SFEBES2021 Oral Communications Bone and Calcium (6 abstracts)
Diacylglycerol kinase delta haploinsufficiency in mice causes hypocalcaemia: relevance to human Autosomal Dominant Hypoclacemia (ADH)
Michelle Goldsworthy 1,2 , Catherine Lovegrove 1,2 , Lee Moir 3 , Akira Wiberg 4 , Benjamin Turney 1 , Dominic Furniss 4 , Fadil Hannan 5 , Rajesh Thakker 2 & Sarah Howles 1,2
1Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom; 2Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; 3MRC Harwell Institute, Mary Lyon Centre, Harwell, United Kingdom; 4Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; 5Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, United Kingdom
Diacylglycerol kinase delta (DGKD) has been implicated in calcium homeostasis and nephrolithiasis by genome-wide association studies. We have previously demonstrated that alterations in expression of DGKD cause biased calcium-sensing receptor (CaSR) signalling in vitro. To further elucidate the physiological role of DGKD we examined the biochemical phenotype of a Dgkd-haploinsufficient (+/-) mutant mouse developed by the International Mouse Phenotyping Consortium. Dgkd (+/-) animals were found to be hypocalcaemic when compared to wildtype mice (+/+) (serum calcium +/+ = 2.42 mmol/l±0.01 vs. +/- = 2.34 mmol/l±0.02,P = 0.008 male mice, +/+ = 2.39 mmol/l±0.01 vs. +/- = 2.30mmol ± 0.04,P = 0.02 female mice) with inappropriately normal parathyroid hormone concentrations indicating an alteration in the homeostatic set-point for extracellular calcium (serum PTH +/+ = 61.89pmol/l±17.48 vs. +/- = 58.47pmol/l±9.24 male mice, +/+ = 106.3pmol/l±27.42 vs. +/- = 35.54pmol/l±5.76 female mice). In addition, Dgkd +/- mice were hyperkalaemic (serum potassium +/+ = 4.28 mmol/l±0.04 vs. +/- = 4.68 mmol/l±0.08, p = 0.0009 male mice, +/+ = 3.81 mmol/l±0.07 vs. +/- = 4.63 mmol/l±0.14 female mice,P = 0.0009 female mice), female mice were hyperphosphatasic (serum ALP +/+ = 65.78U/l±2.26 vs. +/-= 79.50U/l±2.41 male mice, +/+ = 107.9U/l±1.98 vs. +/-= 128.0U/l±4.08 female miceP = 0.0009), and male mice had a reduced bone mineral density (BMD) (+/+ = 2.480mg/cm2±0.008 vs. +/-= 2.18 mg/cm2±0.068,P = 0.0009 male mice, +/+ = 3.00 mg/cm2±0.012 vs. +/-= 2.94 mg/cm2±0.045 female mice). These studies have established a mouse model of Dgkd-haploinsufficiency with hypocalcaemia due to a homeostatic set-point abnormality in keeping with Autosomal Dominant Hypocalcaemia (ADH), a human disorder due to gain-of-function mutations in components of the CaSR-signalling pathway and associated with hypercalciuria. However, in contrast to previously reported mouse models and human cases of ADH, alterations in serum potassium, ALP, and BMD were detected suggesting that alterations in DGKD expression may also affect signalling pathways other than the CaSR.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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