A Novel Intragenic Deletion Related to the Arginine Vasopressin V2 Receptor Causes Nephrogenic Diabetes Insipidus

Abstract Congenital Nephrogenic Diabetes Insipidus with First Presentation as an Adult: A Case Report Background: Congenital nephrogenic diabetes insipidus (NDI) is a rare inherited condition, usually presenting during the first year of life. It is characterized by a renal insensitivity to arginine vasopressin. About 90% of patients are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. Females are typically asymptomatic. Here, we report female case of NDI initially presenting and diagnosed in an adult woman. Clinical Case: A previously well 47-year-old woman of Italian descent underwent an elective laparoscopic repair of an abdominal hernia. Her medical history included obesity and migraine headaches. She was not taking any medications prior to admission. She had a bowel perforation 6 days after surgery, necessitating an emergency right hemicolectomy and small bowel resection. Upon instituting bowel rest with nil per os (NPO), she developed severe hypernatremia (Na+ 163 mmol/L) with polyuria (>6 L/day) and dilute urine (osmolality 174 mmol/kg). Further inquiry revealed that the patient routinely drank at least 10 L/day of fluids throughout her entire adult life. Her family history was remarkable for polydipsia affecting at least additional six people across three generations (including her son, her mother, 3 maternal uncles and 1 nephew). Following administration of desmopressin 1 ug subcutaneously, her urine remained inappropriately dilute (osmolality 160 mmol/kg) with no significant change in urine output (rate 350 mL/h for 3 hours). Her arginine vasopressin level was detectable (3.2 pmol/L, reference range 0.8–3.5 pmol/L), consistent with nephrogenic diabetes insipidus. Subsequent molecular analysis of the AVPR2 gene, located on chromosome Xq28, confirmed a pathogenic mutation (c.253G>A), consistent with a p.Asp85Asn substitution resulting in decreased binding affinity between the V2 receptor and arginine vasopressin. Thus, X-linked NDI was diagnosed according to the patient’s presentation, compatible family history, and genetic analysis. When she was able to eat and drink ad lib again, a low-salt, low-protein diet along with a trial of a thiazide diuretic were recommended. The patient remained well with 3 years of follow-up. Conclusion: The diagnosis of congenital NDI may be delayed until adulthood because of a relatively mild phenotype and compensatory drinking behavior, so that the disorder will not be clinically apparent until a person is deprived of free water. Men and women alike can be affected by this X-linked dominant condition which should be considered in any polyuric, hypernatremic hospitalized patient.

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Mutations in the Vasopressin V2 Receptor and Aquaporin-2 Genes in Twelve Families with Congenital Nephrogenic Diabetes Insipidus

Advances in Experimental Medicine and Biology - Vasopressin and Oxytocin ◽

10.1007/978-1-4615-4871-3_49 ◽

1998 ◽

pp. 387-390 ◽

Cited By ~ 8

Author(s):

Rosa Vargas-Poussou ◽

Lionel Forestier ◽

Marie Dominique Dautzenberg ◽

Patrick Niaudet ◽

Michèle Déchaux ◽

...

Keyword(s):

Diabetes Insipidus ◽

Nephrogenic Diabetes Insipidus ◽

Aquaporin 2 ◽

Vasopressin V2 Receptor ◽

Congenital Nephrogenic Diabetes Insipidus ◽

V2 Receptor

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Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus

AJP Renal Physiology ◽

10.1152/ajprenal.00247.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. F253-F260 ◽

Cited By ~ 65

Author(s):

J. H. Robben ◽

M. Sze ◽

N. V. A. M. Knoers ◽

P. M. T. Deen

Keyword(s):

Diabetes Insipidus ◽

Nephrogenic Diabetes Insipidus ◽

Mdck Cells ◽

Basolateral Membrane ◽

Surface Expression ◽

Cell Surface Expression ◽

High Affinity ◽

Vasopressin V2 Receptor ◽

Camp Generation ◽

V2 Receptor

Intracellular retention of a functional vasopressin V2 receptor (V2R) is a major cause of congenital nephrogenic diabetes insipidus (NDI) and rescue of V2R mutants by nonpeptide antagonists may restore their basolateral membrane (BM) localization and function. However, the criteria for efficient functional rescue of G protein-coupled receptor (GPCR) mutants at clinically feasible antagonist concentrations are unknown. We found that the four nonpeptide antagonists SR49059, OPC31260 , OPC41061 , and SR121463B induced maturation and rescued the BM expression of eight of nine different V2R mutants, stably expressed in physiologically relevant polarized cells. The extent of maturation and rescued BM expression correlated with the antagonists' concentration and affinity for the V2R. Displacement of the antagonists by AVP and subsequent cAMP generation inversely correlated with the antagonists' affinities for the V2R but is partially influenced by antagonist-specific aspects. Despite limited increases in maturation and cell-surface expression of V2R mutants, the low-affinity SR49059 optimally induced functional rescue at high concentrations, due to its easy displacement by vasopressin. At clinically feasible antagonist concentrations, however, only the high-affinity antagonists OPC31260 and OPC41061 induced functional rescue, as at these concentrations the extent of BM expression became limited. In conclusion, functional rescue of mutant V2Rs at clinically feasible concentrations is most effective with high-affinity antagonists. As OPC31260 and OPC41061 are clinically safe, they are promising candidates to relieve NDI. Moreover, as numerous other diseases are caused by endoplasmic reticulum-retained GPCRs for which cell-permeable antagonists become available, our finding that high-affinity antagonists are superior is anticipated to be important for pharmacotherapy development of these diseases.

