In many mendelian diseases, some mutations result in the synthesis of misfolded proteins that cannot reach a transportcompetent conformation. In X-linked nephrogenic diabetes insipidus, most of the mutant vasopressin 2 (V2) receptors are trapped in the endoplasmic reticulum and degraded. They are unable to reach the plasma membrane and promote water reabsorption through the principal cells of the collecting ducts. Herein is reported two types of experiments: In vivo studies to assess clinically a short-term treatment with a nonpeptide V1a receptor antagonist (SR49059) and in vitro studies in cultured cell systems. In patients, SR49059 decreased 24-h urine volume (11.9 ؎ 2.3 to 8.2 ؎ 2.0 L; P ؍ 0.005) and water intake (10.7 ؎ 1.9 to 7.2 ؎ 1.6 L; P < 0.05). Maximum increase in urine osmolality was observed on day 3 (98 ؎ 22 to 170 ؎ 52 mOsm/kg; P ؍ 0.05). Sodium, potassium, and creatinine excretions and plasma sodium were constant throughout the study. A lthough the activities of the protein synthesis quality control systems are generally advantageous to the cell, on occasion this stringent monitoring process can lead to intracellular retention of salvageable proteins. In recent years, its has been observed that a group of diseases stem from mutations that promote such retention and are collectively referred to as conformational or protein-misfolding diseases (1,2). Nephrogenic diabetes insipidus (NDI) (3,4), which is characterized by a loss of arginine vasopressin (AVP)-mediated antidiuresis, is one of these diseases. In congenital NDI that results from mutations in the AVPR2 gene that encodes the V2 receptor, most missense mutations are misfolded, trapped in the endoplasmic reticulum, and unable to reach the basolateral cell surface to engage the circulating antidiuretic hormone, AVP (5-14).The natural history of untreated X-linked NDI includes hypernatremia, hyperthermia, mental retardation, and repeated episodes of dehydration in early infancy (15,16). In five new patients who were younger than 1 year and were from North America and in whom we provided molecular testing over the past 12 mo, plasma sodium was in every case Ͼ155 mEq/L at the time of diagnosis. We and others initially thought that close monitoring of infants whose AVPR2 mutations were diagnosed pre-or perinatally not only would prevent episodes of dehydration but also would permit close to normal growth and development. Although a low-sodium diet and distal tubule diuretics prescribed to these patients may achieve a 20 to 30% decrease in urine output (17), the low-sodium diet is difficult to follow, and affected children continue to drink large amounts of water. As a result of a physiologic gastroesophageal reflux and to the large amount of water in their stomach, these children often vomit, and, as a consequence, their nutritional intake is not optimal. There is a need, therefore, for a safe further reduction in urine output. We recently used pharmacologic compounds to rescue misfolded mutant V2 receptors by demonstrating in cultured cells t...
