Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism associated with mutations in the human Ca2+-sensing receptor gene in three Danish families

We screened three unrelated Danish families with familial hypocalciuric hypercalcemia (FHH) for mutations in the Ca2+-sensing receptor (CASR) gene by polymerase chain reaction amplification and DNA sequencing of exons 2-7, which include the entire coding region of the gene. In one family the affected individuals have a T --> C mutation that changes the normal arginine at codon 220 to a tryptophan. In the other two FHH families, affected individuals have the same A --> G mutation, leading to conversion of the normal glycine at codon 552 to an arginine. These results confirm that FHH can be caused by nonconservative missense mutations in the CASR gene leading to abnormal calcium homeostasis. Both mutations are located in the amino-terminal extracellular domain of the receptor, which contains the binding site for extracellular Ca2+ the CASR's principal physiological agonist.