The PTH/PTHrP receptor belongs to a novel family of G-protein-coupled receptors which also includes an insect receptor for a diuretic hormone and the protein encoded by a genomic DNA clone from Caenorhabditis elegans. Despite significant structural conservation, rat, opossum, and human PTH/PTHrP receptor homologs display distinct functional characteristics when tested with either [Arg2, Tyr34]hPTH(1-34)amide or [Nle8.18, Tyr34]bPTH(7-34)-amide. These PTH analogs, and chimeras between rat/opossum and between rat/human PTH/PTHrP receptors, led to the identification of receptor residues that appear to be involved in ligand/receptor interaction and receptor activation, respectively. The search for mutations in the PTH/PTHrP receptor gene in genomic DNA of patients with pseudohypoparathyroidism type Ib (PHP-Ib) revealed several silent polymorphisms and a missense mutation in the receptor's tail region which did not affect receptor function. Mutations in the PTH/PTHrP receptor are therefore rarely, if at all, responsible for PHP-Ib. A mutation in the PTH/PTHrP receptor is, however, the most likely cause of Jansen-type metaphyseal chondrodysplasia, a rare form of short-limbed dwarfism which is associated with severe hypercalcemia despite normal or low levels of circulating PTH and PTHrP. A missense mutation was identified which causes constitutive, ligand-independent receptor activation, and thus explains the laboratory and the growth-plate abnormalities in affected individuals.