Multiple endocrine neoplasia type 1 knockout mice develop parathyroid, pancreatic, pituitary and adrenal tumours with hypercalcaemia, hypophosphataemia and hypercorticosteronaemia

<jats:p>Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized in man by parathyroid, pancreatic, pituitary and adrenal tumours. The <jats:italic>MEN1</jats:italic> gene encodes a 610-amino acid protein (menin) which is a tumour suppressor. To investigate the <jats:italic>in vivo</jats:italic> role of menin, we developed a mouse model, by deleting <jats:italic>Men1</jats:italic> exons 1 and 2 and investigated this for MEN1-associated tumours and serum abnormalities. <jats:italic>Men1</jats:italic><jats:sup>+/−</jats:sup> mice were viable and fertile, and 220 <jats:italic>Men1</jats:italic><jats:sup>+/−</jats:sup> and 94 <jats:italic>Men1</jats:italic><jats:sup>+/+</jats:sup> mice were studied between the ages of 3 and 21 months. Survival in <jats:italic>Men1</jats:italic><jats:sup>+/−</jats:sup> mice was significantly lower than in <jats:italic>Men1</jats:italic><jats:sup>+/+</jats:sup> mice (&lt;68% vs &gt;85%, <jats:italic>P</jats:italic>&lt;0.01). <jats:italic>Men1</jats:italic><jats:sup>+/−</jats:sup> mice developed, by 9 months of age, parathyroid hyperplasia, pancreatic tumours which were mostly insulinomas, by 12 months of age, pituitary tumours which were mostly prolactinomas, and by 15 months parathyroid adenomas and adrenal cortical tumours. Loss of heterozygosity and menin expression was demonstrated in the tumours, consistent with a tumour suppressor role for the <jats:italic>Men1</jats:italic> gene. <jats:italic>Men1</jats:italic><jats:sup>+/−</jats:sup> mice with parathyroid neoplasms were hypercalcaemic and hypophosphataemic, with inappropriately normal serum parathyroid hormone concentrations. Pancreatic and pituitary tumours expressed chromogranin A (CgA), somatostatin receptor type 2 and vascular endothelial growth factor-A. Serum CgA concentrations in <jats:italic>Men1</jats:italic><jats:sup>+/−</jats:sup> mice were not elevated. Adrenocortical tumours, which immunostained for 3-β-hydroxysteroid dehydrogenase, developed in seven <jats:italic>Men1</jats:italic><jats:sup>+/−</jats:sup> mice, but resulted in hypercorticosteronaemia in one out of the four mice that were investigated. Thus, these <jats:italic>Men1</jats:italic><jats:sup>+/−</jats:sup> mice are representative of MEN1 in man, and will help in investigating molecular mechanisms and treatments for endocrine tumours.</jats:p>