Endocrine Abstracts

The prolactin receptor (PRLR) is a type-I cytokine receptor that plays critical roles in mammary gland development, lactation and glucose metabolism, and PRLR mutations have been associated with breast cancer and familial hyperprolactinaemia. The PRLR signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation, and we hypoth...

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the occurrence of parathyroid, pancreatic and pituitary tumours, and is due to mutations of the MEN1 gene, which encodes menin. We have investigated identical twins with MEN1, one of whom developed primary hyperparathyroidism (PHPT) and a prolactinoma that caused pubertal arrest, and the other had PHPT only. DNA sequence analysis of the MEN1 coding region had not ide...

Pseudohypoparathyroidism (PHP) is due to parathyroid hormone (PTH) resistance that results in hypocalcaemia, hyperphosphataemia and elevated plasma PTH concentrations. Some PHP patients also have Albright’s hereditary dystrophy (AHO), which is characterised by short stature, round faces, dental hypoplasia, brachydactyly, subcutaneous ossifications and reduced mental acuity. The 3 major types of PHP referred to as PHP type 1a (PHP1a), PHP1b and pseudopseudohypoparathyroidi...

Neuroendocrine tumours (NETs) occur in multiple sites including, the pancreas, gastrointestinal tract, lung, thymus, parathyroid, adrenals and pituitary. Current treatments for advanced NETs such as surgery, chemotherapy or radiotherapy, rarely achieve a cure due to metastases at presentation therefore additional therapeutic treatments are required. Identification of cell surface receptors or binding sites that are unique or up-regulated on tumour or neuroendocrine tissue coul...

Loss-of-function mutations of the calcium-sensing receptor (CaSR), a G-protein-coupled receptor (GPCR), result in familial hypocalciuric hypercalcaemia (FHH), a disorder of extracellular calcium homeostasis affecting the parathyroids and kidneys. However, around 35% of FHH patients do not have CaSR mutations. A form of FHH, designated FHH2, has been mapped to chromosome 19p. The GNA11 gene, encoding G-protein α11 (Gα11), a component of the CaSR sign...

Dent’s disease, due to mutations in the chloride/proton antiporter, CLC-5, represents one form of familial hypophosphataemic rickets. Dent’s disease patients also have: low-molecular-weight-proteinuria; hypercalciuria with nephrolithiasis and renal failure; and urinary loss of parathyroid hormone and vitamin D-binding protein, due to defective receptor-mediated endocytosis within the renal proximal tubule. However, there is variability in these clinical phenotypes su...

The calcium-sensing receptor (CaSR) is a G protein-coupled receptor with an extracellular bilobed venus flytrap domain (VFTD) predicted to contain five calcium-binding sites. The major site for calcium-binding is comprised of amino acid residues that line the cleft between the two lobes of the VFTD. We investigated the structure-function relationships of VFTD CaSR mutations identified in patients with familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperpa...

Kyphosis and scoliosis are common spinal disorders that lead to significant morbidity in childhood, adolescence and adulthood. Familial and twin studies have implicated a genetic involvement, although the causative genes remain to be identified. To facilitate these studies, we investigated 12-week-old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments that included dysmorphology, radiography and dual-energy ...

Receptor-mediated endocytosis (RME), involving megalin and cubilin, mediates renal proximal-tubular reabsorption of glucose, proteins and hormones including insulin, parathyroid-hormone and vitamin D. RME disruption occurs in Dent’s disease patients with mutations of the chloride/proton antiporter, CLC-5, who suffer from low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis and renal failure. To further investigate the RME role of CLC-5 we established conditio...

Multiple endocrine neoplasia type 1 (MEN1) is characterised by the combined occurrence of pituitary, pancreatic and parathyroid tumours. The MEN1 gene encodes a 610-amino acid tumour suppressor, menin, and MEN1-associated tumours show loss of heterozygosity. This indicates that replacement of the wild-type MEN1 gene may inhibit tumourigenesis. We have previously demonstrated that a recombinant adenoviral vector could be safely injected directly into pituit...