title: Calcium-sensing receptor (CaSR) mutations and disorders of calcium, electrolyte and water metabolism.
abstract: The extracellular calcium-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that is expressed at multiple sites, including the parathyroids and kidneys. The human CASR gene, located on chromosome 3q21.1, encodes a 1078 amino acid protein. More than 230 different disease-causing mutations of the CaSR have been reported. Loss-of-function mutations lead to three hypercalcemic disorders, which are familial hypocalciuric hypercalcemia (FHH), neonatal severe hyperparathyroidism and primary hyperparathyroidism. Gain-of-function mutations, on the other hand, result in the hypocalcemic disorders of autosomal dominant hypocalcemia and Bartter syndrome type V. Moreover, autoantibodies directed against the extracellular domain of the CaSR have been found to be associated with FHH in some patients, and also in some patients with hypoparathyroidism that may be part of autoimmune polyglandular syndrome type 1. Studies of disease-causing CASR mutations have provided insights into structure-function relationships and highlighted intra-molecular domains that are critical for ligand binding, intracellular signaling, and receptor trafficking.
authors.affiliation: Academic Endocrine Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK. fadil.hannan@ocdem.ox.ac.uk
authors.forename: Fadil M
authors.initials: FM
authors.lastname: Hannan
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D006801:Humans; D006934:Hypercalcemia / Q000235:genetics* / Q000378:metabolism; D006996:Hypocalcemia / Q000235:genetics* / Q000378:metabolism; D007011:Hypoparathyroidism / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D044169:Receptors, Calcium-Sensing / Q000235:genetics* / Q000378:metabolism; D014882:Water-Electrolyte Balance / Q000235:genetics*
chemical_list: D044169:Receptors, Calcium-Sensing
keywords: Bartter syndrome; G-protein-coupled receptor; autoantibodies; autosomal dominant hypocalcemia; familial hypocalciuric hypercalcemia; parathyroid hormone; primary hyperparathyroidism