Mutations in the Human Ca2+-Sensing-Receptor Gene That Cause Familial Hypocalciuric Hypercalcemia

We report five novel mutations in the human Ca²⁺-sensing-receptor gene that cause familial hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism. Each gene defect is a missense mutation (²²⁸Arg→Gln, ¹³⁹Thr→Met, ¹⁴⁴Gly→Glu, ⁶³Arg→Met, and ⁶⁷Arg→Cys) that encodes a nonconservative amino acid alteration. These mutations are each predicted to be in the Ca²⁺-sensing receptor's large extracellular domain. In three families with FHH linked to the Ca²⁺-sensing-receptor gene on chromosome 3 and in unrelated individuals probands with FHH, mutations were not detected in protein-coding sequences. On the basis of these data and previous analyses, we suggest that there are a wide range of mutations that cause FHH. Mutations that perturb the structure and function of the extracellular or transmembrane domains of the receptor and those that affect noncoding sequences of the Ca²⁺-sensing-receptor gene can cause FHH.