Searchable abstracts of presentations at key conferences in endocrinology

ea0044p47 | Bone and Calcium | SFEBES2016

Studies of an Autosomal Dominant Hypocalcemia type-1 (ADH1) associated calcium-sensing receptor (CaSR) mutation, Arg680Gly, provides insights into biased signalling

Gorvin Caroline , Babinsky Valerie , Schou Anders , Nissen Peter , Hannan Fadil , Thakker Rajesh

The CaSR, a G-protein-coupled receptor that regulates extracellular calcium (Ca2+o), predominantly signals via G-protein-αq/11 (Gαq/11), initiating IP3-mediated intracellular calcium (Ca2+i) accumulation, and mitogen-activated protein kinase (MAPK) signalling. CaSR also activates MAPK signalling via Gαi/o, or by associating with the scaffolding protein β-arrestin. CaSR g...

ea0034p17 | Bone | SFEBES2014

The calcilytic NPS2143 rectifies the gain-of-function associated with G-protein α 11 mutations causing autosomal dominant hypocalcaemia type 2

Babinsky Valerie , Hannan Fadil , Nesbit M Andrew , Howles Sarah , Hu Jianxin , Spiegel Allen , Thakker Rajesh

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...

ea0031oc1.7 | Young Endocrinologists prize session | SFEBES2013

Autosomal dominant hypocalcemia type 2 is caused by germline GNA11 gain-of-function mutations

Howles Sarah , Nesbit Andrew , Hannan Fadil , Babinsky Valerie , Head Rosie , Cranston Treena , Rust Nigel , Thakker Rajesh

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...

ea0031p177 | Obesity, diabetes, metabolism and cardiovascular | SFEBES2013

Association of calcium-sensing receptor polymorphisms with vascular calcification and glucose homeostasis in renal transplant recipients

Babinsky Valerie N , Hannan Fadil M , Youhanna Sonia , Devuyst Olivier , Thakker Rajesh V

The calcium-sensing receptor (CaSR) is a G-protein coupled receptor that regulates extracellular calcium concentration. The CaSR is also implicated in the pathogenesis of non-calcium disorders such as vascular calcification and diabetes, which are leading causes of cardiovascular disease. Common CaSR single nucleotide polymorphisms (SNPs) have been demonstrated to be determinants of calcium metabolism. The aim of this study was to investigate whether CaSR SNPs may influence va...

ea0044p44 | Bone and Calcium | SFEBES2016

The calcilytic SHP635 rectifies hypocalcaemia and reduced parathyroid hormone concentrations in a mouse model for autosomal dominant hypocalcaemia type 1 (ADH1)

Hannan Fadil , Babinsky Valerie , Gorvin Caroline , Hough Tertius , Joynson Elizabeth , Stewart Michelle , Wells Sara , Cox Roger , Nemeth Edward , Thakker Rajesh

Autosomal dominant hypocalcaemia type 1 (ADH1) is a systemic disorder of calcium homeostasis caused by gain-of-function mutations of the calcium-sensing receptor (CaSR). ADH1 may lead to symptomatic hypocalcaemia, inappropriately low parathyroid hormone (PTH) concentrations and hypercalciuria. Active vitamin D metabolites are the mainstay of treatment for symptomatic ADH1 patients, however their use predisposes to nephrocalcinosis, nephrolithiasis and renal impairment. Calcily...

ea0031p1 | Bone | SFEBES2013

GNA11 loss-of-function mutations cause familial hypocalciuric hypercalcaemia type 2 (FHH2)

Hannan Fadil , Nesbit M A , Howles Sarah , Babinsky Valerie , Cranston Treena , Rust Nigel , Hobbs Maurine , Heath III Hunter , Thakker Rajesh

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...

ea0065op3.4 | Metabolism and Obesity | SFEBES2019

Mice with a gain-of function Gα11 mutation have autosomal dominant hypocalcaemia, but not impaired glucose metabolism

Gluck Anna , Lines Kate , Gorvin Caroline , Babinsky Valerie , Piret Sian , Sarbu Stefan , Stewart Michelle , Bentley Liz , Wells Sara , Cox Roger , Ecker Rupert , Ellinger Isabella , Hannan Fadil , Thakker Rajesh

The calcium-sensing-receptor (CaSR) is a G-protein-coupled receptor that plays a fundamental role in extracellular calcium homeostasis, but is also implicated in non-calcitropic disorders including colon cancer and asthma. In addition, CaSR is highly expressed in pancreatic islets where it has a role in insulin secretion. Patients with gain-of-function CaSR mutations, and mice (referred to as Nuf) with a gain-of-function CaSR mutation (Leu723Gln), develop autosomal dominant hy...

ea0038p186 | Obesity, diabetes, metabolism and cardiovascular | SFEBES2015

Studies of Nuf mice with an activating calcium-sensing receptor (CaSR) mutation demonstrate the CaSR to regulate pancreatic beta-cell mass and glucose homeostasis

Babinsky Valerie N , Hannan Fadil M , Nesbit M Andrew , Hough Alison , Stewart Michelle , Joynson Elizabeth , Hough Tertius A , Bentley Liz , Aggarwal Abhishek , Kallay Eniko , Wells Sara , Cox Roger D , Richards Duncan , Thakker Rajesh V

The modulation of pancreatic islet mass represents a novel therapeutic approach for the management of diabetes mellitus. G-protein coupled receptors (GPCRs) regulate beta-cell expansion and proliferation, and the objective of this study was to assess whether the calcium-sensing receptor (CaSR), which is an abundantly expressed beta-cell GPCR, may influence islet mass and systemic glucose homeostasis, and thus represent an exploitable drug target in some forms of diabetes. We c...

ea0034p14 | Bone | SFEBES2014

Clinical studies of adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 reveal genotype–phenotype correlations and effectiveness of cinacalcet

Hannan Fadil , Rogers Angela , Howles Sarah , Cranston Treena , McKenna Malachi , Richardson Tristan , Babinsky Valerie , Reed Anita , Thakker Clare , Bockenhauer Detlef , Brown Rosalind , Cook Jacqueline , Darzy Ken , Ehtisham Sarah , Graham Una , Hulse Tony , Hunter Steven , Kumar Dhavendra , McKnight John , Morrison Patrick , Mughal Zulf , Pearce Simon , Scheers Isabelle , Wang Timothy , Whyte Michael , Nesbit M Andrew , Thakker Rajesh

Familial hypocalciuric hypercalcaemia (FHH) comprises three types: FHH1, FHH2, and FHH3, which are due to mutations of the calcium-sensing receptor (CaSR), G-protein α 11 subunit (Gα11), and adaptor protein-2 sigma subunit (AP2σ), respectively. The aims of this study were: to assess for genotype–phenotype correlations among the three reported FHH3-causing AP2σ mutations, which all involve the Arg15 residue, and comprise Arg15Cys, Arg15His, and Arg15Leu...