Searchable abstracts of presentations at key conferences in endocrinology

ea0077oc5.4 | Bone and Calcium | SFEBES2021

Nuclear factor I/X (NFIX) regulates the transcriptional activity of the cellular retinoic acid binding protein 2 (CRABP2) promoter and alters CRABP2 expression in Marshall-Smith Syndrome (MSS) patients.

Kooblall Kreepa , Stevenson Mark , Lines Kate , Stewart Michelle , Wells Sara , Teboul Lydia , Hennekam Raoul , Thakker Rajesh

Marshall-Smith syndrome (MSS) is a congenital disorder affecting skeletal and neural development, due to mutations in the nuclear factor I/X (NFIX) gene. NFIX encodes a ubiquitously expressed transcription factor that regulates the expression of viral and cellular genes. To identify novel genes that are misregulated by NFIX mutations, RNA sequencing and proteomics analyses were performed on mouse embryonic fibroblast (MEF) cells derived from a repres...

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...

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...

ea0086oc1.2 | Bone and Calcium | SFEBES2022

Hypercalcaemic mice harbouring a germline ablation of G-protein subunit alpha-11 have anaemia that is corrected by treatment with erythropoietin

Hannan Fadil , Stevenson Mark , Kooblall Kreepa , Olesen Mie , Yon Marianne , Stewart Michelle , Wells Sara , Duncan Bassett J.H. , Williams Graham , Thakker Rajesh

G-protein subunit α-11 (Gα11), which is encoded by GNA11, plays a major role in calcium homeostasis by regulating parathyroid hormone (PTH) secretion, and germline loss-of-function mutations cause familial hypocalciuric hypercalcaemia type 2 (FHH2). Since Gα11 is ubiquitously expressed, we investigated whether FHH2 is associated with additional non-calcitropic phenotypes by analysing mice harbouring a homozygous germline deletion o...

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...

ea0065oc3.1 | Bone and Calcium | SFEBES2019

A mouse model generated by CRISPR-Cas9 with a frameshift mutation in the nuclear factor 1/X (NFIX) gene has phenotypic features reported in Marshall-Smith Syndrome (MSS) patients

Kooblall Kreepa , Stevenson Mark , Stewart Michelle , Szoke-Kovacs Zsombor , Hough Tertius , Leng Houfu , Horwood Nicole , Vincent Tonia , Hennekam Raoul , Potter Paul , Cox Roger , Brown Stephen , Wells Sara , Teboul Lydia , Thakker Rajesh

Marshall-Smith syndrome (MSS) is a congenital disorder characterised by developmental delay, short stature, respiratory difficulties, distinctive facial features, skeletal abnormalities (such as kyphoscoliosis, dysostosis and osteopenia) and delayed neural development, and is due to heterozygous mutations that are clustered in exons 6–10 of the transcription factor nuclear factor I/X (NFIX) gene. These frameshift and splice-site NFIX variants result in t...

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...

ea0013p4 | Bone | SFEBES2007

Mapping of a renal calcification locus to a 5-megabase region on mouse chromosome 17B1/B2

Stechman Michael , Loh Nellie , Reed Anita , Ahmad Bushra , Stewart Michelle , Hacker Terry , Wells Sara , Hough Tertius , Bentley Liz , Harding Brian , Christie Paul , Cox Roger , Dear Neil , Brown Steve , Thakker Rajesh

Calcium-containing renal stones, which affect 7% of adults, may be associated with endocrine and metabolic disorders that include primary hyperparathyroidism, renal tubular acidosis, hypercalciuria and hyperoxaluria. In addition, ∼40% of patients with stones have a familial history, although the genetic defects remain to be elucidated. To facilitate this, we have established a mouse model for renal calcification, designated Rcalc1, and determined its chromosomal l...

ea0013p12 | Bone | SFEBES2007

Localisation of a renal calcification locus to a 5 Mbp-region on mouse chromosome 11D-E2

Ahmad Bushra , Loh Nellie , Reed Anita , Stechman Michael , Stewart Michelle , Hacker Terry , Wells Sara , Hough Tertius , Bentley Liz , Harding Brian , Christie Paul , Cox Roger , Dear Neil , Brown Steve , Thakker Rajesh

Kidney stones, which affect 5% of adults, are most frequently associated with hypercalciuria or hypercalcaemia. Furthermore, kidney stones may occur in families in ∼40% of patients, thereby implicating the involvement of genetic mechanisms. To further elucidate these, we have established a mouse model for renal calcification, designated Rcalc2, and determined its chromosomal localisation. Mice were kept in accordance with UK Home Office welfare guidelines and proj...