Activating mutations of the calcium - sensing receptor in primary hypoparathyroidism Mini - review

Familial hypoparathyroidism (also termed autosomal dominant hypocalcemia) is characterized by hypocalcemia, hyperphosphatemia, and relative hypercalciuria, particularly during treatment with vitamin D and calcium to correct the hypocalcemia. Serum parathyroid hormone is inappropriately suppressed. Over 30 activating missense mutations in the calcium-sensing receptor gene have been identified in familial hypoparathyroidism. Functional expression studies in vitro show that such mutations typically increase the receptor’s sensitivity to Ca2+ resulting in suppression of parathyroid hormone secretion and increased urinary calcium excretion at inappropriately low concentrations of serum Ca2+. Identification of calcium-sensing receptor gene mutations in subjects who present with hypocalcemia is important to avoid development of nephrolithiasis during treatment. Activating calcium-sensing receptor gene mutations are non-randomly distributed in the receptor protein. Study of these naturally occurring activating mutations has provided important insights into the structure and function of the receptor.