Searchable abstracts of presentations at key conferences in endocrinology

ea0021oc4.3 | Bone and parathyroid | SFEBES2009

Mice deleted for the transcription factor Gata3 have fewer parathyroid cells expressing Gcm2, develop hypocalcaemia and have an earlier onset of mortality when challenged with a low calcium-vitamin D diet

Grigorieva Irina , Mirczuk Samantha , Gaynor Katie , Nesbit M Andrew , Grigorieva Elena , Wei Qiaozhi , van der Wees Jacqueline , Fraser William , Hough Tertius , Manley Nancy , Grosveld Frank , Thakker Rajesh

Heterozygous mutations of GATA3, a dual zinc-finger transcription factor, cause the hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome. To study the role of GATA3 in parathyroid function we have investigated Gata3+/− mice for hypoparathyroidism. Gata3+/− and Gata3+/+ mice were challenged at weaning with a diet low in calcium (0.001%) and vitamin D (0.0 IU/g). The low calcium-vitamin D diet led to a ...

ea0021oc4.4 | Bone and parathyroid | SFEBES2009

Rapid screening for novel bone phenotypes in 100 consecutive lines from the Wellcome Trust Sanger Institute Gene Targeting Programme

Gogakos Apostolos , Bassett Duncan , van der Spek Anne , Evans Holly , White Jacqui , Ramirez-Solis Ramiro , Steel Karen , Bradley Allan , Thakker Rajesh , Croucher Peter , Williams Graham

The Wellcome Trust Sanger Institute Gene Targeting Programme is deleting all mouse genes and has already generated 400 knockout mice in a C57/BL6N background with a further 4000 genes targeted in ES cells. Two hundred and fifty new knockouts will undergo limited phenotyping each year. However, the programme lacks a sensitive and sufficiently detailed screen for individual physiological systems, each of which requires high throughput methodology and unique expertise. Thus, we p...

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...

ea0021p19 | Bone | SFEBES2009

Hereditary renal calcification locus, Rcalc1, is associated with altered expression of cell survival genes

Loh Nellie Y , Stechman Michael J , Schulz Herbert , Jeyabalan Jeshmi , Reed Anita A C , Ahmad Bushra , Stewart Michelle , Brown Steve D M , Huebner Norbert , V. Thakker Rajesh

Renal stone disease is a common disorder for which the underlying causes remain largely unknown. We have investigated a hereditary renal calcification mouse model, Rcalc1, that is not associated with hypercalciuria for underlying mechanisms. Kidney RNA from 30 to 33 week-old Rcalc1 and control BALB/c and C3H female mice (n=4/group) was extracted and hybridised to Mouse Genome 430 2.0 arrays (Affymetrix). Following Robust Multichip Average normalization, pair-wise compar...

ea0021p21 | Bone | SFEBES2009

Transient receptor potential cation channel, subfamily Vanilloid, member 5 (Trpv5) mutation (Ser682Pro) results in loss of apical membrane expression in the distal convoluted tubule, thereby resulting in hypercalciuria

Loh Nellie Y , Dimke Henrik , Bentley Liz , Tammaro Paolo , Hough Tertius , Cox Roger D , Brown Steve D M , Ashcroft Frances M , Hoenderop Joost , Bindels Rene , Thakker Rajesh V

Transient receptor potential cation channel, subfamily Vanilloid, member 5 (TRPV5) is a member of the TRP superfamily. TRPV5, which functions as a tetramer, is localized to apical membranes of distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, and is involved in vitamin D-regulated calcium reabsorption. Mice with a targeted deletion of Trpv5 (Trpv5−/−) develop severe hypercalciuria, compensatory hyperabsorption of dietary ...

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...

ea0015p191 | Endocrine tumours and neoplasia | SFEBES2008

In vivo delivery of an adenoviral gene therapy vector to pituitary tumours in Men1 deficient mice

Lemos Manuel , Harding Brian , Reed Anita , Walls Gerard , Tyler Damian , Bazan-Peregrino Miriam , Ansorge Olaf , Clarke Kieran , Seymour Len , Thakker Rajesh

The mouse knockout model for multiple endocrine neoplasia type 1 (MEN1) closely resembles the phenotype of the human disorder, with frequent development of tumours of the parathyroids, pancreas and pituitary. These tumours have loss of heterozygosity (LOH) of the Men1 locus and lack expression of the encoded protein (menin).The aim of this study was to investigate the feasibility of detecting pituitary tumours in heterozygous (Men1+/−...

ea0013p10 | Bone | SFEBES2007

Calcium homeostasis and parathyroid function in Gata3 knockout mice: relevance to the human hypoparathyroidism, deafness and renal dysplasia syndrome

Grigorieva Irina , Harding Brian , Nesbit M Andrew , Fairclough Rebecca , Grigorieva Elena , Ali Asif , Hough Tertius , Fraser William , van Wees Jaqueline , Grosveld Frank , Thakker Rajesh

The Hypoparathyroidism, Deafness and Renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by mutations in the dual zinc-finger transcription factor GATA-3. Gata3 heterozygous (+/−) knockout mice develop deafness, while Gata3 homozygous (−/−) mice, which are embryonically lethal at 11.5 to 12.5 days post-coitum (dpc), develop renal hypoplasia. The parathyroids have not been studied, and we therefore investigated these mice for ...

ea0013p126 | Growth and development | SFEBES2007

Characterisation of parathyroid-specific transcription factor Glial Cells Missing Homolog B (GCMB) in 3 families with autosomal recessive hypoparathyroidism

Bowl Michael , Mirczuk Samantha , Southam Lorraine , Mughal Zulf , Ryan Fiona , Shaw Nick , Tham Elaine , Hochberg Ze’ev , Tiosano Dov , Loughlin John , Andrew Nesbit M , Thakker Rajesh

GCMB, which is the mammalian homologue of the Drosophila gene Glial cells missing, encodes a 506 amino acid parathyroid-specific transcription factor that contains: a DNA-binding domain at residues 21–174; a predicted nuclear localization signal at residues 176–193; an inhibitory domain at residues 258–347; and two transactivation domains at residues 174–263, and residues 428–506. Mutations of GCMB, which is located on chrom...

ea0013p140 | Diabetes, metabolism and cardiovascular | SFEBES2007

cDNA expression profiling studies reveal 7 differentially expressed genes on mouse chromosome 7 that may influence renal calcification in C3H/HeH inbred mice

Loh Nellie , Stechman Michael , Reed Anita , Ahmad Bushra , Stewart Michelle , Hacker Terry , Schulz Herbert , Born Gabi , Dear Neil , Brown Steve , Hubner Norbert , Thakker Rajesh

Vascular calcification, occurring in organs such as heart and kidneys, is associated with increased risk of cardiovascular mortality. The underlying molecular mechanisms remain unknown. To elucidate these, we investigated C3H mice, an inbred strain susceptible to vascular, myocardial and renal calcification. Myocardial calcification in C3H mice involves 4 genetic loci, Dyscalc1-4, that map to chromosomes 7, 4, 12 and 14, respectively. Dyscalc1 contributes to myoc...