CONSTITUTIVELY ACTIVATED RECEPTORS FOR PARATHYROID-HORMONE AND PARATHYROID HORMONE-RELATED PEPTIDE IN JANSENS METAPHYSEAL CHONDRODYSPLASIA

Background An activating mutation of the receptor for parathyroid horm one (PTH) and parathyroid hormone-related peptide (PTHrP) was recently found in a patient with Jansen's metaphyseal chondrodysplasia, a rare form of short-limbed dwarfism associated with hypercalcemia and norma l or low serum concentrations of the two hormones. To investigate this and other activating mutations and to refine the classification of th is unusual disorder, we analyzed genomic DNA from six additional patie nts with Jansen's disease. Methods Exons encoding the PTH-PTHrP recept or were amplified by the polymerase chain reaction (PCR), and the prod ucts were analyzed by gel electrophoresis or direct nucleotide-sequenc e analysis. Nucleotide changes were confirmed by restriction-enzyme di gestion of genomic DNA or the PCR products. Results The previously rep orted mutation, which changes a histidine at position 223 to arginine (H223R), was found in genomic DNA from three of the six patients but n ot in DNA from their healthy relatives or 45 unrelated normal subjects . A novel missense mutation that changes a threonine in the receptor's sixth membrane-spanning region to proline (T410P) was identified in a nother patient but not in 62 normal subjects. In two patients with rad iologic evidence of Jansen's metaphyseal chondrodysplasia but less sev ere hypercalcemia, no receptor mutations were detected. In COS-7 cells expressing PTH-PTHrP receptors with the T410P or H223R mutation, basa l cyclic AMP accumulation was four to six times higher than in cells e xpressing wild-type receptors. Conclusions The expression of constitut ively active PTH-PTHrP receptors in kidney, bone, and growth-plate cho ndrocytes provides a plausible genetic explanation for mineral-ion abn ormalities and metaphyseal changes in patients with Jansen's disease. (C) 1996, Massachusetts Medical Society.