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."
- SourceAvailable from: Martina Kocan[Show abstract] [Hide abstract]
ABSTRACT: The bioluminescence resonance energy transfer (BRET) technique has become extremely valuable for the real-time monitoring of protein-protein interactions in live cells. This method is highly amenable to the detection of G protein-coupled receptor (GPCR) interactions with proteins critical for regulating their function, such as β-arrestins. Of particular interest to endocrinologists is the ability to monitor interactions involving endocrine receptors, such as orexin receptor 2 or vasopressin type II receptor. The BRET method utilizes heterologous co-expression of fusion proteins linking one protein of interest (GPCR) to a bioluminescent donor enzyme, a variant of Renilla luciferase, and a second protein of interest (β-arrestin) to an acceptor fluorophore. If in close proximity, energy resulting from oxidation of the coelenterazine substrate by the donor will transfer to the acceptor, which in turn fluoresces. Using novel luciferase constructs, we were able to monitor interactions not detectable using less sensitive BRET combinations in the same configuration. In particular, we were able to show receptor/β-arrestin interactions in an agonist-independent manner using Rluc8-tagged mutant receptors, in contrast to when using Rluc. Therefore, the enhanced BRET methodology has not only enabled live cell compound screening as we have recently published, it now provides a new level of sensitivity for monitoring specific transient, weak or hardly detectable protein-protein complexes, including agonist-independent GPCR/β-arrestin interactions. This has important implications for the use of BRET technologies in endocrine drug discovery programs as well as academic research.Frontiers in Endocrinology 01/2010; 1:12. DOI:10.3389/fendo.2010.00012
- [Show abstract] [Hide abstract]
ABSTRACT: A 31-year-old man had been treated with carbamazepine (CBZ) for 6 years and warfarin with bucolome for 2 years before developing hyponatremia 7 days after an injection of interferon-alpha 2b and starting oral ribavirin for chronic hepatitis C virus infection. Despite the hyponatremia, urinary osmolality exceeded plasma osmolality, and urinary excretion volume decreased markedly after water loading. Restriction of water intake and administration of dimethylchlortetracycline improved the hyponatremia, and lithium therapy maintained the normonatremia for one year. The hyponatremia recovered 6 months after the interferon-alpha 2b therapy was completely stopped. In the present case, the syndrome of inappropriate antidiuresis may have been caused by the effect of interferon-alpha 2b on the renal distal tubules that had been sensitized by CBZ. Patients on CBZ therapy should be carefully observed for the development of hyponatremia when they are started on interferon-alpha 2b injections.International Journal of General Medicine 11/2009; 1:21-5.
- [Show abstract] [Hide abstract]
ABSTRACT: We report a familial case of the nephrogenic syndrome of inappropriate antidiuresis (NSIAD), including 30-year followup data on two patients. The proband and one maternal uncle presented in their infancy with severe recurrent hyponatremia, and clinical pictures consistent with the syndrome of inappropriate antidiuretic hormone (SIADH) in the absence of an elevated ADH level. They were both confirmed to be hemizygous for the R137C mutation on the V2R gene (AVPR2), the same locus of the gain of function mutation demonstrated in the original reports of this condition. The proband's mother was identified as an asymptomatic carrier of this X-linked condition. Our case describes a favourable long-term outcome for NSIAD, in particular, successful treatment with oral urea during the infancy period, and with self-regulated precautions on fluid intake into adult life.International Journal of Pediatric Endocrinology 01/2009; 2009:431527. DOI:10.1155/2009/431527