NEPHROGENIC DIABETES-INSIPIDUS - A V2 VASOPRESSIN RECEPTOR UNABLE TO STIMULATE ADENYLYL CYCLASE

The coding region of the human vasopressin type 2 receptor gene bears mutations in the individuals affected with congenital nephrogenic diab etes insipidus, a disease characterized by the inability of the kidney to concentrate urine in response to vasopressin. Although it is assum ed that the mutations result in loss of receptor function, proof of th is hypothesis is lacking. We introduced one of these naturally occurri ng point mutations leading to a single amino acid change (Arg137 --> H is) into wild type cDNA. The mutant protein was expressed, and the fun ctional properties of the receptor were examined. The mutant receptor exhibited an unaltered binding affinity for vasopressin compared to th e wild type but failed to stimulate the G(s)/adenylyl cyclase system. These data provide biochemical proof that the mutant receptor is the c ause of the disease.