The PTH1R variant H442D co-segregating with PFE localizes to cell membranes but fails to elicit adequate PTH-dependent cAMP levels

BACKGROUND: Primary failure of eruption (PFE) is a rare disorder characterized by failure of teeth to erupt, which leads to severe lateral open bite. It is often caused by heterozygous mutations in the parathyroid hormone receptor (PTH1R) gene. Although a variety of PTH1R mutants has been shown to be associated with PFE, molecular disease-causing mechanism are rarely identified. FINDINGS: We here describe a co-segregation study and the cell biological characterisation of the PTH1R variant H442D that hitherto has been classified as of uncertain clinical significance. In a cohort study, we show that the H442D variant segregates with PFE. Moreover, while it displays correct localization to cell membranes, it evokes only modest levels of the downstream second messenger cAMP upon stimulation with PTH. CONCLUSIONS: Our study provides a molecular mechanism for the co-segregation of the PTH1R variant H442D with PFE. The decreased PTH-dependent cAMP signal may be causative for the observed PFE phenotype in subjects carrying this heterozygous mutation.