Analysis of vasopressin receptor type II (V2R) gene in three Japanese pedigrees with congenital nephrogenic diabetes insipidus: identification of a family with complete deletion of the V2R gene.

To investigate the association of mutations in the arginine vasopressin receptor type II (V2R) gene with congenital nephrogenic diabetes insipidus (CNDI) in the Japanese, we analyzed the V2R gene, located on the X chromosome, in three Japanese pedigrees with CNDI. In one pedigree, a large deletion spanning the entire coding region of the V2R gene was identified. In another pedigree, a G to A transition responsible for a substitution of Met88 (ATG) for Val88 (GTG) was detected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis revealed that this was a de novo mutation that had occurred in the proband's mother. Because CNDI was observed only in those with this mutation, the pathogenicity of this mutation seemed clear. In the last pedigree, only a silent mutation at Leu309 (CTA-->CTG) was found. All the individuals studied in this pedigree by allele-specific oligonucloetide-polymerase chain reaction (ASO-PCR) analysis showed a complete association of this mutation to the clinical symptoms. Because the silent mutation detected was unlikely to be a direct cause of CNDI, mutations in other regions of the V2R gene, such as a promoter region or other regulatory regions, may be responsible for the cause of CNDI in this pedigree. Thus, association of the V2R gene abnormality to clinical symptoms of CNDI was confirmed in three Japanese pedigrees, and a strong contribution of the V2R gene mutation to the development of CNDI was suggested.