SFEBES2009 Oral Communications Bone and Calcium (8 abstracts)
Nuf mice with an activating calcium sensing receptor mutation, Leu723Gln, have hypercalciuria and diabetes insipidus
F Hannan 1 , G Walls 1 , M Nesbit 1 , T Hough 2 , B Shine 3 , M Cheeseman 2 , M Lyon 2 , R Cox 2 & R Thakker 1
1Academic Endocrine Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 2Medical Research Council, Harwell, Oxfordshire, UK; 3Department of Clinical Biochemistry, Oxford Radcliffe Hospitals Trust, Oxfordshire, UK.
The calcium sensing receptor (CaSR) is a G protein coupled receptor that is expressed in the parathyroids and kidneys, where it plays a pivotal role in the regulation of extracellular calcium homeostasis. Patients with activating CaSR mutations have autosomal dominant hypocalcaemia with hypercalciuria (ADHH), which is associated with polydipsia, polyuria, nephrocalcinosis and renal impairment. The Nuf mouse, which has an activating CaSR mutation (Leu723Gln) has been reported to have hypocalcaemia. We have performed metabolic cage studies to assess for the occurrence of polydipsia, polyuria and hypercalciuria. Mice were kept in accordance with UK Home Office welfare guidelines and project license restrictions and housed in metabolic cages with ad libitum feeding for 5 days to allow acclimatisation. Daily water intake and urine volume were measured and plasma and urine samples obtained for biochemical analysis. Mouse genotypes were determined by PCR amplification using auricular biopsy DNA and Pst1 restriction endonuclease analysis. Nuf/Nuf mice were significantly hypercalciuric, polyuric and polydipsic when compared to wild-type (WT) litter-mates (24-hour urine calcium creatinine clearance ratio=3.8±0.34×10−4 versus 2.9±0.29×10−4, P<0.05; 24-hour urine volume=4.0±0.41 vs 2.72±0.18 ml, P<0.01; 24-hour water intake=8.88±0.41 vs 7.38±0.36 ml, P<0.05). In addition, Nuf/Nuf mice had a significantly raised plasma osmolality and decreased urine osmolality when compared to WT litter-mates (plasma osmolality=367.6±4.3 vs 356.0±3.2 mOsm/kg, P<0.05; urine osmolality=1692±105 vs 2142±141 mOsm/kg; P<0.05), consistent with a urinary concentrating defect. These results demonstrate that Nuf/Nuf mice have hypercalciuria, polyuria, polydipsia and a urinary concentrating defect. Thus, Nuf mice represent a model for the human disorder of ADHH, and highlight a potential role of the CaSR in water homeostasis.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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