Endocrine Abstracts

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by the occurrence of anterior pituitary, pancreatic islet and parathyroid tumours. Mice (Men1+/−) deleted for an MEN1 allele develop these tumours. The MEN1 gene encodes a 610 amino acid protein that has been reported to upregulate caspase 8 expression and promote apoptosis. To characterize the functional effects of menin loss in vivo, we asse...

MicroRNAs (miRNAs) are small non-coding RNAs of ~22 nucleotides that negatively regulate gene expression through imperfect base pairing to the 3′ untranslated regions (UTRs) of target mRNAs. We have investigated the role of the miR-15a–miR-16-1 cluster in pituitary tumourigenesis, as it functions in other cancers as a tumour suppressor via regulation of the cell-cycle regulator cyclin D1. We have used two approaches: 1) in vitro studies examinin...

Glial-cell missing b (GCMB) is a parathyroid-specific gene whose loss results in parathyroid agenesis while haploinsufficiency of GATA3, which belongs to a family (GATA1-6) of dual zinc-finger transcription factors causes the hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome. We investigated the possibility that GATA3 regulates GCMB expression. Our bioinformatics analysis revealed 5 putative GATA3 binding sites in the 1.3 kb region upstream of exon 1 of GCMB...

Familial Juvenile Hyperuricaemic Nephropathy (FJHN) is an autosomal dominant disorder that is associated with gout and progressive renal failure. FJHN in 43 families has been reported to be caused by mutations in the UMOD gene, which encodes Uromodulin, also known as the Tamm-Horsfall Glycoprotein, and two families have been reported to have mutations in the transcription factor Hepatocyte Nuclear Factor 1β (HNF-1β), mutations of which usually cause maturity-o...

Pancreatic endocrine tumours (PETs) have a low proliferation index and this partially accounts for their lack of response to chemotherapy. The assessment of proliferation rates relies largely on the use of markers such as Ki67 in patients, and uptake of DNA nucleotide precursors such as tritiated thymidine or 5-bromo-2-deoxyuridine (BrdU) in animals. Amongst these, BrdU is recognised to be the most reliable marker of cell proliferation as it allows the substitution of an endog...

D cells comprise 3–10% of the human endocrine pancreas and secrete somatostatin, which inhibits cell proliferation and hormone secretion. Pancreatic tumours secreting somatostatin are associated with the somatostatinoma syndrome, which is characterised by hyperglycaemia, cholethiasis, a low acid output and anaemia. We have examined for the presence of somatostatin secreting cells in pancreatic tumours from a multiple endocrine neoplastic type 1 (MEN1) knockout mouse model...

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of tumours of the parathyroids, pancreas and pituitary. MEN1 is caused by germline inactivating mutations of the MEN1 gene which is located on chromosome 11q13 and encodes a 610 amino acid protein, menin. MEN1 tumours show loss of heterozygosity (LOH) of chromosome 11q13, and lack menin expression, consistent with a tumour suppressor role for MEN1...

The calcium-sensing receptor (CaSR) plays a central role in regulating parathyroid hormone (PTH) secretion in response to changes in extracellular calcium. The CaSR is a G-protein-coupled receptor and ligand binding results in stimulation of phospholipase C (PLC) activity, causing accumulation of inositol 1,4,5-triphosphate (IP3) and the rapid release of calcium ions from intracellular stores. Given the pivotal role of the CaSR in calcium homeostasis, we decided to ...

Ligand binding by the calcium-sensing receptor (CaSR), which belongs to family C of the G-protein coupled receptor super-family, activates the phospholipase C-inositol triphosphate pathway and leads to an increase in intracellular calcium. CaSR inactivating mutations result in the hypercalcaemic disorders of familial benign hypocalciuric hypercalcaemia (FBHH) and neonatal severe primary hyperparathyroidism (NSHPT), whilst activating mutations result in the hypocalcaemic disord...

Mutations leading to haploinsufficiency of the dual zinc finger transcription factor GATA3 result in the hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome which is an autosomal dominant disorder. We investigated 21 HDR probands and 14 patients with isolated hypoparathyroidism for GATA3 abnormalities. Venous blood was obtained after informed consent, as approved by the local ethical committee, and leukocyte DNA extracted. GATA3 specific primers were used for PCR amplif...