Searchable abstracts of presentations at key conferences in endocrinology

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...

ea0065ec1.4 | Clinical Endocrinology Trust Best Abstract Basic | SFEBES2019

Mice harbouring a germline heterozygous AP2S1 mutation, Arg15Leu, are a model for familial hypocalciuric hypercalcaemia type 3 (FHH3)

Hannan Fadil , Stokes Victoria , Gorvin Caroline , Stevenson Mark , Hough Tertius , Stewart Michelle , Wells Sara , Teboul Lydia , Thakker Rajesh

Familial hypocalciuric hypercalcaemia (FHH) comprises three genetic variants: FHH types 1 and 2 are due to mutations of the calcium-sensing receptor (CaSR) and G-protein subunit alpha-11, whereas, FHH type 3 (FHH3) is caused by heterozygous mutations affecting the Arg15 residue (Arg15Cys, Arg15His, Arg15Leu) of the adaptor-related protein complex 2-sigma subunit (AP2S1), which regulates CaSR endocytosis. FHH is usually associated with mild hypercalcaemia, normal parathyroid ho...

ea0044p44 | Bone and Calcium | SFEBES2016

The calcilytic SHP635 rectifies hypocalcaemia and reduced parathyroid hormone concentrations in a mouse model for autosomal dominant hypocalcaemia type 1 (ADH1)

Hannan Fadil , Babinsky Valerie , Gorvin Caroline , Hough Tertius , Joynson Elizabeth , Stewart Michelle , Wells Sara , Cox Roger , Nemeth Edward , Thakker Rajesh

Autosomal dominant hypocalcaemia type 1 (ADH1) is a systemic disorder of calcium homeostasis caused by gain-of-function mutations of the calcium-sensing receptor (CaSR). ADH1 may lead to symptomatic hypocalcaemia, inappropriately low parathyroid hormone (PTH) concentrations and hypercalciuria. Active vitamin D metabolites are the mainstay of treatment for symptomatic ADH1 patients, however their use predisposes to nephrocalcinosis, nephrolithiasis and renal impairment. Calcily...

ea0015oc24 | Tumours, diabetes, bone | SFEBES2008

The calcilytic agent NPS2143 rectifies hypocalcaemia in a mouse model, Nuf, that is due to an activating calcium-sensing-receptor (CaSR) mutation: relevance to autosomal dominant hypocalcaemia with hypercalciuria

Hannan Fadil , Walls Gerard , Kallay Eniko , Nesbit M Andrew , Hough Tertius , Cox Roger , Hu Jianxin , Spiegel Allen , Thakker Rajesh

The G-protein coupled calcium-sensing-receptor (CaSR) regulates calcium homeostasis and inactivating mutations result in familial hypocalciuric hypercalcaemia (FHH), whilst activating mutations result in autosomal dominant hypocalcaemia with hypercalciuria (ADHH). Allosteric CaSR modulators consist of: calcimimetics, which activate the CaSR e.g. Cinacalcet, that is used to treat the hypercalcaemia of chronic renal failure and metastatic parathyroid carcinoma; and calcilytics e...

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. ...

ea0013p149 | Diabetes, metabolism and cardiovascular | SFEBES2007

Metabolic cage studies reveal that mice require 5 days for acclimatisation: establishing normal urinary and blood biochemistry values in BALB/c and C3H/HeH inbred mouse strains

Stechman Michael , Ahmad Bushra , Loh Nellie , Reed Anita , Hough Tertius , Bentley Liz , Cox Roger , Brown Steve , Thakker Rajesh

Inbred laboratory mice are widely used to generate, by homologous recombination, transgenic and chemical mutagenesis routes, genetic models of human disease. However, physiological studies of such models are hampered by the lack of normal ranges for serum and urinary biochemistry, particularly in relation to acclimatisation following placement in metabolic cages. To establish such values, we investigated urinary and serum parameters in forty, 24–30 week-old C3H/HeH, BALB/...

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 ...

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 ...

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 ...