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Endocrine Abstracts (2014) 35 S28.3 | DOI: 10.1530/endoabs.35.S28.3

ECE2014 Symposia Molecular pathophysiology for clinicians: receptor-related disorders (3 abstracts)

Disorders related to calcium-sensing receptor signalling

Fadil Hannan


University of Liverpool, Liverpool, UK.


The extracellular calcium (Cao2+)-sensing receptor (CaSR) is a family C G-protein-coupled receptor (GPCR) that regulates Cao2+ homeostasis by detecting alterations in Cao2+ concentrations and triggering Gq/11 signaling cascades, which modulate parathyroid hormone (PTH) secretion and urinary calcium excretion. Loss-of-function mutations of the CASR gene, located on chromosome 3q21.1, lead to familial hypocalciuric hypercalcaemia (FHH), which is an autosomal dominant disorder characterized by mild-to-moderate elevations of serum calcium concentrations, normal or elevated PTH concentrations, and inappropriately low urinary calcium excretion. On the other hand, gain-of-function CASR mutations result in autosomal dominant hypocalcaemia (ADH), a disorder associated with susceptibility to nephrocalcinosis and renal failure when treated with activated vitamin D preparations. CASR mutations are only detected in ~65% of FHH and ADH patients, and mapping studies in FHH kindreds have revealed additional loci on chromosome 19p and 19q13.3, thereby indicating genetic heterogeneity for FHH. These two genetically distinct types of FHH are designated as FHH2 and FHH3. Mutations of G-protein subunit α11 (Gα11), encoded by GNA11 on chromosome 19p, have recently been identified as the cause of FHH2. In vitro expression of FHH2-associated GNA11 mutations diminished the sensitivity of CaSR-expressing cells to Cao2+, consistent with a loss-of-function. GNA11 mutations have also been reported to lead to a form of ADH designated ‘ADH2’, and these ADH2-associated GNA11 mutations induce a gain-of-function in CaSR-expressing cells. Loss-of function mutations of adaptor protein 2 sigma subunit 2 (AP2σ2), encoded by AP2S1 on chromosome 19q13.3, have been identified as the cause for FHH3, and >20% of FHH patients who do not harbor CaSR mutations have an AP2S1 mutation. AP2σ2 is involved in clathrin-mediated endocytosis and demonstrated to regulate CaSR cell surface expression and signal transduction. The discovery of key proteins involved in CaSR signalling and recycling has provided new insights into GPCR function and calcium homeostasis.

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