Searchable abstracts of presentations at key conferences in endocrinology

ea0021p154 | Diabetes and metabolism | SFEBES2009

Infidelity of ectopic transcription using a pseudo splice site: lessons from HNF-1β mutation causing familial juvenile hyperuricaemic nephropathy

Piret Sian , Reed Anita , Reilly Jennifer , Turner Neil , Thakker Rajesh

Ectopic (or ‘illegitimate’) transcripts, which have been widely used to study disease-causing mutations when samples from the appropriate tissue cannot be obtained, are generally faithful representations of the normal tissue-specific counterparts. Here, we report the occurrence of ectopic transcripts of the hepatocyte nuclear factor-1 beta (HNF-1β) gene, mutations of which may result in maturity onset diabetes of the young type 5 (MODY5), the renal cysts ...

ea0015p145 | Diabetes, metabolism and cardiovascular | SFEBES2008

Tamm-Horsfall glycoprotein mutants, which cause familial juvenile hyperuricaemic nephropathy are retained in the endoplasmic reticulum, resulting in delayed maturation and trafficking to the plasma membrane

Williams Sian , Reed Anita , Antignac Corinne , Galvanovskis Juris , Thakker Rajesh

Background: Mutations in the UMOD gene, which encodes the Tamm-Horsfall Glycoprotein (THP), cause FJHN, an autosomal dominant disorder characterised by gout and renal failure. THP is a 640 amino acid glycosylphosphatidylinositol-anchored protein, containing three Epidermal Growth Factor (EGF)-like domains, a cysteine-rich region and a Zona Pelllucida (ZP) domain. THP is translated into the Endoplasmic Reticulum (ER) lumen, glycosylated in the Golgi apparatus, trafficked...

ea0031yep1.1 | Young endocrinologists' prize lectures | SFEBES2013

Clinical and pre-clinical studies of neuroendocrine tumours (NETs) in multiple endocrine neoplasia type 1 (MEN1), and evaluation of MEN1 gene replacement therapy for MEN1-associated NETs.

Walls Gerard , Newey Paul , Lemos Manuel , Javid Mahsa , Piret Sian , Reed Anita , Thakker Rajesh

We have studied clinical and pre-clinical models to investigate neuroendocrine tumour (NET) development and efficacy of novel therapy for NETs. We focused on multiple endocrine neoplasia type 1 (MEN1), an autosomal dominantly inherited condition characterised by the combined occurrence of pancreatic islet and anterior pituitary NETs with parathyroid and adrenocortical tumours. MEN1 is due to MEN1 gene mutations that inactivate Menin, a tumour suppressor. Our clinical studies r...

ea0021oc3.4 | Young Endocrinologists prize session | SFEBES2009

MicroRNAs, let-7 and miR-302, have an altered expression in Men1-null embryos, consistent with abnormal embryonic development

Bowl Michael , Newey Paul , Reed Anita , Walls Gerard , Baban Dilair , Nesbit Andrew , Thakker Rajesh

The multiple endocrine neoplasia type 1 (MEN1) gene, which when mutated gives rise to parathyroid, pancreatic and pituitary tumours, has been shown to have a role in embryogenesis, as Men1-null mice (Men1−/−) are embryonic lethal by 12.5 days post coitum (dpc). MicroRNAs (miRNAs) are emerging as potent regulators of early mammalian embryogenesis, and we therefore undertook expression profiling of miRNAs in Men1+/+ and M...

ea0021p177 | Diabetes and metabolism | SFEBES2009

Mice harbouring the familial juvenile hyperuricaemic nephropathy disease-causing uromodulin (Tamm--Horsfall glycoprotein) mutation Cys125Arg, have a urine concentrating defect, progressive renal failure, and altered uric acid handling

Piret Sian , Reed Anita , Nesbit M Andrew , Hough Tertius , Bentley Liz , Cox Roger , Thakker Rajesh

Familial juvenile hyperuricaemic nephropathy (FJHN), an autosomal dominant disorder characterised by raised serum urate, reduced fractional excretion of uric acid (FEUA), a urine concentrating defect, and progressive renal failure, is caused by mutations in the UMOD gene, encoding uromodulin (Tamm–Horsfall glycoprotein). The FJHN-causing UMOD mutations are missense mutations (>90%) or inframe deletions (<10%), and none result in prematurely truncated...

ea0021p305 | Pituitary | SFEBES2009

MicroRNAs, miR-15a and miR-16-1, are implicated in pituitary tumourigenesis via regulation of cyclin D1

Newey Paul , Dyar Rebecca , Nesbit Andrew , Javid Mahsa , Walls Gerard , Reed Anita , Bowl Michael , Thakker Rajesh

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...

ea0015p156 | Diabetes, metabolism and cardiovascular | SFEBES2008

Familial juvenile hyperuricaemic nephropathy is due to mutations in Tamm-Horsfall protein and hepatocyte nuclear factor 1β: further evidence for genetic heterogeneity

Williams Sian , Reed Anita , Reilly Jennifer , Karet Fiona , Lhotta Karl , Strehlau Juergen , Turner Neil , Thakker Rajesh

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...

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...

ea0013oc22 | Novartis Basic Endocrinology Award | SFEBES2007

Mice deleted for a Multiple Endocrine Neoplasia Type 1 (MEN1) allele develop pancreatic, pituitary and parathyroid tumours in association with hypercalcaemia

Lemos Manuel , Harding Brian , Bowl Michael , Reed Anita , Tateossian Hilda , Hough Tertius , Fraser William , Cheeseman Michael , 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. The MEN1 gene, which is located on chromosome 11q13 and encodes a 610 amino acid protein (menin), belongs to the class of tumour suppressors. To investigate the role of menin in tumour suppression, three different mouse models have been generated through targeted disruption of the Men1 gene. ...