Vasopressin receptor mutations and nephrogenic diabetes insipidus

X-linked recessive nephrogenic diabetes insipidus is caused by mutations in the gene encoding the V2 vasopressin receptor (V2R), the mediator of the a ntidiuretic effect of arginine vasopressin (AVP) in mammalian kidneys. Upon binding to AVP, the receptor activates the G protein G(s), stimulating a p hosphorylation cascade that promotes translocation of presynthesized water channels to the apical surface of the principal cells lining the last segme nts of the nephron. The presence of these channels allows the flow of water from the hypotonic lumen of the nephron into the hypertonic interstitium. More than 100 different mutations have been identified since the receptor g ene was characterized-in most cases one per family, although some families bear two and three mutations in the same gene. The frequency of the de novo mutations identified suggests that the DNA at the end of the long arm of t he X chromosome is very susceptible to alteration. The mutations are scatte red within the coding region, not confined to a particular segment of the r eceptor protein, and in most cases confined to a single amino acid change t hat significantly reduces the number of receptors present on the plasma mem brane. Some mutations do not affect protein synthesis but significantly red uce the coupling efficiency between the receptor and G protein. Analysis of the biochemical impact of the mutations has provided valuable information about the synthesis and regulation of the receptor. (C) 2000 IMSS. Publishe d by Elsevier Science Inc.