Nephrogenic diabetes insipidus (NDI) is an inherited X-linked disorder in which affected subjects are resistant to the actions of vasopressin (AVP) on renal medullary cells responsible for water concentration. Clinical manifestations include severe polydipsia and polyuria, and resultant severe dehydration can lead to cerebral swelling and death. Treatment with a potent AVP analog (DDAVP), useful in other forms of DI, is ineffective in NDI because of end-organ resistance to the hormone. The renal actions of AVP are mediated through a V2 type receptor linked via the Gs protein to stimulation of the 2nd messenger cAMP. In theory, the inherited gene defect could be located anywhere along the signal transduction path, but indirect evidence suggested a likely receptor defect. The recent cloning of a human V2 receptor permitted chromosomal localization studies which showed that the receptor is localized to Xq28, the site of the gene defect as determined by family linkage studies. This strongly suggested but did not prove that a receptor gene mutation is the underlying defect in NDI. We have obtained genomic DNA samples on multiple families with NDI, and in eight families thus far have identified mutations predicted to disrupt formation of a normal V2 receptor. These findings have important implications for our understanding of the pathogenesis of NDI and of normal V2 receptor structure and function, for identification of affected subjects and carriers, and eventually for gene therapy of the disease.
