MUTATIONS IN THE HUMAN CA2-SENSING RECEPTOR GENE CAUSE FAMILIAL HYPOCALCIURIC HYPERCALCEMIA AND NEONATAL SEVERE HYPERPARATHYROIDISM()

We demonstrate that mutations in the human Ca2+-sensing receptor gene cause familial hypocalciuric hypercalcemia (FHH) and neonatal severe h yperparathyroidism (NSHPT), two inherited conditions characterized by altered calcium homeostasis. The Ca2+-sensing receptor belongs to the superfamily of seven membrane-spanning G protein-coupled receptors. Th ree nonconservative missense mutations are reported: two occur in the extracellular N-terminal domain of the receptor; the third occurs in t he final intracellular loop. One mutated receptor identified in FHH in dividuals was expressed in X. laevis oocytes. The expressed wild-type receptor elicted large inward currents in response to perfused polyval ent cations; a markedly attenuated response was observed with the muta ted protein. We conclude that the mammalian Ca2+-sensing receptor ''se ts'' the extracellular Ca2+ level and is defective in individuals with FHH and NSHPT.