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 ...

ea0038p2 | Bone | SFEBES2015

Exploring the N-ethyl-N-nitrosourea mutagenesis DNA archive for mutations in nuclear factor I/X to derive mouse models for Marshall-Smith syndrome

Kooblall Kreepa , Stevenson Mark , Piret Sian , Potter Paul , Cox Roger , Brown Steve , Hennekam Raoul , Thakker Rajesh

Marshall-Smith syndrome (MSS) is a congenital disorder affecting skeletal and neural development due to mutations in the nuclear factor I/X (NFIX) gene. Of these mutations, 61% are small insertions/deletions, 12% are splice site mutations and 27% are large exonic deletions clustered in exons 6–10 of the NFIX gene. In order to derive a MSS mouse model, the N-ethyl-N-nitrosourea (ENU) mutagenesis DNA archive was screened ...

ea0034oc4.1 | Thyroid and bone | SFEBES2014

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 exert dominant-negative effects

Howles Sarah , Nesbit M Andrew , Hannan Fadil , Rogers Angela , Piret Sian , Rust Nigel , Thakker Rajesh

Adaptor protein-2 (AP2) is a heterotetramer of α, β, μ, and σ subunits that is pivotal in clathrin-mediated endocytosis and facilitates internalisation of plasma membrane constituents such as the calcium-sensing receptor (CaSR). AP2 σ subunit (AP2σ) missense mutations (Arg15Cys, Arg15His and Arg15Leu) result in familial hypocalciuric hypercalcaemia type 3 (FHH3) and decrease the sensitivity of CaSR-expressing cells to changes in extracellular calc...

ea0034oc4.5 | Thyroid and bone | SFEBES2014

A mutation in the 5′-UTR of GNA11 causes familial hypocalciuric hypercalcemia type 2 due to reduced translational efficiency

Howles Sarah , Nesbit MAndrew , Hannan Fadil , Piret Sian , Cranston Treena , Rahman Mushtaqur , Thakker Rajesh

The calcium-sensing receptor (CaSR) is a guanine-nucleotide-binding protein (G-protein)-coupled receptor that has a central role in calcium homeostasis. Loss-of-function mutations of the CaSR result in familial hypocalciuric hypercalcemia type 1 (FHH1) and loss-of-function coding mutations in the CaSR-associated G-protein subunit Gα11 have been reported to cause FHH2 in only two patients to date. The aim of our study was therefore to characterise additional <em...

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...

ea0031p3 | Bone | SFEBES2013

Mutations in CLC-5 cause disturbances in cytoskeletal dynamics and solute transport in Dent's disease renal proximal tubule cell-lines

Gorvin Caroline , Piret Sian , Baban Dilair , Wilmer Martijn , van den Heuvel Lambertus , Levtchenko Elena , Thakker Rajesh

Dent’s disease is a renal proximal tubular Fanconi disorder characterised by generalised loss of solutes incuding insulin, glucose, PTH, amino acids and vitamin-D binding protein and is associated with rickets in 25% and phosphaturia in ~40% of patients. Dent’s disease is caused by mutations in the chloride/proton antiporter CLC-5, which, with megalin and cubilin has a role in receptor-mediated endocytosis and vesicle trafficking. To further elucidate the role of CLC...

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...

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...

ea0065op3.4 | Metabolism and Obesity | SFEBES2019

Mice with a gain-of function Gα11 mutation have autosomal dominant hypocalcaemia, but not impaired glucose metabolism

Gluck Anna , Lines Kate , Gorvin Caroline , Babinsky Valerie , Piret Sian , Sarbu Stefan , Stewart Michelle , Bentley Liz , Wells Sara , Cox Roger , Ecker Rupert , Ellinger Isabella , Hannan Fadil , Thakker Rajesh

The calcium-sensing-receptor (CaSR) is a G-protein-coupled receptor that plays a fundamental role in extracellular calcium homeostasis, but is also implicated in non-calcitropic disorders including colon cancer and asthma. In addition, CaSR is highly expressed in pancreatic islets where it has a role in insulin secretion. Patients with gain-of-function CaSR mutations, and mice (referred to as Nuf) with a gain-of-function CaSR mutation (Leu723Gln), develop autosomal dominant hy...