Analysis of a novel AVPR2 mutation in a family with nephrogenic diabetes insipidus

Congenital nephrogenic diabetes insipidus (NDI) is a rare X-linked recessive disorder associated with germline mutations of the arginine vasopressin (AVP) receptor type 2 (AVPR2) gene. Recent molecular studies have demonstrated that insensitivity of renal tubule cells to AVP is associated with AVPR2 mutations. We identified a novel deletion mutation at nucleotide position 302 (302delC), in a Korean NDI family, that results in a frameshift and a truncated receptor protein. To identify the mutant AVPR2 protein we developed an expression vector for the AVPR2 mutation by a PCR-based restriction fragment replacement strategy. COS-7 cells were transiently transfected with expression vectors for the wild-type and mutant genes, and we analyzed AVP-induced cyclic adenosine monophosphate (cAMP) responses, and assessed the localization of AVPR2 receptors, in the transfected COS-7 cells. In the cells expressing the mutant gene, the maximum AVP-induced cAMP response was reduced and the truncated receptor proteins were retained within the cytoplasmic compartment. These results suggest that the novel frameshift AVPR2 (302delC) mutation is responsible for the AVP resistance in the family with congenital NDI.