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)

We recently identified vasopressin type 2 receptor gene mutations in two unrelated Japanese families with X-linked nephrogenic diabetes insipidus, which were a missense mutation from Arg143 to Pro (R143P) and a single amino acid deletion of Val278 or 279 (delta V278). To investigate the mechanism by which the mutations cause arginine vasopressin (AVP) resistance in this disorder, we expressed them in mammalian cells and analyzed their functional properties. Stable expression study with Chinese hamster ovary (CHO) cells demonstrated that the R143P mutation reduced receptor binding capacity to 10% of normal. However, the R143P mutant itself had a normal affinity for AVP and stimulated adenylyl cyclase production at up to 50% of the wild-type level, suggesting that the mutant receptors could function normally despite their reduced surface expression. In contrast, the delta V278 mutation totally abolished receptor-ligand binding and subsequent adenylyl cyclase stimulation, indicating that delta V278 mutant is virtually nonfunctional receptor. Northern blotting revealed that mutant CHO cell lines produced levels of receptor mRNA similar to the wild-type cell line. Our results suggest that the two mutations impair binding activity of the receptor without affecting mRNA accumulation, thereby causing AVP resistance through a posttranscriptional mechanism.
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PMID:Two vasopressin type 2 receptor gene mutations R143P and delta V278 in patients with nephrogenic diabetes insipidus impair ligand binding of the receptor. 759 29

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

The molecular cloning and characterization of receptors for [Arg8] vasopressin and oxytocin were recently accomplished. These receptors form a subfamily among the large number of guanine nucleotide-binding regulatory protein (G protein)-coupled receptors with seven transmembrane domains. The molecular cloning of the human V2 receptor was rapidly followed by the identification of mutations in the V2 receptor gene segregating with the clinical phenotype in families with X-linked nephrogenic diabetes insipidus. These naturally occurring mutations will be useful to identify critical functional regions of the vasopressin V2 receptor. Carrier detection and early diagnosis of affected male infants are available and can avert the physical and mental retardation that are the consequences of episodes of dehydration. Together with the recent cloning of the vasopressin-regulated water channels in the apical membrane of the collecting tubule, these developments will enable direct investigation of the mammalian concentrating mechanism.
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PMID:Molecular and cellular biology of vasopressin and oxytocin receptors and action in the kidney. 785 Apr 11

The mutation of the type-2 vasopressin receptor (V2R) apparently responsible for X-linked congenital nephrogenic diabetes insipidus (CNDI) in the Q3 family consists of a T to C transition in codon 113, causing the change of Arg-113 to Trp. Arg-113 is located in the putative first extracellular loop of the V2R next to a frequently conserved Cys thought to interact via a disulfide bridge with a Cys of the second extracellular loop. The present study explored whether this mutation may account for the CNDI phenotype. The mutation was excised from the genomic DNA of a Q3 patient and introduced into the V2R cDNA, which was then placed into an expression plasmid and transfected into COS cells for transient expression and murine L cells for stable expression. Studies with L cells expressing similar levels of wild type and Q3 receptors showed that the mutant receptor has a 20-fold reduced affinity for arginine vasopressin (AVP) and stimulates adenylyl cyclase with an EC50 that is increased by a factor of about 60-fold. The same shift in the EC50 for adenylyl cyclase stimulation was obtained when deamino[8-D-Arg]vasopressin was substituted for AVP. Studies with COS cells revealed that at equal levels of transfected DNA, the mutant receptor is expressed at lower levels (about 20%) than the wild type receptor, indicating that the mutation hinders the transport of the receptor to the cell membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:An extracellular congenital nephrogenic diabetes insipidus mutation of the vasopressin receptor reduces cell surface expression, affinity for ligand, and coupling to the Gs/adenylyl cyclase system. 798 50

