Searchable abstracts of presentations at key conferences in endocrinology

ea0013p19^ | Endocrine tumours and neoplasia | SFEBES2007

Genetic background influences expression of Multiple Endocrine Neoplasia type 1 (MEN1) mutation, implicating a role for genetic modifiers

Lemos Manuel , Harding Brian , Thakker Rajesh

The Multiple Endocrine Neoplasia type 1 (MEN1) gene is located on chromosome 11q13 and patients with mutations develop parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP) and the same MEN1 mutations, in different families, can cause either FIHP or MEN1. This emphasises the importance of genetic background in altering the expression of a mutation, and suggests the presence of genetic ...

ea0013p203 | Endocrine tumours and neoplasia | SFEBES2007

Multiple endocrine neoplasia Type 1 (MEN1) caused by a novel mutation in intron 9 in a family with the McCune-Albright syndrome

Harding Brian , Lemos Manuel , Shalet Stephen , Thakker Rajesh

Objective: To investigate a family with the unusual combination of Multiple Endocrine Neoplasia (MEN1) and the McCune-Albright syndrome for mutations of the MEN1 and GNAS1 genes. MEN1 is an autosomal dominant disorder characterised by parathyroid, pancreatic and pituitary tumours whereas the McCune-Albright syndrome is a sporadic disorder characterised by polyostotic fibrous dysplasia, skin pigmentation and hyperfunctioning endocrine tumours.<p class="abstext...

ea0015p175 | Endocrine tumours and neoplasia | SFEBES2008

Assessment of in vivo proliferation rates in insulinomas of multiple endocrine neoplasia type 1 knockout mice: implications for evaluating effectiveness of future treatments

Walls Gerard V , Reed Anita AC , Harding Brian , Jeyabalan Jeshmi , Thakker Rajesh V

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...

ea0015p180 | Endocrine tumours and neoplasia | SFEBES2008

Somatostatin producing cells are significantly decreased in insulinoma islets of multiple endocrine neoplasia type 1 (MEN1) knockout mice: implication for pancreatic proliferation rates

Reed Anita AC , Jeyabalan Jeshmi , Walls Gerard V , Harding Brian , Thakker Rajesh V

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...

ea0015p190 | Endocrine tumours and neoplasia | SFEBES2008

Construction of a recombinant adenovirus vector for Men1 gene delivery

Lemos Manuel , Bazan-Peregrino Miriam , Harding Brian , Seymour Len , Thakker Rajesh

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...

ea0013p1 | Bone | SFEBES2007

Characterisation of 25 calcium-sensing receptor mutations in disorders of calcium homeostasis

Christie Paul , Curley Alan , Nesbit M Andrew , Harding Brian , Bowl Michael , Thakker Rajesh

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...

ea0013p2 | Bone | SFEBES2007

Mechanisms of DNA binding by the transcription factor GATA3 revealed by mutations causing the hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome

Grigorieva Irina , Christie Paul , Ali Asif , Harding Brian , Nesbit M Andrew , Thakker Rajesh

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...

ea0013p116 | Comparative | SFEBES2007

Genome comparison between human chromosome 19q13 and syntenic region on mouse chromosome 7 reveals loss, in man, of 5.1 Mb containing 4 mouse G-protein coupled receptors: relevance to familial benign hypocalciuric hypercalcaemia type 3

Hannan Fadil , Andrew Nesbit M , Christie Paul , Harding Brian , Whyte Michael , Thakker Rajesh

The calcium-sensing receptor (CaSR) belongs to family C of G-protein coupled receptors (GPCRs) that bind glutamate, GABA, taste molecules and pheromones. Loss-of-function mutations of the CASR gene located on chromosome 3q21–24, cause familial benign hypocalciuric hypercalcaemia type 1 (FBHH1). The genes causing FBHH2 and FBHH3, whose chromosomal locations are on 19p and 19q13.3, respectively, remain unknown. FBHH3, sometimes called the Oklahoma variant (FBHHO...

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...

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...