Endocrine Abstracts (2007) 13 P10

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

Irina Grigorieva1, Brian Harding1, M Andrew Nesbit1, Rebecca Fairclough1, Elena Grigorieva2, Asif Ali1, Tertius Hough5, William Fraser3, Jaqueline van Wees4, Frank Grosveld4 & Rajesh Thakker1

1Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; 2The National Institute for Medical Research, London, United Kingdom; 3Royal Liverpool University Hospital, Liverpool, United Kingdom; 4Erasmus University, Rotterdam, Rotterdam, Netherlands; 5Mary Lyon Centre, Medical Research Council, Harwell, Oxfordshire, United Kingdom.

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 abnormalities of calcium metabolism and parathyroid function. Mice were kept in accordance with UK Home Office welfare guidelines and project license restrictions. Wild-type (+/+; male n=20, female n=23) and Gata3+/− (male n=21, female n=26) mice were fed a standard mouse diet (containing 0.79% calcium, 1500 U/kg vitamin D) and 60 days following weaning, plasma calcium and parathyroid hormone (PTH) concentrations were measured. Statistical analyses were performed using Mann-Whitney U tests. Parathyroid histology was performed using haematoxylin and eosin stained sections. Gata3+/− mice did not show signs of neuromuscular irritability or seizures and had normal renal and liver function. Plasma concentrations of calcium, corrected for albumin, were similar in Gata3+/− (2.28±0.14 mmol/L) and wild-type (2.25±0.10 mmol/L) mice, as were concentrations of plasma phosphate (2.70±0.72 mmol/L in +/−, versus 2.48±0.56 mmol/L in +/+). Concentrations of plasma PTH in Gata3+/− (5.44±3.63 pmol/L) and wild-type (5.92±4.48 pmol/L) mice were also similar. Histology confirmed the presence of parathyroid glands in the Gata3+/− mice. However, Gata3−/− embryos at 12.5 dpc had gross defects of the third and fourth pharyngeal pouch development that resulted in the absence of the parathyroid/thymus primordium. Thus, parathyroid agenesis occurs in Gata3−/− mice, but haploinsufficiency in Gata3+/− mice is not associated with parathyroid dysfunction, hypocalcaemia or low plasma PTH concentrations. The absence of hypoparathyroidism in Gata3+/− mice, which contrasts to the HDR situation in man, suggests involvement of compensatory mechanisms by other GATA members or genetic modifiers in mice.