Novel mutations in the V2 vasopressin receptor gene were identified in two Japanese pedigrees with X-linked congenital nephrogenic diabetes insipidus. The V2 receptor belongs to the family of G-protein-coupled receptors that contain seven distinct transmembrane domains, and the V2 receptor gene is encoded by three exons. The coding regions amplified by polymerase chain reaction were directly sequenced. In a pedigree, one of four consecutive guanine sequences (nucleotides 528-531) in the second exon was deleted (528delG). This deletion mutation results in a frame shift beginning at codon 154 in the second intracellular domain and a premature termination at codon 161. In another pedigree, a missense mutation (A-->G) was identified at nucleotide position 310 in the second exon. This point mutation, H80R, changes a histidine at codon 80 in the second transmembrane domain to an arginine that is more positively charged than histidine under the neutral environment. Each mutation cosegregated with the phenotype of diabetes insipidus and supposed to be a cause for resistance to arginine vasopressin.
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PMID:Novel mutations in the V2 vasopressin receptor gene in two pedigrees with congenital nephrogenic diabetes insipidus. 804 48

In X-linked nephrogenic diabetes insipidus (NDI) the urine of male patients is not concentrated after the administration of the antidiuretic hormone arginine-vasopressin. This disease is due to mutations in the V2 receptor gene that maps to chromosome region Xq28. In 1969, Bode and Crawford suggested that most NDI patients in North America shared common ancestors of Ulster Scot immigrants who arrived in Halifax in 1761 on the ship Hopewell. A link between this family and a large Utah kindred was also suggested. DNA was obtained from 17 affected male patients from the "Hopewell" kindred and from four additional families from Nova Scotia and New Brunswick who shared the same Xq28 NDI haplotype. The Utah kindred and two families (Q2, Q3) from Quebec were also studied. The "Hopewell" mutation, W71X, is a single base substitution (G-->A) that changes codon 71 from TGG (tryptophan) to TGA (stop). The W71X mutation was found in affected members of the Hopewell and of the four satellite families. The W71X mutation is the cause of X-linked NDI for the largest number of related male patients living in North America. Other families (Utah, Q2 and Q3) that are historically and ethnically unrelated bear other mutations in the V2 receptor gene.
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PMID:X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. 810 96

Congenital nephrogenic diabetes insipidus (NDI) is an X-linked inherited disorder characterized by renal resistance to the antidiuretic hormonal action of arginine vasopressin. The disease gene has been assigned to the subtelomeric region of the X chromosome long arm by demonstrating close linkage between NDI and several X-chromosomal DNA markers. The finding of closely linked genetic markers is useful in the diagnosis of NDI. Receptor studies in patients have indicated that NDI might be due to the absence or an abnormality of the adenylate cyclase-bound vasopressin type 2 receptor. This assumption was supported by the discovery of functional vasopressin V2 receptor activity in somatic cell hybrid cell lines that carried at least the distal part of the human X chromosome long arm. Definite evidence for a V2 receptor defect being the cause of NDI was found in a recent study demonstrating point mutations in the V2 receptor gene from affected individuals. Direct mutation analysis is now applicable for accurate carrier detection and early (prenatal) diagnosis.
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PMID:Nephrogenic diabetes insipidus: identification of the genetic defect. 825 44

Nephrogenic diabetes insipidus (NDI) is a rare X-linked disorder exhibiting renal resistance to the antidiuretic action of arginine vasopressin (AVP). Recent elucidation of the vasopressin V2 (renal type) receptor gene structure has enabled us to test the hypothesis that the genetic defect in the V2 receptor is the likely molecular basis of NDI. By using the polymerase chain reaction (PCR)-direct sequencing, we identified novel V2 receptor gene mutations in two unrelated Japanese kindreds with NDI. In the male patients of kindred A, a single codon deletion in one of two consecutive GTC triplets (nucleotide 832 to 837) was detected. This base change resulted in the loss of a valine residue in the 6th transmembrane domain. In the affected males of kindred B, a G to C substitution was found at nucleotide 428, altering codon 143 from arginine (CGT) to proline (CCT) in the second cytoplasmic domain. PCR-single strand conformation polymorphism (SSCP) analysis of family members demonstrated that the mutations cosegregated with clinically affected individuals and were absent in normal subjects. Our results suggest that different V2 receptor defects could be responsible for AVP resistance in individual NDI kindreds.
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PMID:Two novel mutations in the vasopressin V2 receptor gene in unrelated Japanese kindreds with nephrogenic diabetes insipidus. 826 67

