A FAMILIAL SYNDROME OF HYPOCALCEMIA WITH HYPERCALCIURIA DUE TO MUTATIONS IN THE CALCIUM-SENSING RECEPTOR

Background The calcium-sensing receptor regulates the secretion of par athyroid hormone in response to changes in extracellular calcium conce ntrations, and mutations that result in a loss of function of the rece ptor are associated with familiar hypocalciuric hypercalcemia. Mutatio ns involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hyper calciuria. Methods We studied six kindreds given a diagnosis of autoso mal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that s uggested a defect of the calcium-sensing receptor. The hypocalcemia wa s associated with hypercalciuria, and treatment with vitamin D resulte d in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA -sequence analysis and expressed in human embryonic kidney cells (HEK- 293). Results Five heterozygous missense mutations (Asn118Lys, Phe128L eu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracel lular domain of the calcium-sensing-receptor gene and shown to cosegre gate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the do se-response curves so that the extracellular calcium concentrations ne eded to produce half-maximal increases in total inositol phosphate in the cells were significantly (P = 0.02 to P < 0.001) lower than those required for the wild-type receptor. Conclusions Gain-of-function muta tions in the calcium-sensing receptor are associated with a familial s yndrome of hypocalcemia with hypercalciuria that needs to be distingui shed from hypoparathyroidism.