Alternative titles; symbols
HGNC Approved Gene Symbol: AVPR2
SNOMEDCT: 723440000;
Cytogenetic location: Xq28 Genomic coordinates (GRCh38) : X:153,902,625-153,907,166 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq28 | Diabetes insipidus, nephrogenic, 1 | 304800 | X-linked recessive | 3 |
| Nephrogenic syndrome of inappropriate antidiuresis | 300539 | X-linked recessive | 3 |
The AVPR2 gene encodes the arginine vasopressin receptor-2 (V2R), a G protein-coupled receptor. The biologic effects of arginine vasopressin (AVP; 192340) are mediated by 3 receptor subtypes: the V1A (600821) and V1B (600264) receptors that activate phospholipases via Gq/11, and the V2 receptor that activates adenylyl cyclase by interacting with G(s). In the collecting ducts of the kidney, the AVPR2 receptor is involved in the maintenance of water homeostasis (Birnbaumer, 2000).
Using a genomic expression cloning approach, Birnbaumer et al. (1992) isolated the cDNA corresponding to the human AVPR2 gene from a human renal cDNA library. The deduced 371-amino acid protein has a molecular mass of 40.3 kD, and shows a hydropathy profile characteristic of receptors with 7 putative transmembrane regions. This and the comparison with other cloned receptors indicated that the ADH receptor is a member of the superfamily of G protein-coupled receptors.
Seibold et al. (1992) also cloned and sequenced the human V2R gene. Lolait et al. (1992) obtained a partial-length human V2R cDNA by screening a human kidney cDNA library with a rat probe.
Lolait et al. (1992) cloned the rat kidney V2 receptor gene. The cDNA encoded a 370-amino acid protein with the characteristic 7 membrane-spanning domains. V2R mRNA was detected only in the kidney.
Seibold et al. (1992) determined that the V2R gene spans 2.2 kb and contains 3 exons. The structure of the V2R gene is unusual in that it is the first G protein-coupled receptor gene that contains 2 very small intervening sequences, the second of which separates the region encoding the seventh transmembrane region from the rest of the open reading frame.
Seibold et al. (1992) localized the V2R gene to chromosome Xq28 using PCR applied to DNA from hybrid cells.
Lolait et al. (1992) localized the V2R gene to the human X chromosome by Southern analysis of human-rodent somatic cell hybrids, and narrowed the assignment to Xq27-q28 by study of DNAs isolated from a series of mouse cell lines containing limited regions of the human X chromosome after chromosome-mediated gene transfer. This localization was consistent with the mapping of X-linked nephrogenic diabetes insipidus (NDI1; 304800) to Xq28. By family linkage studies using DNA markers, van den Ouweland et al. (1992) likewise demonstrated the localization of the genes for X-linked nephrogenic diabetes insipidus and the vasopressin V2 receptor to the same region of Xq28. They presented genetic evidence that the disease locus is distal to DXS305, and that the functional gene for the V2 receptor is localized between markers DXS269 and F8 (300841). The refinements in the localization of both genes strengthened the assumption that they were identical. The connection was also supported by the finding of Jans et al. (1990) of a close correlation between the presence of the nephrogenic diabetes insipidus locus and V2 receptor expression, as measured biochemically.
In the kidney, water reabsorption is mainly regulated by the binding of arginine vasopressin to vasopressin type 2 receptors. These receptors are expressed selectively in principal cells of the collecting ducts. To identify molecular mechanisms responsible for the cell-specific expression of the V2 receptor, Calmont et al. (2000) analyzed the proximal promoter. They reported identification of a 33-bp enhancer, designated collecting duct tissue-specific element-1 (CSE1), that induced high levels of expression of the luciferase reporter gene in 3 collecting duct cell lines, but not in other renal cell lines. CSE1 appeared to act mostly by counteracting the inhibitory effects of a strong ubiquitous repressor element that the authors called CIE1.
Crystal Structure
Shukla et al. (2013) reported the crystal structure of beta-arrestin-1 (107940) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide had been shown to functionally and conformationally activate beta-arrestin-1. To capture this active conformation, Shukla et al. (2013) used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of beta-arrestin-1. The structure of the beta-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in beta-arrestin-1 compared to its inactive conformation. These differences included rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of beta-arrestin-1. Shukla et al. (2013) concluded that their results revealed, at high resolution, a receptor-interacting interface on beta-arrestin, and they indicated a potentially general molecular mechanism for activation of these multifunctional signaling and regulatory proteins.
