A novel parathyroid hormone (PTH)/PTH-related peptide receptor mutation inJansen's metaphyseal chondrodysplasia

Two heterozygous PTH/PTH-related peptide (PTHrP) receptor missense mutation s were previously identified in patients with Jansen's metaphyseal chondrod ysplasia (JMC), a rare form of short limb dwarfism associated with hypercal cemia and normal or undetectable levels of PTH and PTHrP. Both mutations, H 223R and T410P, resulted in constitutive activation of the cAMP signaling p athway and provided a plausible explanation for the abnormalities in skelet al development and mineral ion homeostasis. In the present study we analyze d genomic DNA from four additional sporadic cases with JMC to search for no vel activating mutations in the PTH/PTHrP receptor, to determine the freque ncy of the two previously identified missense mutations, H223R and T410P, a nd to determine whether different mutations present with different severity of the disease. The H223R mutation was identified in three novel JMC patie nts and is, therefore, to date the mast frequent; cause of JMC. In the four th patient, a novel heterozygous missense mutation was found that changes i soleucine 458 in the receptor's seventh membrane-spanning region to arginin e (I458R). In COS-7 cells expressing the human PTH receptor with the I458R mutation, basal cAMP accumulation was approximately 8 times higher than tha t in cells expressing the wild-type receptor despite impaired surface expre ssion of the mutant receptor. Furthermore, the I458R mutant showed higher r esponsiveness to PTH than the wild-type receptor in its ability to activate both down-stream effecters, adenylyl cyclase and phospholipase C. Like the H223R and the T410P mutants, the I458R mutant had no detectable effect on basal inositol phosphate accumulation. Overall, the patient. with the I458R mutation exhibited clinical and biochemical abnormalities similar to those in patients with the previously identified H223R and T410P mutations.