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Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations

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The extracellular calcium (Ca2+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 Ca2+o and to respond with changes in function that are directed at normalizing the blood calcium concentration. Several disorders of Ca2+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.

Section snippets

Physiology of the CaSR

PTH, calcitonin and 1,25-dihydroxyvitamin D [1,25(OH)2D3] are the three most important Ca2+o-regulating hormones.9 As noted earlier, there is a functionally critical inverse relationship between Ca2+o and PTH, a calcium-elevating hormone. In contrast, high Ca2+o stimulates the secretion of calcitonin, a Ca2+o-lowering hormone; an action that is likewise mediated by the CaSR.10 Available data have demonstrated that the CaSR is expressed not only in the organs that secrete calcium-regulating

Molecular biology of the CaSR

This section briefly introduces key aspects of the structure and function of the CaSR to provide sufficient background information to understand the molecular basis for both normal mineral ion homeostasis and diseases from mutations of the CaSR.

Disorders of calcium sensing that involve casr mutations

The principal disorders of Ca2+o sensing are listed in Table 2.

Polymorphisms of the CaSR

In addition to clinically relevant activating and inactivating mutations, single nucleotide polymorphisms (SNPs) have been identified in the general population or in families with FHH and ADH in which the base pair change is present in affected and unaffected persons and does not segregate with known diseases of divalent ion metabolism. Six SNPs have been found in the CaSR gene; one in intron 5 just before exon 6 (IVS 5–88t/c) and the remaining five in exon 7 in the coding region [one in the

CaSR-based therapeutics

Specific gene-based therapies for disorders of mineral metabolism as a result of mutations of the CaSR are not yet available. Similarly, there are currently no pharmacological agents approved by the Food and Drug Administration (FDA) for treatment of these disorders. However, clinically symptomatic disease as a result of these mutations could potentially be addressed with the use of modulators of the CaSR. The development of allosteric activators (‘calcimimetics’)41 and antagonists

Summary and future issues

The CaSR is a membrane-bound 7TM receptor expressed in several tissues such as the parathyroid gland, kidney, gut and bone, and regulates Ca2+o homeostasis by acting as the body's ‘calciostat’.

Patients who have loss-of-function mutations in the CaSR gene exhibit a form of hypercalcaemia that is accompanied by absolute calciuria or hypocalciuria. In the heterozygous form, it produces a benign hypercalcaemic condition, FHH. In the homozygous form (NSHPT), the hypercalcaemia may be lethal if it is

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