Searchable abstracts of presentations at key conferences in endocrinology

ea0031oc1.7 | Young Endocrinologists prize session | SFEBES2013

Autosomal dominant hypocalcemia type 2 is caused by germline GNA11 gain-of-function mutations

Howles Sarah , Nesbit Andrew , Hannan Fadil , Babinsky Valerie , Head Rosie , Cranston Treena , Rust Nigel , 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 gain-of-function mutations in autosomal dominant hypocalcemia (ADH). Recently, loss-of-function Gα11 mutations have been identified to cause FHH2 and we hypothesised that gain-of-function Gα11...

ea0025oc4.1 | Bone and diabetes | SFEBES2011

A mouse with an ENU-induced mutation (Tyr209Asn) in the natriuretic peptide receptor 3 (Npr3) develops autosomal recessive kyphosis

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

Kyphosis is a common spinal disorder affecting up to 8.3% of the population, and associated with significant morbidity. Familial and twin studies have implicated a genetic involvement. However, the causative genes have not been identified. Studies investigating the underlying molecular mechanisms are hampered by genetic heterogeneity, small families and variable modes of inheritance displayed by different kindreds. To overcome these limitations, we investigated 12 week old pro...

ea0025p17 | Bone | SFEBES2011

A 5′-untranslated region mutation of the growth and differentiation factor 5 (Gdf5) gene increases expression and is associated with decreased urinary excretion of the cartilage degradation product, CTX-II: relevance to osteoarthritis

Nesbit M Andrew , Esapa Chris , Head Rosie , Gaynor Katie , Cox Roger , Brown Steve , Thakker Rajesh

Osteoarthritis (OA) may be associated with endocrine disorders such as hypothyroidism, obesity, primary hyperparathyroidism or acromegaly, although often its cause remains undefined. To facilitate investigations of the underlying molecular mechanisms of OA we have investigated N-ethyl-N-nitrosourea (ENU) mutant mice using a genotype-driven approach in which candidate genes are examined for mutations. One such investigated gene is growth and differentiation factor...

ea0021p214 | Endocrine tumours and neoplasia | SFEBES2009

Mutations of the transcription factor, GATA3, in oestrogen receptor positive breast cancers

Gaynor Katherine , Grigorieva Irina , Esapa Chris , Head Rosie , Christie Paul , Nesbit Andrew , Jones Louise , Thakker Rajesh

Mutations of the transcription factor GATA3, which is important for maintaining human breast luminal epithelial cell differentiation and quiescence, have been reported in 17 oestrogen receptor (ER) positive breast cancers, although the functional effects of these mutations have not been studied. We therefore investigated 56 ER-positive breast cancers for GATA3 mutations. The tumours were macrodissected, and immunohistochemistry for GATA3 revealed a strong correlation between E...

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 ...

ea0021p5 | Bone | SFEBES2009

A mouse model, Slip, for an X-linked metaphyseal chondrodysplasia

Esapa Chris , Head Rosie , Di Pretoro Simona , Crane Elisabeth , Evans Holly , Thomas Gethin , Brown Steve , Cox Roger , Brown Matt , Croucher Peter , Thakker Rajesh

Investigations of skeletal dysplasias which are often inherited have yielded important insights in the molecular mechanisms of bone development, osteoporosis and osteoarthritis. However, these studies have been hampered by the lack of available patients and affected families. To overcome this limitation, we have investigated mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for hereditary musculoskeletal disorders. Mice were kept in accordance wi...

ea0021p23 | Bone | SFEBES2009

A mouse model of early-onset renal failure, tertiary hyperparathyroidism and renal osteodystrophy

Esapa Chris , Head Rosie , Di Pretoro Simona , Crane Elisabeth , Loh Nellie , Devuyst Olivier , Thomas Gethin , Brown Steve , Brown Matt , Croucher Peter , Cox Roger , Thakker Rajesh

Abnormalities of calcium homeostasis such as secondary or tertiary hyperparathyroidism, and renal osteodystrophy often occur in patients with kidney failure. However, investigations of the underlying molecular mechanisms have been hampered by the lack of available tissues from patients and the lack of suitable animal models. We therefore sought to overcome this limitation by investigating mice treated with the chemical mutagen N-ethyl-N-nitrosourea and identified...

ea0031oc2.6 | Steroids and thyroid | SFEBES2013

An N-ethyl-N-nitrosourea induced Corticotrophin releasing hormone promoter mutation provides a mouse model of Cushing's syndrome

Bentley Liz , Esapa Christopher T , Nesbit M Andrew , Head Rosie A , Evans Holly , Lath Darren , Hough Tertius A , Podrini Christine , Fraser William D , Croucher Peter I , Brown Matthew A , Brown Steve D M , Cox Roger D , Thakker Rajesh V

Cushing’s syndrome, which is characterised by excessive circulating glucocorticoid (GC) concentrations, may be due to ACTH-dependent or -independent causes that include anterior pituitary and adrenal cortical tumours, respectively. In the course of our phenotype-driven screens of mouse mutants induced by the chemical mutagen N-ethyl-N-nitrosourea (ENU), we observed a mutant mouse with obesity, hyperglycaemia and low bone mineral density, features that ar...

ea0031oc5.3 | Pituitary and neoplasia | SFEBES2013

Whole-exome sequencing studies of non-functioning pituitary adenomas

Newey Paul , Nesbit M Andrew , Rimmer Andrew , Head Rosie , Gorvin Caroline , Attar Moustafa , Gregory Lorna , Wass John , Buck David , Karavitaki Niki , Grossman Ashley , McVean Gilean , Ansorge Olaf , Thakker Rajesh

Pituitary non-functioning adenomas (NFAs), arising mostly from gonadotroph cells, represent the second most common type of pituitary tumour, after prolactinomas. NFAs are monoclonal in origin, but mutations of genes associated with hereditary pituitary syndromes (e.g. MEN1, AIP, CDKN1B, and PRKAR1A), classic oncogenes or tumour suppressor genes are rarely found. We therefore performed whole-exome sequence analysis to determine the tumourigenic events in pituitary NFAs using DN...