The identification of calcium-sensing receptor (CaSR) mutations in human disorders (Table 1) has highlighted that this G-protein-coupled receptor (GPCR) is central to extracellular calcium (Ca2+o) homeostasis. Moreover, disease-causing CaSR mutations have demonstrated that this receptor has additional physiological roles that include the regulation of salt and water metabolism. The human CaSR is a widely expressed 1078 amino acid GPCR that belongs to class C, which includes the metabotropic glutamate receptors.1 The CaSR consists of a 612 amino acid extracellular domain (ECD) that is critical for co-translational processing,2 receptor dimerization,3 binding ligands,4, 5, 6 and transmitting activation signals through the seven transmembrane domains (TMDs), which comprise residues 613–862, and the intracellular domain (ICD), which comprises residues 863–1078.7 Ligand binding by the CaSR ECD results in the activation of multiple signaling cascades including Gq/11-protein dependent stimulation of phospholipase C activity, causing an accumulation of inositol 1,4,5-trisphosphate and a rapid increase of the cytosolic Ca2+ (Ca2+i) concentration.8 These intracellular events mediate a decrease in parathyroid hormone (PTH) secretion from the parathyroid chief cell and a reduction in renal tubular calcium reabsorption, as illustrated by CaSR mutations, which result in alterations in plasma calcium and urinary calcium excretion. For example, inactivating CaSR mutations result in familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism (NSHPT), and primary hyperparathyroidism (PHPT)9, *10; whereas activating CaSR mutations result in autosomal dominant hypocalcemia (ADH), or a form of Bartter syndrome, designated type V.9 In addition, autoantibodies to the CaSR ECD also result in hypercalcemic and hypocalcemic disorders that are similar to FHH and ADH, respectively. This chapter will review those disorders associated with CaSR mutations and autoantibodies.
CaSR abnormalities are associated with four hypercalcemic disorders, which are familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism (NSHPT), primary hyperparathyroidism (PHPT) and autoimmune hypocalciuric hypercalcemia (AHH) (Table 1).
CaSR abnormalities are associated with three hypocalcemic disorders, which are autosomal dominant hypocalcemia (ADH), Bartter syndrome type V and autoimmune hypoparathyroidism (Table 1).
Mutations of the CASR have been described in both chronic pancreatitis and idiopathic epilepsy syndrome. Chronic pancreatitis is characterized by recurrent inflammation of the pancreas, and in rare cases is associated with single gene defects, such as in genes encoding the cystic fibrosis transmembrane conductance regulator (CFTR) and the protease serine 1 (PRSS1).78, 79 Moreover, the combined association of heterozygous mutations in the CASR and serine protease inhibitor, Kazal type 1 (SPINK1)
The carboxyl-terminus of the CaSR is the location of three clustered non-synonymous coding-region polymorphisms – A986S, R990G and Q1011E.84 Of these, A986S is the most commonly occurring CaSR variant, and has been studied extensively for associations with indices of mineral metabolism. In particular, a number of studies have investigated possible associations between A986S and serum total or ionized calcium concentrations.85, 86, 87, 88, 89, 90, 91, 92, 93 The results of these studies have
Loss-of-function CASR mutations display a gene dosage effect with an abnormality of a single CASR allele leading to mild hypercalcemia associated with FHH. However, mutations of both alleles cause life-threatening NSHPT. Moreover, some patients with loss-of-function CaSR mutations present atypically after infancy with features of PHPT. Studies of FHH patients who do not harbor CASR mutations have revealed that AP2S1 mutations or CaSR autoantibodies may also cause this disorder. Gain-of-function
The authors have no disclosures. FHH may be distinguished from primary hyperparathyroidism by measurement of the 24-h urine calcium to creatinine clearance ratio in vitamin D replete patients Approximately one third of FHH patients will not harbor a CASR coding-region mutation, and CaSR autoantibodies or AP2S1 mutations should also be considered in these patients Active vitamin D preparations should be used cautiously in ADH patients, with the aim of alleviatingClinical practice points
The work in the Academic Endocrine Unit is supported by the United Kingdom Medical Research Council (MRC) programme grants – G9825289 and G1000467, and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme.