A novel brachydactyly type E syndrome caused by variants in helix 8 of the PTH1R

The parathyroid hormone receptor 1 (PTH1R) transmits stimuli provided by PTH and PTH-related protein (PTHrP) and thus plays key roles in calcium and phosphate homeostasis as well as skeletal development. Variants in PTH1R have been linked to several conditions, including Jansen metaphyseal chondrodysplasia, Blomstrand chondrodysplasia, primary failure of tooth eruption, and Eiken syndrome. Here, we report a novel skeletal phenotype identified in two unrelated families associated with PTH1R variants. The clinical features include brachydactyly type E, mild short stature, and dental anomalies. A novel heterozygous PTH1R substitution (p.E469K) was identified in affected members of Family 1, while the affected individual from Family 2 had a previously described heterozygous de novo substitution (p.E465K); these two mutated sites lie within helix 8 (H8) of the PTH1R. Cell-based assays revealed reduced cell surface expression, as well as impaired basal and PTH- or PTHrP-induced cAMP signaling responses for both mutants, as compared to WT-PTH1R. Introduction of the p.E469K substitution into humanized PTH1R mice resulted in mildly increased mineralization of bones in the paws as well as shortening of long bones. Our findings demonstrate a new skeletal phenotype associated with PTH1R variants and suggest that H8 of the receptor contributes to PTH1R expression and/or signaling during bone development.