PTH1R – Jansen Metaphyseal Chondrodysplasia

Jansen metaphyseal chondrodysplasia (JMC) is a rare autosomal dominant skeletal dysplasia caused by activating variants in the parathyroid hormone receptor 1 gene (PTH1R), leading to PTH-independent hypercalcemia, hypercalciuria, and hypophosphatemia. The disorder is defined clinically by early‐onset growth plate abnormalities, nephrocalcinosis, and chronic mineral ion dysregulation (Jansen metaphyseal chondrodysplasia).

The mode of inheritance is autosomal dominant with high penetrance. A recurrent missense variant c.668A>G (p.His223Arg) has been identified in 18 unrelated patients (PMID:29788189) and additional activating mutations (T410P, I458R, I458K, T410R) bring the total to 24 affected individuals, all exhibiting PTH‐independent hypercalcemia and growth impairment. Segregation of c.668A>G (p.His223Arg) was confirmed in a mother and her two sons in one kindred, supporting vertical transmission of the disease allele (PMID:27410178).

Functional characterization in HEK293T cells demonstrates that H223R and other JMC‐associated mutants exhibit ligand-independent constitutive cAMP accumulation, altered N-glycosylation, and receptor dimerization defects. Inverse agonist peptides such as [Leu11,dTrp12,Trp23,Tyr36]-PTHrP(7-36)NH2 effectively normalize basal cAMP signaling in vitro (PMID:27160269).

In vivo, transgenic C1HR mice expressing PTH1R-H223R in osteoblasts recapitulate JMC skeletal abnormalities, including excessive trabecular bone mass, marrow fibrosis, and elevated bone turnover markers. Twice‐daily administration of the inverse agonist ligand [Leu11,dTrp12,Trp23,Tyr36]-PTHrP(7-36)NH2 partially rescues these phenotypes, reducing bone mass and biochemical indices of hyperactivity (PMID:31693237).

Clinically, management of hypercalciuria with alendronate and thiazide diuretics achieves normocalciuria and stabilizes serum FGF23 levels in adult JMC patients, with no detectable cardiovascular disease after two decades of mild hypercalcemia (PMID:22278430). Regular genetic testing of PTH1R hotspots expedites diagnosis and informs targeted therapeutic strategies.

Key take-home: Activating PTH1R mutations are definitively associated with Jansen metaphyseal chondrodysplasia; integration of genetic, functional, and in vivo rescue data supports precision diagnosis and the development of inverse agonist–based therapies.

References

• The Journal of clinical endocrinology and metabolism • 2012 • Potential effects of alendronate on fibroblast growth factor 23 levels and effective control of hypercalciuria in an adult with Jansen's metaphyseal chondrodysplasia. PMID:22278430
• The Journal of clinical endocrinology and metabolism • 2016 • Jansen Metaphyseal Chondrodysplasia due to Heterozygous H223R-PTH1R Mutations With or Without Overt Hypercalcemia. PMID:27410178
• The Journal of clinical endocrinology and metabolism • 2018 • Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia. PMID:29788189
• Odontology • 2017 • Characterization of a PTH1R missense mutation responsible for Jansen type metaphyseal chondrodysplasia. PMID:27160269
• Journal of bone and mineral research • 2020 • An Inverse Agonist Ligand of the PTH Receptor Partially Rescues Skeletal Defects in a Mouse Model of Jansen's Metaphyseal Chondrodysplasia. PMID:31693237

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