Endocrine Abstracts

Nephrolithiasis is a major clinical and economic health burden. We performed a genome-wide association study in British and Japanese nephrolithiasis populations and identified twenty nephrolithiasis-associated loci, five of which (DGKD, DGKH, WDR72, GPIC1 and BCR) were predicted to influence calcium-sensing receptor (CaSR) signalling. Gain-of-function CaSR-signalling pathway mutations cause enhanced signalling via intracellular calcium ([Ca2+]...

Familial hypocalciuric hypercalcaemia (FHH) is an autosomal dominant disorder characterised by hypercalcaemia and inappropriately low renal calcium excretion. FHH can be classified into three types: FHH1, caused by calcium-sensing receptor (CaSR) loss-of-function mutations, accounting for >65% of cases; FHH2, due to loss-of-function mutations of the G-protein α11 subunit (Gα11); and FHH3, resulting from loss-of-function mutations in the adap...

Adaptor protein-2 (AP2) is a heterotetramer of α, β, μ, and σ subunits that is pivotal in clathrin-mediated endocytosis and facilitates internalisation of plasma membrane constituents such as the calcium-sensing receptor (CaSR). AP2 σ subunit (AP2σ) missense mutations (Arg15Cys, Arg15His and Arg15Leu) result in familial hypocalciuric hypercalcaemia type 3 (FHH3) and decrease the sensitivity of CaSR-expressing cells to changes in extracellular calc...

The calcium-sensing receptor (CaSR) is a guanine-nucleotide-binding protein (G-protein)-coupled receptor that has a central role in calcium homeostasis. Loss-of-function mutations of the CaSR result in familial hypocalciuric hypercalcemia type 1 (FHH1) and loss-of-function coding mutations in the CaSR-associated G-protein subunit Gα11 have been reported to cause FHH2 in only two patients to date. The aim of our study was therefore to characterise additional <em...

Autosomal dominant hypocalcaemia (ADH) is a disorder that needs to be distinguished from hypoparathyroidism, as ADH patients are at risk of nephrocalcinosis and renal failure when treated with activated vitamin D preparations. ADH types 1 and 2 are due to gain-of-function mutations of the calcium-sensing receptor (CaSR) and G-protein α 11 (Gα11), respectively. CaSR targeted drugs, known as calcilytics, rectify the gain-of-function associated with ADH1-causing mutatio...

The calcium-sensing receptor (CaSR) is a guanine-nucleotide-binding protein (G-protein)-coupled receptor that has a central role in calcium homeostasis. Loss-of-function mutations of the CaSR result in familial hypocalciuric hypercalcemia type 1 (FHH1) and gain-of-function mutations in autosomal dominant hypocalcemia (ADH). Recently, loss-of-function Gα11 mutations have been identified to cause FHH2 and we hypothesised that gain-of-function Gα11...

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...

Introduction: The pathogenesis of kidney stone disease (KSD) is poorly understood and has been linked to features of metabolic syndrome (MetS). Using conventional and genetic epidemiological analyses we studied associations of MetS phenotypes with risk of KSD.Methods: Multivariate Cox-proportional hazard models were used to assess association of BMI and waist-hip ratio (WHR) with KSD in 492,380 UK Biobank participants. Causal relationships between WHR, B...

Loss-of-function mutations of the calcium-sensing receptor (CaSR), a G-protein-coupled receptor (GPCR), result in familial hypocalciuric hypercalcaemia (FHH), a disorder of extracellular calcium homeostasis affecting the parathyroids and kidneys. However, around 35% of FHH patients do not have CaSR mutations. A form of FHH, designated FHH2, has been mapped to chromosome 19p. The GNA11 gene, encoding G-protein α11 (Gα11), a component of the CaSR sign...