Nephrogenic Diabetes Insipidus 1, X-Linked
In 2 unrelated patients with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Rosenthal et al. (1992) identified 2 different mutations in the AVPR2 gene (300538.0001; 300538.0002). In 3 unrelated patients with X-linked nephrogenic diabetes insipidus, van den Ouweland et al. (1992) identified 3 different mutations in the AVPR2 gene (300538.0003-300538.0005). All of the mutations occurred in a highly conserved extracellular domain.
Wildin et al. (1994) found a different change in the AVPR2 gene in each of 11 unrelated males with X-linked congenital NDI. At least 2 of the changes were demonstrated to represent de novo mutations. All the changes predicted frameshifts, truncations, or nonconservative amino acid substitutions in evolutionarily conserved positions of the receptor protein and related receptors. In 1 patient they found a 28-bp deletion, while another unrelated patient had a tandem duplication of the same 28-bp segment, suggesting that both mutations resulted from the same unequal crossing-over mechanism facilitated by 9-mer direct sequence repeats.
Tsukaguchi et al. (1995) described AVPR2 mutations in affected members of 4 unrelated families with X-linked NDI. All 4 mutations reduced ligand-binding activity to less than 10% of normal without affecting mRNA accumulation. Three distinct phenotypes resulted from different mechanisms: a simple binding impairment at the cell surface, blocked intracellular transport, and ineffective biosynthesis and/or accelerated degradation of the receptor.
In 6 unrelated Korean families with X-linked NDI, Cheong et al. (1997) found 6 novel AVPR2 mutations.
Carroll et al. (2006) identified the molecular basis of NDI in Arab families. Carroll et al. (2006) identified 2 novel missense mutations in AQP2 (107777), 1 novel and 1 previously reported missense mutation in AVPR2, and 1 novel contiguous gene deletion involving AVPR2. They also described evidence of skewed X inactivation associated with the novel deletion.
Nephrogenic Syndrome of Inappropriate Antidiuresis
In 2 unrelated male infants with nephrogenic syndrome of inappropriate antidiuresis (NSIAD; 300539), Feldman et al. (2005) identified 2 different mutations in codon 137 of the AVPR2 gene (R137C; 300538.0021 and R137L; 300538.0022). Functional expression studies showed that the R137C and R137L mutations caused constitutive activation of the receptor with high levels of cAMP. Feldman et al. (2005) noted that a loss-of-function mutation in the same codon, R137H (300358.0015), causes nephrogenic diabetes insipidus, and commented that this was the first example in which mutations affecting the same amino acid cause 2 different genetic diseases.
Strategies for Rescue of Pathogenic AVPR2 Mutations
Schoneberg et al. (1996) showed that expression of a carboxy-terminal fragment of the wildtype V2 receptor, the V2 tail, could rescue the cellular phenotype in COS-7 cells transfected with mutant V2 receptors. Schoneberg et al. (1997) showed that recombinant adenovirus enabled transfer of the AVPR2 gene transfer into both Chinese hamster ovary cells and Madin-Darby canine kidney tubular cells. Schoneberg et al. (1997) developed a sandwich ELISA that demonstrated that the V2 tail was able to interact with the mutant receptor and restore receptor function. The authors also showed that a high level of expression of the V2 tail did not interfere with the function of other G protein-coupled receptors.
Schulz et al. (2002) identified 6 novel and 2 recurrent AVPR2 mutations in patients with NDI. One patient had a 3.2-kb genomic deletion encompassing most of the AVPR2 gene and the last exon/3-prime-region of a neighboring gene. To rescue this truncated receptor, Schulz et al. (2002) applied an aminoglycoside approach. They showed that the misreading capacity of the aminoglycoside antibiotic geneticin was sufficient to restore function of mutant AVPR2 receptors harboring premature stop codons in an in vitro expression system.
