Two novel mutations in the aquaporin-2 and the vasopressin V2 receptor genes in patients with congenital nephrogenic diabetes insipidus

The vasopressin V2 receptor (V2R) and the aquaporin-2 genes of two unrelated male patients with congenital nephrogenic diabetes insipidus were analyzed. The V2R gene of the patient of family 1 had the wild-type sequence. Consequently, the coding region of the aquaporin-2 gene including the exon-intron junctions was sequenced. A novel G to T transversion at codon 202, predictive of an exchange of tryptophan 202 by cysteine, was identified. As the mutation occurs at G-1 of the 5′ splice donor site of intron 3, aberrant splicing is also likely. The mutation involves one of the supposed water pore-forming loops. Therefore, both aberrant splicing and amino acid substitution are likely to result in a functionally defective protein. Sequencing of the complete V2R gene of the male patient of family 2 revealed a novel single-base deletion at codon 310 (ΔC1001), shifting the reading frame to give an altered amino acid sequence beginning at codon 311. The mutation is unique in predicting a C-terminally extended protein (termination after codon 434 in the mutant receptor instead of codon 371 in the wild-type). The deduced mutant protein is likely to be nonfunctional since the amino acid sequence of the seventh transmembrane domain and the C-terminus is altered.