Endocrine Abstracts

The calcium sensing receptor (CaSR) is a G protein coupled receptor that is expressed in type A intercalated cells of the distal convoluted tubule and cortical collecting ducts, where it is involved in renal proton excretion. We have therefore investigated the Nuf mouse, which has an activating CaSR mutation (Leu723Gln) that leads to hypocalcaemia, hypercalciuria, renal calcification, a urinary concentrating defect, and cataracts, for disturbances in acid-base homeostasis. Mic...

The calcium-sensing receptor (CaSR) is a G protein coupled receptor that is expressed widely, including pancreatic beta cells where it has been shown to modulate insulin secretion in vitro. However, the role of the CaSR in regulating in vivo insulin secretion and glucose homeostasis remains unknown. We have therefore investigated the Nuf mouse, which has an activating CaSR mutation (Leu723Gln), to determine whether abnormal CaSR function in vivo affects gl...

The calcium-sensing receptor (CaSR) plays a central role in regulating parathyroid hormone (PTH) secretion in response to changes in extracellular calcium. The CaSR is a G-protein-coupled receptor and ligand binding results in stimulation of phospholipase C (PLC) activity, causing accumulation of inositol 1,4,5-triphosphate (IP3) and the rapid release of calcium ions from intracellular stores. Given the pivotal role of the CaSR in calcium homeostasis, we decided to ...

The calcium-sensing receptor (CaSR) belongs to family C of G-protein coupled receptors (GPCRs) that bind glutamate, GABA, taste molecules and pheromones. Loss-of-function mutations of the CASR gene located on chromosome 3q21–24, cause familial benign hypocalciuric hypercalcaemia type 1 (FBHH1). The genes causing FBHH2 and FBHH3, whose chromosomal locations are on 19p and 19q13.3, respectively, remain unknown. FBHH3, sometimes called the Oklahoma variant (FBHHO...

Kidney stone disease (KSD) is a recurrent condition with limited prophylactic therapies. This study aimed to use Mendelian randomisation (MR) and colocalization analyses to identify novel drug targets for KSD. Utilising UK Biobank genome-wide association study data for MR, we identified forty-nine 1Mbp regions where genetic loci increase risk of KSD via effects on albumin-adjusted serum calcium or phosphate concentrations. Multi-trait statistical colocalization analyses identi...

Diacylglycerol kinase delta (DGKD) has been implicated in calcium homeostasis and nephrolithiasis by genome-wide association studies. We have previously demonstrated that alterations in expression of DGKD cause biased calcium-sensing receptor (CaSR) signalling in vitro. To further elucidate the physiological role of DGKD we examined the biochemical phenotype of a Dgkd-haploinsufficient (+/-) mutant mouse developed by the International Mouse Phenotyping Consor...

Heterozygous germline gain-of-function mutations of the extracellular calcium-sensing receptor (CaSR), a G-protein coupled receptor (GPCR), result in autosomal dominant hypocalcaemia type 1 (ADH1), which may cause symptomatic hypocalcaemia with low circulating parathyroid hormone (PTH) concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, rectify the gain-of-function caused by CaSR mutations and are a potential targeted therapy for ADH1....

Familial hypocalciuric hypercalcaemia (FHH) comprises three genetic variants: FHH types 1 and 2 are due to mutations of the calcium-sensing receptor (CaSR) and G-protein subunit alpha-11, whereas, FHH type 3 (FHH3) is caused by heterozygous mutations affecting the Arg15 residue (Arg15Cys, Arg15His, Arg15Leu) of the adaptor-related protein complex 2-sigma subunit (AP2S1), which regulates CaSR endocytosis. FHH is usually associated with mild hypercalcaemia, normal parathyroid ho...

Background: Autosomal dominant hypocalcaemia (ADH) is most commonly due to activating mutations in the Calcium Sensing Receptor (ADH Type 1), in which treatment with vitamin D analogues is frequently associated with hypercalciuria. More recently, activating mutations in the alpha-subunit of the G-protein α-11 (Gα11), encoded by GNA11, have been identified in a small number of ADH kindreds (ADH Type 2). The impact of vitamin D analogue treatment in ADH2 patie...

Mutations of the calcium-sensing receptor (CaSR), G-protein alpha-11 subunit (Gα11), and adaptor protein-2 sigma subunit (AP2σ) resulting in a loss-of-function, cause familial hypocalciuric hypercalcemia types 1-3 (FHH1-3), respectively. We investigated a family with FHH (four affected and two unaffected members) for CaSR, Gα11 and AP2σ mutations, and identified a heterozygous Gα11 missense mutation, Phe220Ser, which is predicted to disrupt a cluster o...