In a 37-year-old man with X-linked nephrogenic diabetes insipidus (NDI1; 304800) since birth, Rosenthal et al. (1992) identified a 1-bp deletion (733delG) in the AVPR2 gene, resulting in a frameshift and premature termination of the protein at codon 270. The mutant receptor lacked the entire carboxy-terminal third, and conserved only 17 of the 42 amino acids of the third intracellular loop. The patient had a lifelong history of polyuria, polydipsia, and mental retardation resulting from repeated and prolonged episodes of dehydration in the first year of life. A normal receptor gene was found in the patient's unaffected brother. Both the normal and the mutant allele were detected in their mother. Rosenthal et al. (1992) suggested that this was the first example of a genetic defect in a G protein-coupled hormone receptor.
In a patient with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Rosenthal et al. (1992) identified a 395C-A transversion in the AVPR2 gene, resulting in an ala132-to-asp (A132D) substitution in the third transmembrane domain of the protein. The substitution resulted in a change in the hydropathy profile of the receptor protein. The patient's brother did not have the defective gene; the mother had both the normal and the mutant allele.
In a patient with X-linked nephrogenic diabetes insipidus (NDI1; 304800), van den Ouweland et al. (1992) identified a 553G-T transversion in the AVPR2 gene, resulting in a gly185-to-cys (G185C) substitution in a highly conserved extracellular domain.
In a patient with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Van den Ouweland et al. (1992) identified a 614A-G transition in the AVPR2 gene, resulting in a tyr205-to-cys (Y205C) substitution in a highly conserved extracellular domain.
In a patient with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Van den Ouweland et al. (1992) identified a 604C-T transition in the AVPR2 gene, resulting in an arg203-to-cys (R203C) substitution in a highly conserved extracellular domain.
In affected members of a family studied by Bode and Crawford (1969) and Bode and Miettinen (1970) with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Holtzman et al. (1993) identified a C-to-T transition in the AVPR2 gene, resulting in an arg113-to-trp (R113W) substitution. Most of the family members had been longtime residents of a town in central Maine. The finding of various mutations in North American patients with nephrogenic diabetes insipidus rendered the 'Hopewell hypothesis' of a founder mutation (Bode and Crawford, 1969) untenable.
In a child of Lithuanian ancestry with nephrogenic diabetes insipidus (NDI1; 304800), Merendino et al. (1993) identified a 1-bp insertion in codon 228 of the AVPR2 gene. The mutation resulted in disruption of 40% of the predicted protein sequence at the carboxy terminus, first by the generation of a missense amino acid sequence and then by premature termination after approximately 20 amino acid residues.
In affected members of a large kindred, the 'Hopewell' family, with nephrogenic diabetes insipidus (NDI1; 304800) originally thought to be representative of a founder effect for this gene in North America (Bode and Crawford, 1969), Holtzman et al. (1993) identified a G-to-A transition in the AVPR2 gene, resulting in a trp71-to-ter (W71X) substitution. Since this mutation had not been found in other North American pedigrees, the founder hypothesis could be rejected. Bichet et al. (1993) also identified the W71X mutation in members of the Hopewell kindred and 4 so-called satellite families which may have had a common ancestry with the Hopewell immigrants.
In affected members of a family with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Friedman et al. (1994) identified a mutation in the AVPR2 gene, resulting in a tyr280-to-cys (Y280C) substitution in the sixth transmembrane domain of the vasopressin V2 receptor.
In a mother and son with nephrogenic diabetes insipidus (NDI1; 304800), Moses et al. (1995) identified a C-to-T transition in the AVPR2 gene, resulting in an arg337-to-ter (R337X) substitution and truncation of the intracellular carboxy-terminal tail of the V2 receptor. The 32-year-old mother and her 10-year-old son had severe NDI, whereas the 8-year-old daughter was an asymptomatic carrier. Infusion of desmopressin into the mother and son revealed a total lack of antidiuretic response, whereas the daughter increased urinary osmolality normally. After the infusion of desmopressin, the plasma factor VIII concentration in the son did not rise, whereas the mother and daughter had half of the normal factor VIII response, similar to asymptomatic female carriers of NDI. Moses et al. (1995) postulated that the renal tubular cells of the mother demonstrated extreme lyonization of X-chromosome inactivation, whereas in the tissue that subserves the hematologic response to desmopressin, X-chromosome inactivation followed a more typically random distribution.
