The human calcium-sensing receptor (<i>CASR</i>) is the key controller of extracellular Ca<sub>o</sub><sup>2+</sup> homeostasis, and different mutations in the <i>CASR</i> gene have been linked to different calcium diseases, such as familial hypocalciuric hypercalcemia, severe hyperparathyroidism, autosomal-dominant hypocalcemia (ADH), and Bartter's syndrome type V. In this study, two generations of a family with biochemically and clinically confirmed ADH who suffered severe muscle pain, arthralgia, tetany, abdominal pain, and fatigue were evaluated for mutations in the <i>CASR</i> gene.
The calcium-sensing receptor (CaSR) plays an important role in sensing extracellular calcium ions and regulating parathyroid hormone secretion by parathyroid gland cells, and the receptor is a suitable target for the treatment of hyperparathyroidism.
The NSHPT associated with biallelic Gly768Val mutations of the CASR in two siblings with severe hypercalcemia and hyperparathyroidism and their clinically and biochemically normal heterozygous parents was transmitted as an autosomal recessive disorder in this family.
Therefore, CaSR is an important target for treating digestive diseases, and the calcimimetics (CaSR agonist) have been confirmed as practical, feasible and effective clinical therapies for hyperparathyroidism.
In addition, it examines the use or potential use of CaSR agonists or antagonists (calcimimetics and calcilytics) and other drugs mediated through the CaSR, in the management of disorders as diverse as hyperparathyroidism, osteoporosis and gastrointestinal disease.
The CASR is a potential therapeutic target to treatment of diseases including hyperparathyroidism and osteoporosis, since its interaction with pharmacological compounds results in modulation of PTH secretion.
In a case of neonatal severe hyperparathyroidism characterized by moderately severe hypercalcemia and very high PTH levels, coupled with evidence of hyperparathyroidism and effects on brain development not previously demonstrated, we detected point mutations on separate alleles of the CaR, resulting in premature stop codon substitutions at G94 and R648.
In familial hypocalciuric hypercalcemia (FHH), heterozygous inactivating mutations in the CaSR gene produce mild, generally asymptomatic hypercalcemia, whereas in neonatal severe hyperparathyroidism (NSHPT), homozygous inactivating mutations cause severe hypercalcemia and hyperparathyroidism.
Here, we investigate a unique variant of familial hypercalcemia, unrelated to multiple endocrine neoplasia and hyperparathyroidism-jaw tumor syndromes, with hypercalcemia due to a point mutation in the intracellular part of the calcium receptor (CaR) gene.
Finally, we will comment on the development of drugs that modulate CaR function by either activating (calcimimetic drugs) or antagonizing it (calcilytic drugs), and on their potential therapeutic implications, such as medical control of specific cases of primary and uremic hyperparathyroidism with calcimimetic drugs and a potential treatment for osteoporosis with a calcilytic drug.