Inactivating mutations in distinct G protein-coupled receptors (GPCRs) are currently being identified as the cause of a steadily growing number of human diseases. Based on previous studies showing that GPCRs are assembled from multiple independently stable folding units, we speculated that such mutant receptors might be functionally rescued by 'supplying' individual folding domains that are lacking or misfolded in the mutant receptors, by using a co-expression strategy. To test the feasibility of this approach, a series of nine mutant V2 vasopressin receptors known to be responsible for X-linked nephrogenic diabetes insipidus were used as model systems. These mutant receptors contained nonsense, frameshift, deletion or missense mutations in the third intracellular loop or the last two transmembrane helices. Studies with transfected COS-7 cells showed that none of these mutant receptors, in contrast to the wild-type V2 receptor, was able to bind detectable amounts of the radioligand, [3H]arginine vasopressin, or to activate the G(S)/adenylyl cyclase system. Moreover, immunological studies demonstrated that the mutant receptors were not trafficked properly to the cell surface. However, several of the nine mutant receptors regained considerable functional activity upon co-expression with a C-terminal V2 receptor peptide spanning the sequence where the various mutations occur. In many cases, the restoration of receptor activity by the co-expressed receptor peptide was accompanied by a significant increase in cell surface receptor density. These findings may lead to the design of novel strategies in the treatment of diseases caused by inactivating mutations in distinct GPCRs.
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PMID:Functional rescue of mutant V2 vasopressin receptors causing nephrogenic diabetes insipidus by a co-expressed receptor polypeptide. 863 61

Hereditary diabetes insipidus can occur in two forms: the first, referred to as central diabetes insipidus, is responsive to vasopressin whereas the second, termed nephrogenic diabetes insipidus, is resistant to treatment. Recent advances in molecular genetics have contributed to elucidate the pathogenesis of these affections. Familial central diabetes insipidus depicts two unsimilar illnesses. The first, characterized by an autosomal dominant transmission, is of delayed onset and worsens progressively all through life. It is related to a heterozygous mutation of the vasopressin precursor gene mainly involving either the sequence encoding for the signal peptide or the one encoding for neurophysin II, the hormone carrier protein. Mutations described to date are responsible for impairment of vasopressin precursor transportation and processing. Therefore mutant protein accumulates in the posterior pituitary which is involved in the persistant bright spot seen on magnetic resonance imaging. The second illness or Wolfram syndrome, autosomal recessive, associates obligatory features: insulin-dependant diabetes, bilateral optic atrophy and more inconstantly: diabetes insipidus, deafness, genito-urinary and neuropsychiatric disturbances. The cause of this syndrome, still unknown, may involve mitochondrial ADN mutations. Familial nephrogenic diabetes insipidus, of neonatal onset, are mainly X-linked and associated to mutations in the V2 receptor gene. About 60 mutations have been described until now. Some rare cases, transmission of which is autosomal recessive, result from homozygous mutations of aquaporin 2 gene, a water channel involved in the water reabsorption in the renal collecting duct. Other mutations will be probably discovered in future. In conclusion, familial diabetes insipidus constitutes an interesting pathogenic model because it may be explained by impairment of vasopressin gene precursor as well as by abnormalities of renal receptor or post receptor mechanisms of the hormone.
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PMID:[Congenital diabetes insipidus. Recent advances in molecular genetics]. 868 70


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