Searchable abstracts of presentations at key conferences in endocrinology

ea0044p124 | Neoplasia, cancer and late effects | SFEBES2016

The prolactin receptor variant, Asn492Ile, results in activation of the Akt signalling pathway, and is found more frequently in patients with prolactinomas

Gorvin Caroline , Newey Paul , Stokes Victoria , Rogers Angela , Ntali Georgia , Lees Peter , Karavitaki Niki , Grossman Ashley , Thakker Rajesh

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...

ea0044p125 | Neoplasia, cancer and late effects | SFEBES2016

Multiple endocrine neoplasia type 1 (MEN1) in identical twins, with different MEN1 tumours, is due to a deletion of the MEN1 5′ untranslated region (UTR)

Kooblall Kreepa , Cranston Treena , Lines Kate , Stevenson Mark , Rogers Angela , Grozinsky-Glasberg Simona , Flanagan Daniel , Thakker Rajesh

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...

ea0059p053 | Bone and calcium | SFEBES2018

Identification of a frame-shifting c.348dupC GNAS mutation in a family with Pseudohypoparathyroidism type 1a (PHP1a) by Whole Genome Sequencing

Warner Bronwen E , Pagnamenta Alistair T , Stevenson Mark , Lines Kate E , Ahmed S Faisal , Taylor Jenny C , Thakker Rajesh V

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...

ea0034oc2.2 | Endocrine regulation of cell behaviour | SFEBES2014

Inhibition of human NET cell proliferation by a peptide identified through phage display screening

Stevenson Mark , Lines Kate , Zalmas Lykourgos-Panagiotis , Javid Mahsa , Galvanovskis Juris , Grozinsky-Glasberg Simona , Wood Matthew , Grossman Ashley , Thakker Rajesh

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...

ea0031p1 | Bone | SFEBES2013

GNA11 loss-of-function mutations cause familial hypocalciuric hypercalcaemia type 2 (FHH2)

Hannan Fadil , Nesbit M A , Howles Sarah , Babinsky Valerie , Cranston Treena , Rust Nigel , Hobbs Maurine , Heath III Hunter , Thakker Rajesh

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...

ea0031p7 | Bone | SFEBES2013

Alterations of CLC-5 expression, function and trafficking in Dent's disease

Gorvin Caroline , Wilmer Martijn , Piret Sian , Harding Brian , van den Heuvel Lambertus , Jat Parmjit , Lippiat Jonathan , Levtchenko Elena , Thakker Rajesh

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...

ea0028oc1.2 | Young Endocrinologists prize session | SFEBES2012

Structure-function analysis of calcium-sensing receptor (CaSR) mutations reveal clustering at calcium binding sites of the extracellular bilobed venus flytrap domain

Hannan Fadil , Nesbit M Andrew , Zhang Chen , Cranston Treena , Christie Paul , Fratter Carl , Brown Edward , Yang Jenny , Thakker Rajesh

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...

ea0025p14 | Bone | SFEBES2011

A gene causing autosomal dominant kyphoscoliosis in an N-ethyl-N-nitrosourea (ENU) mutagenised mouse model is located on a 5 Mb interval on mouse chromosome 4 band A3

Esapa Christopher , Head Rosie , Evans Holly , Thomas Gethin , Brown Matthew , Croucher Peter , Cox Roger , Brown Steve , Thakker Rajesh

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 ...

ea0025p136 | Diabetes, metabolism and cardiovascular | SFEBES2011

The Megalin-Cubilin receptor-mediated endocytic pathway is impaired in Dent's disease renal proximal tubule cell-lines

Gorvin Caroline , Wilmer Martijn , Loh Nellie , Piret Sian , Harding Brian , van den Heuvel Lambertus , Levtchenko Elena , Thakker Rajesh

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...

ea0021oc3.6 | Young Endocrinologists prize session | SFEBES2009

Men1 gene replacement therapy using a modified adenoviral vector demonstrates reduced proliferation rates in pituitary tumours from mice deleted for a multiple endocrine neoplasia type 1 allelle

Javid Mahsa , Walls Gerard , Lemos Manuel , Jeyabalan Jeshmi , Bazan-Peregrino Miriam , Tyler Damian , Stuckey Daniel , Seymour Len , Thakker Rajesh

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...