Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nephrogenic diabetes insipidus (NDI) is most often an X-linked disorder in which urine is not concentrated due to renal resistance to arginine vasopressin. We recently identified four vasopressin type 2 receptor gene mutations in unrelated X-linked NDI families, including R143P, delta V278, R202C, and 804insG. All these mutations reduced ligand binding activity to < 10% of the normal without affecting mRNA accumulation. To elucidate whether the receptors are expressed on the cell surface, we analyzed biosynthesis and localization of tagged or untagged receptors stably expressed in Chinese hamster ovary (CHO) cells, using two antibodies directed against distinct termini. Whole-cell and surface labeling studies revealed that the R202C clone had both surface-localized (50-55 kD) and intracellular proteins (40 and 75 kD), similar to the wild-type AVPR2 clone, whereas the R143P and delta V278 clones lacked the surface receptors, despite relatively increased intracellular components. The 804insG mutant cell produced no proteins despite an adequate mRNA level. Immunofluorescence staining confirmed that the R202C mutant reaches the cell surface, whereas the R143P and delta V278 mutants are retained within the cytoplasmic compartment. Thus, R202C, R143P/delta V278, and 804insG result in three distinct phenotypes, that is, a simple binding impairment at the cell surface, blocked intracellular transport, and ineffective biosynthesis or/and accelerated degradation of the receptor, respectively, and therefore are responsible for NDI. This phenotypic classification will help understanding of molecular pathophysiology of this disorder.
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PMID:Binding-, intracellular transport-, and biosynthesis-defective mutants of vasopressin type 2 receptor in patients with X-linked nephrogenic diabetes insipidus. 756 98

The advances in our understanding of the pathophysiology of defects in the antidiuretic hormone, the V2 receptor and the water channel, owing to mutations in the prepro-AVP-NPII, AVPR2 and AQP2 genes respectively, is providing insight into inherited diabetes insipidus as well as the more numerous sporadic cases. Further structure-function analyses of these mutated genes will increase our understanding of normal vasopressin-regulated water transport across the kidney epithelium at the molecular level.
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PMID:Diabetes insipidus. 757 30

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 described 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 absence of extra-renal responses to 1-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 patients, the possibility of heterozygosity for an AVPR2 gene mutation has to be considered in addition to homozygosity for mutations in the aquaporin 2 gene.
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PMID:Clinical phenotype of nephrogenic diabetes insipidus in females heterozygous for a vasopressin type 2 receptor mutation. 760 58

Congenital nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by the inability of the kidney to concentrate urine in response to vasopressin (AVP). Following the recent characterization of the cDNA and genomics sequences encoding the human V2 receptor to AVP (AVPR2), X-linked NDI has been found to be due to mutations in the AVPR2 gene that maps to the chromosome Xq28 region. To date more than 30 mutations, insertions or deletions have been reported in independent families, without any significant differences in the phenotypic expression of the disease. The AVPR2 is a member of the superfamily of 7 transmembrane domain, G protein-coupled receptor, linked to cyclic AMP second messenger system. Other types of inheritance have been described in NDI, and recently, a mutation of the aquaporin-2 gene, encoding a water channel of the renal collecting duct, has been reported in an autosomal recessive form of NDI.
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PMID:[Hereditary nephrogenic diabetes insipidus]. 764 Jul 59

In a normal adult subject, 12 liters of tubular urine with an osmolality of 100 mmol/kg exit per 24 hours from the loop of Henle. The antidiuretic hormone arginine-vasopressin increases the water permeability of the renal collecting ducts and induces the reabsorption of 11 liters of water: the final urinary osmolality is 1200 mmol/kg for a urinary flow rate of 1 litre per 24 hours. In nephrogenic diabetes insipidus the urine cannot be concentrated maximally. Congenital nephrogenic diabetes insipidus is secondary to either mutations in the AVPR2 gene (Xq28) that codes for the vasopressin antidiuretic (V2) receptor or to mutations in the AQP2 gene (12q13) that codes for the vasopressin dependent water channel. AVPR2 mutations are numerous and diverse: 72 different putative disease causing mutations in the AVPR2 gene have been reported in 102 unrelated families with X-linked nephrogenic diabetes insipidus. AQP2 mutations are rare. Nephrogenic diabetes insipidus could also be secondary to lithium or demeclocycline administration and to hypokaliemia. Some of these conditions are inducing, experimentally, a downregulation of aquaporin II. We encourage physicians who follow families with hereditary nephrogenic diabetes insipidus to recommend molecular genetic analysis because early diagnosis and treatment of infants can avert the physical and mental retardation associated with episodes of dehydration.
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PMID:[Pathological aspects of water transport in the collecting ducts]. 901 68

Loss-of-function mutations in the V2 vasopressin receptor (AVPR2) gene have been identified as a molecular basis for X-linked nephrogenic diabetes insipidus (NDI). Herein, we describe a novel deletion mutation at nucleotide position 102 (delG102) found in a Russian family resulting in a frameshift and a truncated receptor protein. Furthermore, we analyzed the AVPR2 gene of two other unrelated boys with NDI from our patient clientele. These patients showed previously described mutations (R137H, R181C). In-depth characterization of the three mutant AVPR2s by a combination of functional and immunological techniques permitted further insight into molecular mechanisms leading to receptor dysfunction. Premature truncation of the AVPR2 (delG102) led to a drastically reduced receptor protein expression in transfected COS-7 cells and, as expected, precluded specific AVPR2 functions. As indicated by different ELISA and binding studies, the R137H mutant was almost completely retained in the cell interior. In contrast to previous studies, the few mutant receptors in the plasma membrane displayed a low (2.3-fold above basal) but significant ability to stimulate the Gs/adenylyl cyclase system. In contrast to the latter mutation, the R181C mutant is properly delivered to the cell surface but the mutation interferes with high affinity vasopressin binding. Impaired ligand binding is reflected in an about 100-fold shift of the concentration-response curve toward higher vasopressin concentrations with only slightly reduced agonist potency.
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PMID:V2 vasopressin receptor dysfunction in nephrogenic diabetes insipidus caused by different molecular mechanisms. 971 77

