Searchable abstracts of presentations at key conferences in endocrinology

ea0013p116 | Comparative | SFEBES2007

Genome comparison between human chromosome 19q13 and syntenic region on mouse chromosome 7 reveals loss, in man, of 5.1 Mb containing 4 mouse G-protein coupled receptors: relevance to familial benign hypocalciuric hypercalcaemia type 3

Hannan Fadil , Andrew Nesbit M , Christie Paul , Harding Brian , Whyte Michael , Thakker Rajesh

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...

ea0094oc1.4 | Bone and Calcium | SFEBES2023

Mendelian randomisation and colocalization analyses reveal novel drug targets for the prevention of kidney stone disease by modulating serum calcium and phosphate concentrations

Lovegrove Catherine , Hannan Fadil , Mahajan Anubha , Thakker Rajesh , Holmes Michael , Furniss Dominic , Howles Sarah

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...

ea0077oc5.5 | Bone and Calcium | SFEBES2021

Diacylglycerol kinase delta haploinsufficiency in mice causes hypocalcaemia: relevance to human Autosomal Dominant Hypoclacemia (ADH)

Goldsworthy Michelle , Lovegrove Catherine , Moir Lee , Wiberg Akira , Turney Benjamin , Furniss Dominic , Hannan Fadil , Thakker Rajesh , Howles Sarah

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...

ea0077p54 | Metabolism, Obesity and Diabetes | SFEBES2021

Central adiposity and diabetes are causally associated with kidney stone disease

Lovegrove Catherine , Wiberg Akira , Littlejohns Thomas , Allen Naomi , Turney Benjamin , Mahajan Anubha , McCarthy Mark , Thakker Rajesh , Furniss Dominic , Howles Sarah

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...

ea0055p33 | Poster Presentations | SFEEU2018

A case of vitamin D-dependent rickets type 2A (VDDR2A), caused by compound-heterozygous mutations in the vitamin D receptor (VDR)

Stokes Victoria , Pagnamenta Alistair , Stevenson Mark , Lines Kate E , Shine Brian , Taylor Jenny , Richardson Tristan , Thakker Rajesh V

Case history: Vitamin D-dependent rickets type 2 (VDDR2) is an autosomal recessive condition caused by resistance to 1,25(OH)2D3, either through vitamin D receptor (VDR) mutations (type A) or abnormal expression of interfering proteins (type B), resulting in hypocalcaemia despite elevated plasma 1,25(OH)2D3 and parathyroid hormone concentrations. We report a proband, born to Caucasian non-consanguineous parents, who presente...

ea0086oc1.6 | Bone and Calcium | SFEBES2022

The AXT914 calcilytic compound increases plasma calcium and PTH in a mouse model for autosomal dominant hypocalcaemia type 1 (ADH1)

Kooblall Kreepa , Hannan Fadil , Stevenson Mark , Lines Kate , Meng Xin , Stewart Michelle , Wells Sara , Gasser Jurg , Thakker Rajesh

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....

ea0065ec1.4 | Clinical Endocrinology Trust Best Abstract Basic | SFEBES2019

Mice harbouring a germline heterozygous AP2S1 mutation, Arg15Leu, are a model for familial hypocalciuric hypercalcaemia type 3 (FHH3)

Hannan Fadil , Stokes Victoria , Gorvin Caroline , Stevenson Mark , Hough Tertius , Stewart Michelle , Wells Sara , Teboul Lydia , Thakker Rajesh

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...

ea0065p86 | Bone and calcium | SFEBES2019

Effect of vitamin D analogue therapy in a patient with autosomal dominant hypocalcaemia type 2 (ADH2) due to GNA11 p.Arg60Leu mutation

Farrell Catriona , Hannan Fadil , George Jacob , Robinson Emma , McLean Joanne , Boon Hannah , Cranston Treena , Goudie David , Thakker Rajesh , Newey Paul

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...

ea0049oc10.5 | Bone & Calcium Homeostasis | ECE2017

Gα11-Phe220Ser loss-of-function mutation causes familial hypocalciuric hypercalcemia type-2 (FHH2) by disrupting a hydrophobic cluster critical for G-protein signaling

Gorvin Caroline M. , Cranston Treena , Hannan Fadil M. , Valta Helena , Makitie Outi , Schalin-Jantti Camilla , Thakker Rajesh V.

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...

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...