Gain-of-function mutations of the V2 vasopressin receptor in nephrogenic syndrome of inappropriate antidiuresis (NSIAD): molecular characterization and in silico identification of potential therapeutic agents

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is a recently identified chromosome X-linked rare disease associated to gain-of-function mutations of the V2 vasopressin receptor (V2R). The V2R is expressed in kidney where it mediates the reabsorption of water from the distal nephron. Inactivating mutations of the V2R cause some forms of Nephrogenic Diabetes Insipidus (NDI) whereas activating mutations have been found in patients affected by NSIAD syndrome. NSIAD is characterized by decreased ability to excrete a free water load, hyponatremia and undetectable vasopressin circulating levels. It can be quite severe in affected male children. The general goal of this project is to perform an extensive study of the molecular properties of the V2R mutants associated to NSIAD in order to identify the mechanisms of the disease and to propose rational therapeutic interventions. The aim of this study is to identify novel inverse agonists, allosteric ligands or drugs that might target specific receptor-mediated events using virtual screening of chemical libraries.