We conclude that 1) sporadic hypoparathyroidism can be caused by de novo gain-of-function mutations of the CaR; 2) the phenotype can vary from mild to life-threatening hypocalcemia; 3) gain-of-function mutations can involve not only extracellular regions, as previously reported, but also transmembrane domains of the CaR; and 4) the mechanism of activation can involve both increased receptor sensitivity to Ca2+ and increased maximal signal transduction.
C0020626
Hypoparathyroidism