Naturally-occurring mutation in the calcium-sensing receptor reveals the significance of extracellular domain loop III region for class C G-protein-coupled receptor function.

The Journal of Clinical Endocrinology and Metabolism
Qing DongWalter L Miller

Abstract

Inactivating mutations of the calcium-sensing receptor (CaSR) cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Most mutations are clustered in the N-terminal and Cys-rich regions of the extracellular domain (ECD) and seven-transmembrane domain. Disease-causing mutations are uncommon in the C terminus of ECD. The aim of the study was to characterize the CaSR mutations causing neonatal severe hyperparathyroidism in a consanguineous family. Parathyroid glands from the index patient were stained for CaSR protein. The CaSR gene was sequenced, mutations were recreated in CaSR cDNA, and HEK293 cells were transfected with the CaSR mutant expression vector. Cellular CaSR targeting was detected by immunoblotting and immunocytochemistry; CaSR activity was assayed by inositol phosphate accumulation, MAPK activation, and single-cell microfluorimetry. Immunocytochemistry showed reduced intracellular CaSR in patient parathyroids. An in-frame homozygous deletion/insertion mutation, c.1031 > 1034 (delACAAinsT), replaced His344-Asn345 with a single Leu in CaSR loop III. The mutant reduced cell surface expression of CaSR in transfected HEK293 cells. Inositol phosphate accumulation, MAPK activation, and single-ce...Continue Reading

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Citations

Jun 7, 2011·European Journal of Pediatrics·Cristina Aparicio LópezLuis Castaño
Feb 13, 2014·The Journal of Clinical Endocrinology and Metabolism·Dorothea SzczawinskaChristof Schöfl
Nov 30, 2019·The Journal of Clinical Endocrinology and Metabolism·Stephen J Marx, Ninet Sinaii

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