Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations

Abstract

The extracellular calcium (Ca 2+ o )-sensing receptor (CaSR) enables the parathyroid glands and other CaSR-expressing cells involved in calcium homeostasis, such as the kidney and bone, to sense alterations in the level of Ca 2+ o and to respond with changes in function that are directed at normalizing the blood calcium concentration. Several disorders of Ca 2+ o 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. Keywordsseven transmembrane receptor; mutations; polymorphisms; calcium-sensing receptor; calcium homeostasis; calcimimetic; calcilytic; familial hypocalciuric hypercalcaemia; autosomal-dominant hypoparathyroidism; acquired hypoparathyroidism; osteoporosis; hyperparathyroidism; Bartter's syndromeThe calcium-sensing receptor (CaSR) plays key roles in the maintenance of a narrow range (1.1-1.3 mM) of the extracellular ionized calcium concentration (Ca 2+ o ), primarily by modulating the function of chief cells of the parathyroid gland. Here it regulates the synthesis and secretion of parathyroid hormone (PTH) as well as parathyroid cellular proliferation, inhibiting all three when Ca 2+ o is high and stimulating them when Ca 2+ o is low. 1 Both very high and very low levels of Ca 2+ o can lead to serious clinical sequellae and, in some instances,

Antilipolytic effect of calcimimetics depends on the allelic variant of calcium-sensing receptor gene polymorphism rs1042636 (Arg990Gly)

“…Although activating mutations lead to various degrees of hypocalcemia, inactivating mutations lead to hypercalcemia; ranging from an heterozygous benign form with elevated PTH levels, to the homozygous form with severe hypercalcemia, hyperparathyroidism and failure to thrive. 7 In addition, single-nucleotide polymorphisms (SNPs) have been identified, one in intron 5 and five in the coding region of exon 7. One of the few SNPs for which causal effects have been demonstrated on the protein level is rs1042636.…”

Mouse models for inherited endocrine and metabolic disorders

“…The CaSR, which is a 1078 amino acid G-protein coupled receptor with seven transmembrane domains and a large 612 amino acid extracellular domain, is predominantly expressed in the parathyroids and kidneys, and is pivotal in extracellular calcium homoeostasis by mediating alterations in the release of PTH from the parathyroids in response to changes in extracellular calcium concentrations (Thakker 2004, Egbuna & Brown 2008. CaSR mutations resulting in loss-of-function are associated with two hypercalcaemic disorders, which are familial benign hypercalcaemia, also referred to as familial hypocalciuric hypercalcaemia (FHH) and neonatal severe primary hyperparathyroidism (NSHPT; Pollak et al 1993); whilst gain-of-function CaSR mutations result in two hypocalcaemic disorders, which are autosomal dominant hypocalcaemia with hypercalciuria (ADHH; Pollak et al 1994, Pearce et al 1996, and a form of the Bartter syndrome (Vargas-Poussou et al 2002, Watanabe et al 2002.…”

“…FHH is an autosomal dominant disorder caused by heterozygous loss-of-function CaSR mutations, and NSHPT, which is a life-threatening disorder characterised by severe neonatal hypercalcaemia, undermineralisation of bones and multiple fractures, may be caused by homozygous or de novo heterozygous loss-of-function CaSR mutations (Thakker 2004, Egbuna & Brown 2008. The loss-offunction CaSR mutations consist of nonsense mutations, frameshifting insertions and deletions and missense mutations that result in an alteration of the CaSR such that the extracellular calcium concentration at which the CaSR produces a half-maximal response (EC 50 ) is significantly raised.…”

Neonatal severe hyperparathyroidism secondary to a novel homozygous CASR gene mutation

“…Neonatal hyperparathyroidism presents early in infancy, usually within the first six months of life although the majority present in the first few weeks. The young babies present with signs of hypercalcemia and hyperparathyroidism which include poor feeding, polyuria, dehydration, lethargy, failure to thrive, hypotonia, gastrointestinal dysmotility, osteopenia and symptoms of respiratory distress due to a poorly developed chest cage (2). Early diagnosis and treatment for NSHPT is critical; delay in diagnosis and treatment is associated with high morbidity and mortality and devastating neurodevelopmental outcome.…”