In conclusion, through analysis of [Ca2+]i oscillations and the [Ca2+]o- and L-Phe triggered downstream signaling changes, functional positive cooperativity of CaSR was revealed to be disrupted in the identified FHH-associated CaSR mutations, L173P and P221Q, but not in the ADHH related mutations, L173F and P221L. The gene discussed is CASR; the disease is familial hypocalciuric hypercalcemia.