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August 19, 2025Open Access

Human diseases caused by homozygous PTH1R mutations

Key Points

Homozygous mutations in PTH1R can result in conditions like Blomstrand's lethal chondrodysplasia, which leads to severe skeletal issues.
Patients with milder PTH1R mutations show variable skeletal abnormalities, including delayed ossification and hypocalcemia.
Detailed pharmacologic studies of PTH1R mutations have illuminated how minor changes in receptor function can lead to significant disease.
Understanding PTH1R's role may help inform treatments for skeletal conditions caused by these mutations.

Abstract

The parathyroid hormone receptor type 1 (PTH1R) is a G protein-coupled receptor that mediates the actions of parathyroid hormone (PTH) in the regulation of blood calcium levels, as well as PTH-related protein (PTHrP) in the regulation of skeletal development. Severe loss-of-function homozygous mutations in PTH1R are incompatible with life as in Blomstrand’s lethal chondrodysplasia, characterized by accelerated growth plate ossification. More recently, homozygous mutations located in the transmembrane helices, extracellular domains and C-tail of the PTH1R were identified in patients with milder conditions characterized by variable degrees of skeletal and mineral abnormalities. These include delayed ossification in Eiken syndrome, hypocalcemia in a pseudohypoparathyroidism-like disorder, and non-syndromic primary failure of tooth eruption; which is usually caused by heterozygous PTH1R mutations. Recent detailed pharmacologic characterization of these PTH1R mutants has revealed new insights into how even subtle perturbations in PTH1R function can result in disease.

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