['Gain-of-function mutations of the extracellular calcium (Ca(2+)e)-sensing receptor (CaR) have been identified in patients with familial and sporadic hypercalciuric hypocalcaemia. We describe a patient with sporadic severe hypercalciuric hypocalcaemia with undetectable or very low levels of serum parathyroid hormone, carrying a de novo heterozygous missense mutation ( F821L), localized in the sixth transmembrane domain of CaR. Analysis of in vitro functional properties of the mutant receptor to measure Ca(2+)e-evoked changes in intracellular Ca(2+) revealed a leftward shift in the concentration-response curve for the mutant compared to wild-type receptor.'] Is a novel gain-of-function mutation ( F821L ) in the transmembrane domain of calcium-sensing receptor a cause of severe sporadic hypoparathyroidism?