Mutations in the vasopressin V2 receptor and aquaporin-2 genes in twelve families with congenital nephrogenic diabetes insipidus.

Abstract

Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder characterized by renal tubular insensitivity to the antidiuretic effect of arginine vasopressin (AVP). The clinical characteristics of CNDI include polyuria, polydypsia, fever, vomiting, constipation and repeated episodes of hypernatremic dehydration in early infancy. Without treatment, mental retardation and failure to thrive may develop1. In the large majority of the cases, NDI is an X-linked recessive disorder caused by mutations in the AVP V2 receptor gene (AVPR2)2,3. In the remaining cases, the disease is autosomal recessive or dominant and for these patients, mutations in the aquaporin 2 gene (AQP2) have been reported. We analyzed 14 probands (the clinical features of the patients are given in Table 1) belonging to 12 families by SSCP and direct sequencing of the AVPR2 and AQP2 genes. We identified 10 mutations of the AVPR2 gene (Table 2a): 6 previously reported mutations: Y205C, H8OR, R337X, R202C, P322S and A147 V5–12, and 4 novel mutations: G107E, W193X, L43P, and 15delC. Three mutations of the AQP2 gene were also identified in two patients (Table 2b): the first patient is homozygous for the R85X mutation and the second is a compound heterozygote for V168M and S216P mutations. Extra-renal responses to infusion of the strong V2 agonist, 1-des-amino-8-D-arginine vasopressin (DDAVP), allowed us to distinguish V2R and AQP2 associated forms of CNDI in three patients. This test also allows us to identify an unexpectedly high urinary osmolality (614 mOsm/kg) in a patient with a P322S mutation of AVPR2 gene and a mild form of CNDI (ie diagnosed at 9 years of age, without previous episodes of hypernatremic dehydration).