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...

ea0086p273 | Reproductive Endocrinology | SFEBES2022

Interleukin-15, a pleiotropic cytokine, is increased in the mammary gland during lactation

Robinson Maya , Allen Lois , Asteljoki Juho , Rostom Hussam , Meng Xin , Stewart Michelle , Elajnaf Taha , Hannan Fadil

Lactation promotes infant development and confers long-term health benefits to mothers and infants. However, the endocrine and paracrine mechanisms mediating milk synthesis remain to be fully elucidated. Hormones such as prolactin and progesterone trigger the onset of lactation, whereas local mammary factors are considered to play a greater role in the maintenance of milk synthesis. We hypothesised that mammary epithelial cytokines are required for established lactation, and u...

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...

ea0031p220 | Obesity, diabetes, metabolism and cardiovascular | SFEBES2013

Hepatic 11β-hydroxysteroid dehydrogenase type 1 is elevated following weight loss secondary to bariatric surgery

Woods Conor , Taylor Angela , Hughes Beverly , Corrigan Michelle , Stewart Paul , Tomlinson Jeremy , Shea Donal O , Sherlock Mark

In the pathogenesis of obesity, dysregulated tissue cortisol metabolism (controlled by 11β-HSD1), is postulated to be involved. Fifteen patients (seven mens, mean BMI 50.8±7 kg/m2) awaiting Roux En Y gastric Bypass (RYGB) surgery underwent assessment of 11β-HSD1 activity using cortisol generation profile. Corticosteroids in serum and subcutaneous adipose tissue microdialysis fluid and urinary corticosteroid metabolites were analysed by liquid and gas ...

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...

ea0021p19 | Bone | SFEBES2009

Hereditary renal calcification locus, Rcalc1, is associated with altered expression of cell survival genes

Loh Nellie Y , Stechman Michael J , Schulz Herbert , Jeyabalan Jeshmi , Reed Anita A C , Ahmad Bushra , Stewart Michelle , Brown Steve D M , Huebner Norbert , V. Thakker Rajesh

Renal stone disease is a common disorder for which the underlying causes remain largely unknown. We have investigated a hereditary renal calcification mouse model, Rcalc1, that is not associated with hypercalciuria for underlying mechanisms. Kidney RNA from 30 to 33 week-old Rcalc1 and control BALB/c and C3H female mice (n=4/group) was extracted and hybridised to Mouse Genome 430 2.0 arrays (Affymetrix). Following Robust Multichip Average normalization, pair-wise compar...

ea0013p140 | Diabetes, metabolism and cardiovascular | SFEBES2007

cDNA expression profiling studies reveal 7 differentially expressed genes on mouse chromosome 7 that may influence renal calcification in C3H/HeH inbred mice

Loh Nellie , Stechman Michael , Reed Anita , Ahmad Bushra , Stewart Michelle , Hacker Terry , Schulz Herbert , Born Gabi , Dear Neil , Brown Steve , Hubner Norbert , Thakker Rajesh

Vascular calcification, occurring in organs such as heart and kidneys, is associated with increased risk of cardiovascular mortality. The underlying molecular mechanisms remain unknown. To elucidate these, we investigated C3H mice, an inbred strain susceptible to vascular, myocardial and renal calcification. Myocardial calcification in C3H mice involves 4 genetic loci, Dyscalc1-4, that map to chromosomes 7, 4, 12 and 14, respectively. Dyscalc1 contributes to myoc...