10Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations
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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