SPORADIC HYPOPARATHYROIDISM CAUSED BY DE-NOVO GAIN-OF-FUNCTION MUTATIONS OF THE CA2-SENSING RECEPTOR()

Activating mutations of the Ca2+-sensing receptor (CaR) gene have been identified in families with autosomal dominant hypoparathyroidism and in one patient with sporadic hypoparathyroidism. Here, we describe tw o additional patients with sporadic hypoparathyroidism. One patient pr esented with mild symptoms at age 18 yr, the other was severely sympto matic from infancy. A heterozygous missense mutation was identified in each patient. One mutation (L773R) involved the fifth transmembrane d omain of the CaR, the other (N118K) affected the amino-terminal, extra cellular domain. In both cases, the probands' parents lacked the mutat ion, indicating that the mutations arose de novo. In expression studie s the mutations shifted the concentration-response curve to the left a nd increased maximal activity. We conclude that 1) sporadic hypoparath yroidism can be caused by de novo gain-of-function mutations of the Ca R; 2) the phenotype can vary from mild to life-threatening hypocalcemi a; 3) gain-of-function mutations can involve not only extracellular re gions, as previously reported, but also transmembrane domains of the C aR; and 4) the mechanism of activation can involve both increased rece ptor sensitivity to Ca2+ and increased maximal signal transduction.