Molecular analyses of the vasopressin type 2 receptor and aquaporin-2 genes in Brazilian kindreds with nephrogenic diabetes insipidus

Nephrogenic diabetes insipidus (NDI) is associated with germline mutations in two genes: vasopressin receptor type 2 (V2(R)) in X-linked NDI, and the water channel aquaporin-2, in autosomal-recessive disease. Genetic heteroge neity is further emphasized by reports of phenotypically abnormal individua ls with normal structural genes. We analyzed both genes in five Brazilian f amilies and the aquaporin-2 gene in two Swedish families with clinical and laboratory diagnosis of NDI, by a combination of denaturing gradient gel el ectrophoresis (DGGE) and direct DNA sequencing. A novel polymorphism in the aquaporin-2 gene (S167S), but no disease-associated mutations in any teste d individual from all seven families, was detected, In two Brazilian famili es, frameshift mutations were detected in the V2(R) gene: one leading to a premature stop after codon 36 and the other to a longer peptide (462 aa ins tead of the 373 aa wild-type protein), In two other Brazilian families, pro bable disease associated missense mutations were detected: an alanine to pr oline at codon 163 (A163P) and an asparagine to aspartic acid at codon 85 ( D85N). In one Brazilian family, both genes were structurally normal and the aquaporin-2 gene was also normal in the two Swedish kindreds, This report further extends the mutational spectrum of NDI and suggests that there are other mutational or epigenetic events inactivating the two known genes or e ven novel genes that underlie NDI, Hum Mutat 14:233-239, 1999, (C) 1999 Wil ey-Liss, Inc.