Endocrine Abstracts

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...

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....

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...

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...

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...

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...

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...

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...

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...

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...