Mutations of the calcium-sensing receptor (CASR) in familial hypocalciurichypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominanthypocalcemia

The calcium-sensing receptor (CASR) is a plasma membrane G protein coupled receptor that is expressed in the parathyroid hormone (PTH) producing chief cells of the parathyroid gland and the cells lining the kidney tubule, By virtue of its ability to sense small changes in circulating calcium concent ration ([Ca2+](o)) and to couple this information to intracellular signalin g pathways that modify PTH secretion or renal cation handling, the CASR pla ys an essential role in maintaining mineral ion homeostasis, Inherited abno rmalities of the CASR gene located on chromosome 3p13.3-21 can cause either hypercalcemia or hypocalcemia depending upon whether they are inactivating or activating, respectively. Heterozygous loss-of-function mutations give rise to familial (benign) hypocalciuric hypercalcemia (FHH) in which the li felong hypercalcemia is asymptomatic, The homozygous condition manifests it self as neonatal severe hyperparathyroidism (NSHPT), a rare disorder charac terized by extreme hypercalcemia and the bony changes of hyperparathyroidis m which occur in infancy. The disorder autosomal dominant hypocalcemia (ADH ) is due to gain-of-function mutations in the CASR gene. ADH may be asympto matic or present with neonatal or childhood seizures. A common polymorphism in the intracellular tail of the CASR, Ala to Ser at position 986, has a m odest effect on the serum calcium concentration in healthy individuals. Hum Mutat 16:281-296, 2000, (C) 2000 Wiley-Liss, Inc.