Sadeghi et al. (1997) investigated function and biochemical properties of the R337X mutant protein by expression in COS.M6 and HEK293 cells. Binding assays and measurements of adenylyl cyclase activity failed to detect function for the truncated V2R, although metabolic labeling showed normal levels of protein synthesis. ELISA assays performed on cells expressing V2Rs tagged at the amino terminus with the HA epitope failed to detect the mutant protein on the plasma membrane. Treatment with endoglycosidase H revealed that the receptor was present only as a precursor form; the mature R337X mutant protein, resistant to endoglycosidase H treatment, was not detected. The authors concluded that the mutant V2R protein is nonfunctional because it does not reach the plasma membrane.
Sadeghi et al. (1997) noted the identification of 4 families with individuals exhibiting a partial nephrogenic diabetes insipidus phenotype (NDI1; 304800). When subjected to dehydration, the kidneys of these patients produced concentrated urine. Two mutations in the AVPR2 gene found among these patients were asp85-to-asn (D85N) and gly201-to-asp (G201D; 300538.0012) substitutions. Functional expression studies showed that the D85N mutant protein affected coupling of the receptor to Gs (139320). The G201N mutation in the second extracellular loop decreased cell surface expression of AVPR2 with minor reduction in ligand-binding affinity and coupling efficiency to Gs. Sadeghi et al. (1997) concluded that while decreased ligand-binding affinity and decreased coupling to Gs are responsible for the attenuation of response to ligand in the D85N mutant AVPR2, cell surface expression of the AVPR2 is the major factor reducing cellular responses to ligand for the G201D mutant.
See 300538.0011 and Sadeghi et al. (1997).
In 6 members of a Japanese family with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Nomura et al. (1997) identified a 1-bp insertion (804insG) in the AVPR2 gene, resulting in a frameshift and premature termination at codon 258. Three heterozygous females had differences in clinical severity of NDI. The X-inactivation patterns of these females were investigated by studying the methylated trinucleotide repeat in the human androgen receptor gene. The grandmother showed extremely skewed methylation of one X chromosome, while her daughter had moderately skewed methylation. The daughter of the grandmother's sister, who had no symptoms of NDI, showed random methylation. Nomura et al. (1997) suggested that the highly skewed X-inactivation pattern of the grandmother indicated that her NDI phenotype was caused by dominant methylation of the normal allele of AVPR2 gene.
In affected members of a Russian family with nephrogenic diabetes insipidus (NDI1; 304800), Schoneberg et al. (1998) identified a 1-bp deletion (102delG) in the AVPR2 gene, resulting in a frameshift and a truncated receptor protein. The premature termination led to a drastically reduced receptor protein expression in transfected COS-7 cells and precluded specific AVPR2 functions.
Nephrogenic Diabetes Insipidus 1, X-Linked
In a patient with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Schoneberg et al. (1998) identified a 410G-A transition in the AVPR2 gene, resulting in an arg137-to-his (R137H) substitution in a motif highly conserved among G protein-coupled receptors. Functional expression studies showed that the R137H mutant protein was almost completely retained in the cell interior, but the few receptor molecules that found their way to the plasma membrane displayed a low but significant ability to stimulate the Gs/adenylyl cyclase system.
Agonist-dependent desensitization and internalization of G protein-coupled receptors (GPCR) are mediated by the binding of arrestins to phosphorylated receptors. The affinity of arrestins for the phosphorylated GPCR regulates the ability of the internalized receptor to be dephosphorylated and recycled back to the plasma membrane. Barak et al. (2001) showed that the R137H mutation induces constitutive arrestin-mediated desensitization of the receptor. In contrast to the wildtype vasopressin receptor, the nonsignaling R137H receptor is phosphorylated and sequestered in arrestin-associated intracellular vesicles even in the absence of agonist. Eliminating molecular determinants on the receptor that promote high affinity arrestin-receptor interaction reestablished plasma membrane localization and the ability of the mutated receptors to signal. These findings suggested that unregulated desensitization can contribute to the etiology of a GPCR-based disease, implying that pharmacologic targeting of GPCR desensitization may be therapeutically beneficial.
