NEPHROGENIC DIABETES-INSIPIDUS - AN X-CHROMOSOME-LINKED DOMINANT INHERITANCE PATTERN WITH A VASOPRESSIN TYPE-2 RECEPTOR GENE THAT IS STRUCTURALLY NORMAL

Nephrogenic diabetes insipidus is a rare hereditary disorder, most com monly transmitted in an X chromosome-linked recessive manner and chara cterized by the lack of renal response to the action of antidiuretic h ormone [Arg(8)]vasopressin. The vasopressin type 2 receptor (V(2)R) ha s been suggested to be the gene that causes the disease, and its role in disease pathogenesis is supported by mutations within this gene in affected individuals. Using the PCR, denaturing gradient gel electroph oresis, and direct DNA sequencing, we examined the V(2)R gene in four unrelated kindreds. In addition, linkage analysis with chromosome Xq28 markers was done in one large Brazilian kindred with an apparent unus ual X chromosome-linked dominant inheritance pattern. In one family, a mutation in codon 280, causing a Tyr --> Cys substitution in the sixt h transmembrane domain of the receptor, was found. In the other three additional families with nephrogenic diabetes insipidus, the V(2)R-cod ing region was normal in sequence. In one large Brazilian kindred disp laying an unusual X chromosome-linked dominant mode of inheritance, th e disease-related gene was localized to the same region of the X chrom osome as the V(2)R, but no mutations were found, thus raising the poss ibility that this disease is caused by a gene other than V(2)R.