Grant: Operating Grant - E-Rare-2 Joint Transnational Call on Rare Diseases

Idiopathic infantile hypercalcemia (IIH) is a rare genetic condition characterized by hypercalcemia and nephrocalcinosis with unknown long-term implications and limited therapies. The cause was unknown until recently when a team including Jones/Schlingmann on this grant proposal showed that the main underlying defect in a cohort of German families involved mutations of the vitamin D inactivating enzyme, CYP24A1. (Schlingmann et al New Engl J Med, 2011). We hypothesize that mutations in CYP24A1 lead to aberrant control of vitamin D hormone levels in blood and tissues and impaired mineral ion homeostasis, leading to soft-tissue calcification as a result of long-term hypercalcemia. This proposal will attempt to create a broad consortium of clinicians and scientists from Europe and Canada studying CYP24A1 and other genes causing hypercalcemia in order:- 1) To provide better methods for diagnosis, monitoring and long-term surveillance of IIH and related hypercalcemic conditions 2) To use mouse models to recreate and investigate IIH and provide new approaches for the treatment of IIH and related hypercalcemic conditions. Our studies will incorporate genetic testing, employ a unique CYP24A1 enzyme assay to recreate the patient defect in the test-tube and the latest and most sensitive LC-MS/MS technology to detect enzyme products in the blood of IIH patients. This will be augmented by novel CYP24A1 knock-out and knock-in animal models; and SLC-34 knockout animal models to mimic human hypercalcemic conditions in the mouse and then study their long-term biological consequences.