Nephrogenic Syndrome of Inappropriate Antidiuresis
In 2 unrelated male infants with nephrogenic syndrome of inappropriate antidiuresis (NSAID; 300359), Feldman et al. (2005) identified 2 different mutations in codon 137 of the AVPR2 gene (R137C; 300538.0021 and R137L; 300538.0022). Functional expression studies showed that the R137C and R137L mutations caused constitutive activation of the receptor with high levels of cAMP. Feldman et al. (2005) commented that this was the first example in which mutations affecting the same amino acid cause 2 different genetic diseases.
In affected members of a German family with nephrogenic diabetes insipidus (NDI1; 304800), Schoneberg et al. (1998) identified a C-to-T transition in the AVPR2 gene, resulting in an arg181-to-cys (R181C) substitution. Functional expression studies showed that the R181C mutant protein is properly delivered to the cell surface, but shows impaired ligand binding. This mutation had previously been identified in an American kindred, where it was found in combination with an additional deletion of 4 amino acids in the third intracellular loop (Pan et al., 1992).
In a patient with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Pasel et al. (2000) identified a mutation in the AVPR2 gene, resulting in a phe105-to-val (F105V) substitution in a highly conserved extracellular domain of the protein. Functional expression studies showed that the F105V mutant protein was delivered to the cell surface and displayed an unchanged maximum cAMP response; however, impaired ligand-binding abilities of the mutant protein were reflected in a shifted concentration-response curve toward higher vasopressin concentrations.
In a patient with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Pasel et al. (2000) identified a T-to-A transversion in the AVPR2 gene, resulting in an ile46-to-lys (I46K) substitution. Functional expression studies of the mutant protein showed reduced maximum agonist-induced cAMP responses as a result of an improper cell surface targeting.
In a patient with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Pasel et al. (2000) identified an A-to-T transversion in the AVPR2 gene, resulting in an ile130-to-phe (I130F) substitution. Functional expression studies of the mutant protein showed reduced maximum agonist-induced cAMP responses as a result of an improper cell surface targeting.
In a patient with X-linked nephrogenic diabetes insipidus (NDI1; 304800), Inaba et al. (2001) identified a 310C-T transition in exon 2 of the AVPR2 gene, resulting in an arg104-to-cys (R104C) substitution in the first extracellular loop of the V2 receptor. Transient expression studies with COS-7 cells showed that the binding capacity of the R104C mutant protein was to 10% of wildtype, and maximum cAMP accumulation in response to AVP stimulation was decreased to 50% of wildtype. In addition, Inaba et al. (2001) confirmed that the sulfhydryl group of the cysteine-104 caused most of the R104C mutant receptor dysfunction.
In a male infant with a clinical picture resembling that of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), but with undetectable levels of arginine vasopressin, Feldman et al. (2005) identified a 770C-T transition in the AVPR2 gene, resulting in an arg137-to-cys (R137C) substitution in the second cytoplasmic loop of the protein. The authors termed the patient's SIADH-like clinical picture 'nephrogenic syndrome of inappropriate antidiuresis' (NSIAD; 300359). Functional expression studies showed that the R137C mutation caused constitutive activation of the receptor with high levels of cAMP. Feldman et al. (2005) noted that a loss-of-function mutation in the same codon, R137H (300358.0015), causes nephrogenic diabetes insipidus (304800), and commented that this was the first example in which mutations affecting the same amino acid cause 2 different genetic diseases.
In a male infant with a clinical picture resembling that of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), but with undetectable levels of arginine vasopressin, Feldman et al. (2005) identified a 771G-T transversion in the AVPR2 gene, resulting in an arg137-to-leu (R137L) substitution in the second cytoplasmic loop of the protein. The authors termed the patient's SIADH-like clinical picture 'nephrogenic syndrome of inappropriate antidiuresis' (NSIAD; 300539). Functional expression studies showed that the R137L mutation caused constitutive activation of the receptor with high levels of cAMP. Feldman et al. (2005) noted that a loss-of-function mutation in the same codon, R137H (300358.0015), causes nephrogenic diabetes insipidus (304800), and commented that this was the first example in which mutations affecting the same amino acid cause 2 different genetic diseases.
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