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A Novel Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Mutation in Jansen’s Metaphyseal Chondrodysplasia¹

Endocrine Unit, Department of Medicine (E.S., J.H., H.J.), and Children’s Service (H.J.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; INSERM, U-426, Faculté de Médicine, Xavier Bichat (C.S.), and INSERM U-393, Hôpital Necker Enfants Malades (M.L.M.), Paris, Cedex 18 75870, France; the Department of Pediatrics, National University Hospital (K.Y.L.), Singapore 119074; Great Ormond Street Hospital for Children (M.J.D.), London, United Kingdom WC1N 3JH; and the Division of Nephrology, Children’s Memorial Hospital (C.L.), Chicago, Illinois 60614

Address all correspondence and requests for reprints to: Dr. E. Schipani, Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114. E-mail: schipani{at}helix.mgh.harvard.edu

Two heterozygous PTH/PTH-related peptide (PTHrP) receptor missense mutations were previously identified in patients with Jansen’s metaphyseal chondrodysplasia (JMC), a rare form of short limb dwarfism associated with hypercalcemia and normal or undetectable levels of PTH and PTHrP. Both mutations, H223R and T410P, resulted in constitutive activation of the cAMP signaling pathway and provided a plausible explanation for the abnormalities in skeletal development and mineral ion homeostasis. In the present study we analyzed genomic DNA from four additional sporadic cases with JMC to search for novel activating mutations in the PTH/PTHrP receptor, to determine the frequency of the two previously identified missense mutations, H223R and T410P, and to determine whether different mutations present with different severity of the disease. The H223R mutation was identified in three novel JMC patients and is, therefore, to date the most frequent cause of JMC. In the fourth patient, a novel heterozygous missense mutation was found that changes isoleucine 458 in the receptor’s seventh membrane-spanning region to arginine (I458R). In COS-7 cells expressing the human PTH/PTHrP receptor with the I458R mutation, basal cAMP accumulation was approximately 8 times higher than that in cells expressing the wild-type receptor despite impaired surface expression of the mutant receptor. Furthermore, the I458R mutant showed higher responsiveness to PTH than the wild-type receptor in its ability to activate both down-stream effectors, 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.

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