Nephrogenic syndrome of inappropriate antidiuresis

Abstract

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. We describe two infants whose clinical and laboratory evaluations were consistent with the presence of SIADH, yet who had undetectable arginine vasopressin (AVP) levels. We hypothesized that they had gain-of-function mutations in the V2 vasopressin receptor (V2R). DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations in both, with resultant changes in codon 137 from arginine to cysteine or leucine. These novel mutations cause constitutive activation of the receptor and are the likely cause of the patients' SIADH-like clinical picture, which we have termed "nephrogenic syndrome of inappropriate antidiuresis."

Figure 1. Nucleotide Sequence of the Wild-Type and Two Mutant AVPR2 Genes in the Affected Region (Panel A) and Diagram of V2R (Panel B)

In Panel A, the normal CGC sequence encoding R137 is changed to TGC (R137C) in Patient 1 and to CTC (R137L) in Patient 2. In Panel B, R137 is indicated. The inset highlights changes in R137 that result in either congenital nephrogenic diabetes insipidus or NSIAD.

Figure 2. Basal Levels of cAMP Production in Cells Expressing Wild-Type and Mutant V2R

The ability of the mutant V2R from each patient to induce cAMP, as measured by a cAMP-inducible luciferase reporter, was evaluated. Each bar represents cells transfected with the renilla luciferase expression vector, the cAMP-inducible luciferase reporter plasmid, and pCDNA3 either alone (control), reflecting basal cAMP levels in the cells, or with the following inserts subcloned into the pCDNA3 plasmid: wild-type V2R; R137H mutant V2R, found in some patients with nephrogenic diabetes insipidus; R137C mutant V2R, found in Patient 1; or R137L mutant V2R, found in Patient 2. Each value represents the mean (±SE) of three independent experiments with all five samples run simultaneously, each performed in triplicate.