Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations

The extracellular calcium (Ca-o(2+))-sensing receptor (CaSR) enables the parathyroid glands and other CaSR-expressing cells involved in calcium homeostasis, such as the kidney and bone, to and to respond with changes in function that are directed sense alterations in the level of Ca-o(2+) at normalizing the blood calcium concentration. Several disorders of Ca-o(2+). sensing arise from inherited or acquired abnormalities that 'reset' the serum calcium concentration upwards or downwards. Heterozygous inactivating mutations of the CaSR produce a benign form of hypercalcaemia, termed 'familial hypocalciuric hypercalcaemia', while homozygous mutations produce a much more severe hypercalcaemic disorder resulting from marked hyperparathyroidism, called 'neonatal severe hyperparathyroidism'. Activating mutations cause a hypocalcaemic syndrome of varying severity, termed 'autosomal-dominant hypocalcaemia or hypoparathyroidism' as well as Bartter's syndrome type V Calcimimetic CaSR activators and calcilytic CaSR antagonists have also been developed with potential for use in the treatment of these disorders.