In congenital nephrogenic diabetes insipidus, the renal collecting ducts are resistant to the antidiuretic action of arginine vasopressin or to its antidiuretic analog 1-deamino[8-D-arginine] vasopressin (dDAVP). This is a rare, but now well described entity secondary to either mutations in the AVPR2 gene that codes for the vasopressin antidiuretic (V2) receptor or to mutations in the AQP2 gene that codes for the vasopressin-dependent water channel. A majority (> 90%) of congenital nephrogenic diabetes insipidus patients have AVPR2 mutations: Of 115 families with congenital nephrogenic diabetes insipidus, 105 families had AVPR2 mutations, and 10 had AQP2 mutations. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellularly and are unable to reach the plasma membrane. A minority of the mutant receptors reach the cell surface but are unable to bind vasopressin or to trigger an intracellular adenosine 3:5-cyclic phosphate signal properly. Most of the reported mutations are secondary to a complete loss of function of the receptor, and only a few mutations have been associated with a mild phenotype. These advances provide diagnostic tools for physicians caring for these patients because, when the disease causing mutation has been identified, carrier and perinatal testing could be done by mutation analysis.
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PMID:Vasopressin receptor mutations causing nephrogenic diabetes insipidus. 975 88

In nephrogenic diabetes insipidus, the kidney is unable to concentrate urine despite normal or elevated concentrations of the antidiuretic hormone arginine vasopressin (AVP). In congenital nephrogenic diabetes insipidus (NDI), the obvious clinical manifestations of the disease, that is polyuria and polydipsia, are present at birth and need to be immediately recognized to avoid severe episodes of dehydration. Most (>90%) congenital NDI patients have mutations in the AVPR2 gene, the Xq28 gene coding for the vasopressin V2 (antidiuretic) receptor. In <10% of the families studied, congenital NDI has an autosomal recessive inheritance and mutations of the aquaporin-2 gene (AQP2), ie, the vasopressin-sensitive water channel, have been identified. When studied in vitro, most AVPR2 mutations lead to receptors that are trapped intracellularly and are unable to reach the plasma membrane. A minority of the mutant receptors reach the cell surface but are unable to bind AVP or to trigger an intracellular cyclic adenosine-monophosphate (cAMP) signal. Similarly AQP2 mutant proteins are trapped intracellularly and cannot be expressed at the luminal membrane. The acquired form of NDI is much more common than the congenital form, is almost always less severe, and is associated with downregulation of AQP2. The advances described here are examples of "bedside physiology" and provide diagnostic tools for physicians caring for these patients.
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PMID:Nephrogenic diabetes insipidus. 983 28

X-Linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder characterized by the excretion of abnormal large volumes of diluted urine mainly caused by mutations in the V2 vasopressin receptor (AVPR2) gene. By screening NDI patients for mutations within the AVPR2 gene we have identified three novel (I46K, F105V, I130F) and four recurrent (D85N, R106C, R113W, Q225X) mutations. In addition, a recurrent missense mutation (A147T) within the aquaporin-2 gene was identified in a female patient with autosomal recessive NDI associated with sensorineural deafness. Selected clinical data of the NDI patients were compared with the results from the in vitro studies. Functional analysis of I46K and I130F revealed reduced maximum agonist-induced cAMP responses as a result of an improper cell surface targeting. In contrast, the F105V mutation is delivered to the cell surface and displayed an unchanged maximum cAMP response, but impaired ligand binding abilities of F105V were reflected in a shifted concentration-response curve toward higher vasopressin concentrations. As the extracellularly located F105 is highly conserved among the vasopressin/oxytocin receptor family, functional analysis of this residue implicates an important role in high affinity agonist binding.
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PMID:Functional characterization of the molecular defects causing nephrogenic diabetes insipidus in eight families. 1077 Feb 18

The aim of this study was to identify loss-of-function mutations of the V2 vasopressin receptor gene (AVPR2) in Italian patients affected by X-linked nephrogenic diabetes insipidus (NDI). Mutations were found in 15 of the 18 unrelated families investigated: nine of these mutations were previously unknown, including two affecting residues located in regions known to be important for determining the pharmacologic properties of the receptor, which were therefore functionally investigated. The first (A84D) involves a residue located near an aspartic acid (D85) that is highly conserved in all G protein-coupled receptors and that is believed to play a role in the process of their isomerization into functionally active and inactive states. The present study indicates that this mutation not only affects receptor folding in such a way as to lead to its retention inside the intracellular compartments but, as expected, also has profound effects on its binding and coupling properties. The second was a mutation of a tryptophan located at the beginning of the first extracellular loop (W99R) that greatly impaired the binding properties of the receptor and had a minor effect on its intracellular routing. Molecular analysis of the first extracellular loop bearing this mutation suggests that this residue plays a fundamental role in stabilizing the peptide/receptor interactions responsible for the high-affinity binding of agonists to the V2 receptor.
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PMID:Nephrogenic diabetes insipidus: functional analysis of new AVPR2 mutations identified in Italian families. 1082 Jan 67


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