MUTATIONS IN THE VASOPRESSIN V2 RECEPTOR AND AQUAPORIN-2 GENES IN 12 FAMILIES WITH CONGENITAL NEPHROGENIC DIABETES-INSIPIDUS

Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited d isorder characterized by renal tubular insensitivity to the antidiuret ic effect of arginine vasopressin (AVP). In a large majority of the ca ses, nephrogenic diabetes insipidus is an X-linked recessive disorder caused by mutations in the AVP V2 receptor gene (AVPR2). In the remain ing cases, the disease is autosomal recessive or dominant and, for the se patients, mutations in the aquaporin 2 gene (AQP2) have been report ed. Fourteen probands belonging to 12 families were analyzed by single -strand conformational polymorphism and direct sequencing of the AVPR2 and AQP2 genes. Ten mutations of the AVPR2 gene (six previously repor ted mutations and four novel mutations: G107E, W193X, L43P, and 15delC ) were identified. Three mutations of the AQP2 gene were also identifi ed in two patients: the first patient is homozygous for the R85X mutat ion and the second is a compound heterozygote for V168 M and S216P mut ations. Extrarenal responses to infusion of the strong V2 agonist 1-de samino-8-D-arginine vasopressin allowed AVPR2- and AQP2-associated for ms of CNDI to be distinguished in three patients. This test also ident ified an unexpectedly high urinary osmolality (614 mosmol/kg) in a pat ient with a P322S mutation of AVPR2 gene and a mild form of CNDI.