased the binding affinity of Gα CONCLUSIONS: This study indicated that the E302K mutation in PTH1R decreased the binding affinity of PTH1R protein for Gα