Functional Characterization of the Molecular Defects Causing Nephrogenic Diabetes Insipidus in Eight Families 1 (original) (raw)
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Mutations in the vasopressin V2 receptor gene in two families with nephrogenic diabetes insipidus
Pediatric Nephrology, 1995
Congenital nephrogenic diabetes insipidus (CNDI) is a rare X-linked disorder in which the renal collecting duct is unresponsive to arginine vasopressin, and thus, the urine is consistently hypotonic to plasma. As a result, affected individuals are unable to concentrate urine and suffer from episodes of severe dehydration and hypernatremia. Recently, the association between arginine vasopressin V2 receptor gene mutations and CNDI has been demonstrated.
AJP: Renal Physiology, 2009
X-linked congenital nephrogenic diabetes insipidus (CNDI) is characterized by a defective renal response to the antidiuretic hormone (AVP) due to variations in the arginine vasopressin receptor 2 ( AVPR2) gene. In a unique group of patients, the renal insensitivity to the effects of AVP is incomplete resulting in a partial phenotype. To investigate the molecular defects, two previously published variations in the AVPR2 gene, known to cause a partial CNDI phenotype, were expressed in transiently transfected human embryonic kidney cells. One variation (p.Arg104Cys) is located in the first extracellular loop and the other variation (p.Ser329Arg) is located in the intracellular COOH terminal of the receptor protein. Western blotting showed almost equal amounts of WT-V2R and Arg104Cys-V2R protein at steady state, whereas the level of Ser329Arg-V2R protein was lower. Confocal microscopy established that WT-V2R and Arg104Cys-V2R are localized on the cellular surface while the Ser329Arg-V2R...
Vasopressin Receptor Mutations in Nephrogenic Diabetes Insipidus
Seminars in Nephrology, 2008
The purpose of this review is first to describe the importance of early detection of vasopressin receptor mutations responsible for X-linked nephrogenic diabetes insipidus (NDI). We have proposed that all families with hereditary diabetes insipidus should have their molecular defect identified because early diagnosis and treatment of affected infants can avert the physical and mental retardation that results from repeated episodes of dehydration. Secondly, 95 published missense mutations responsible for X-linked NDI are likely to result in misfolded arginine-vasopressin V 2 receptors that are trapped in the endoplasmic reticulum. These misfolded receptors are unable to reach the plasma membrane in principal collecting duct cells and to engage the circulating antidiuretic hormone, arginine-vasopressin. These misfolded proteins potentially could be rescued with pharmacologic chaperones, an active area of research pertinent to other hereditary protein misfolding diseases such as cystic fibrosis, phenylketonuria, and Anderson-Fabry disease among many others. Finally, a longterm careful surveillance of all patients with hereditary NDI should be performed to prevent chronic renal failure likely caused by the long-term functional tract obstruction with reflux.
Proceedings of the National Academy of Sciences, 2009
Binding of the peptide hormone vasopressin to its type-2 receptor (V2R) in kidney triggers a cAMP-mediated translocation of Aquaporin-2 water channels to the apical membrane, resulting in water reabsorption and thereby preventing dehydration. Mutations in the V2R gene lead to Nephrogenic Diabetes Insipidus (NDI), a disorder in which this process is disturbed, because the encoded, often intrinsically functional mutant V2 receptors are misfolded and retained in the endoplasmic reticulum (ER). Since plasma membrane expression is thought to be essential for V2R activation, cell permeable V2R antagonists have been used to induce maturation and rescue cell surface expression of V2R mutants, after which they need to be displaced by vasopressin for activation. Here, however, we show that 3 novel nonpeptide V2R agonists, but not vasopressin, activate NDI-causing V2R mutants at their intracellular location, without changing their maturation and at a sufficient level to induce the translocatio...
Human Genetics, 1995
A bstract Nephrogenic diabetes insipidus (NDI) usually shows an X-linked recessive mode of inheritance caused by mutations in the vasopressin type 2 receptor gene (AVPR2). In the present study, three NDI families are de scribed in which females show clinical features resembling the phenotype in males. Maximal urine osmolality in three female patients did not exceed 200 mosmol/kg and the ab sence of extra-renal responses to l-desamino-8-D-arginine vasopressin was demonstrated in two of them. All affected females and two asymptomatic female family members were shown to be heterozygous for an AVPR2 mutation. Skewed X-inactivation is the most likely explanation for the clinical manifestation of NDI in female carriers of an AVPR2 mutation. It is concluded that, in female NDI pa tients, the possibility of heterozygosity for an AVPR2 gene mutation has to be considered in addition to homozygosity for mutations in the aquaporin 2 gene.
Human Mutation, 2005
Mutations in the V2 vasopressin receptor (AVPR2) are the most frequent genetic cause of the inherited nephrogenic diabetes insipidus (NDI). About 50% of all missense mutations found in extracellular loops of AVPR2 introduce additional cysteine residues, e.g. R181C, G185C, and Y205C. To explain the loss of receptor function two mechanistic models were suggested: First, the introduction of an additional extracellular Cys residue disrupts the conserved disulfide bond connecting the first and the second extracellular loop. And second, the mutationally introduced Cys residue forms a second disulfide bond with a free Cys residue within the second exoloop. Herein, we took advantage of a new NDI-causing mutation Y205H which affects a codon frequently found to be mutated to Cys in NDI patients. In contrast to Y205C the two mechanisms described above cannot account for the loss of receptor function of Y205H. In-depth functional characterization of mutant AVPR2 showed that also for Y205C the lack of a Tyr residue at position 205 is responsible for the abolished receptor function rather than the formation of a disastrous second disulfide bond. The concerted experimental and phylogenetic analysis emphasizes that Y205 is a key residue in maintaining the structure of AVPR2 and other members of the vasopressin receptor family.