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Mutations in the vasopressin V2 receptor and aquaporin-2 genes in 12 families with congenital nephrogenic diabetes insipidus.

Journal of the American Society of Nephrology ◽

10.1681/asn.v8121855 ◽

1997 ◽

Vol 8 (12) ◽

pp. 1855-1862 ◽

Cited By ~ 2

Author(s):

R Vargas-Poussou ◽

L Forestier ◽

M D Dautzenberg ◽

P Niaudet ◽

M Déchaux ◽

...

Keyword(s):

Diabetes Insipidus ◽

Arginine Vasopressin ◽

Nephrogenic Diabetes Insipidus ◽

Direct Sequencing ◽

Receptor Gene ◽

Single Strand Conformational Polymorphism ◽

Aquaporin 2 ◽

Congenital Nephrogenic Diabetes Insipidus ◽

V2 Receptor ◽

Aqp2 Gene

Congenital nephrogenic diabetes insipidus (CNDI) is a rare inherited disorder characterized by renal tubular insensitivity to the antidiuretic effect of arginine vasopressin (AVP). In a large majority of the cases, nephrogenic diabetes insipidus is an X-linked recessive disorder caused by mutations in the AVP V2 receptor gene (AVPR2). In the remaining cases, the disease is autosomal recessive or dominant and, for these patients, mutations in the aquaporin 2 gene (AQP2) have been reported. Fourteen probands belonging to 12 families were analyzed by single-strand conformational polymorphism and direct sequencing of the AVPR2 and AQP2 genes. Ten mutations of the AVPR2 gene (six previously reported mutations and four novel mutations: G107E, W193X, L43P, and 15delC) were identified. Three mutations of the AQP2 gene were also identified in two patients: the first patient is homozygous for the R85X mutation and the second is a compound heterozygote for V168 M and S216P mutations. Extrarenal responses to infusion of the strong V2 agonist 1-desamino-8-D-arginine vasopressin allowed AVPR2- and AQP2-associated forms of CNDI to be distinguished in three patients. This test also identified an unexpectedly high urinary osmolality (614 mosmol/kg) in a patient with a P322S mutation of AVPR2 gene and a mild form of CNDI.

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Characterization of five novel vasopressin V2 receptor mutants causing nephrogenic diabetes insipidus reveals a role of tolvaptan for M272R-V2R mutation

Scientific Reports ◽

10.1038/s41598-020-73089-x ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Federica Prosperi ◽

Yoko Suzumoto ◽

Pierluigi Marzuillo ◽

Vincenzo Costanzo ◽

Sabina Jelen ◽

...

Keyword(s):

Diabetes Insipidus ◽

Nephrogenic Diabetes Insipidus ◽

Mdck Cells ◽

Basolateral Membrane ◽

Functional Characterization ◽

Urinary Concentration ◽

Loss Of Function ◽

Vasopressin V2 Receptor ◽

V2 Receptor

Abstract Nephrogenic diabetes insipidus (NDI) is a rare tubulopathy characterized by urinary concentration defect due to renal resistance to vasopressin. Loss-of-function mutations of vasopressin V2 receptor (V2R) gene (AVPR2) is the most common cause of the disease. We have identified five novel mutations L86P, R113Q, C192S, M272R, and W323_I324insR from NDI-affected patients. Functional characterization of these mutants revealed that R113Q and C192S were normally localized at the basolateral membrane of polarized Madin-Darby Canine Kidney (MDCK) cells and presented proper glycosylation maturation. On the other side, L86P, M272R, and W323_I324insR mutants were retained in endoplasmic reticulum and exhibited immature glycosylation and considerably reduced stability. All five mutants were resistant to administration of vasopressin analogues as evaluated by defective response in cAMP release. In order to rescue the function of the mutated V2R, we tested VX-809, sildenafil citrate, ibuprofen and tolvaptan in MDCK cells. Among these, tolvaptan was effective in rescuing the function of M272R mutation, by both allowing proper glycosylation maturation, membrane sorting and response to dDAVP. These results show an important proof of concept for the use of tolvaptan in patients affected by M272R mutation of V2R causing NDI.

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Characterization of vasopressin V2 receptor mutants in nephrogenic diabetes insipidus in a polarized cell model

AJP Renal Physiology ◽

10.1152/ajprenal.00404.2004 ◽

2005 ◽

Vol 289 (2) ◽

pp. F265-F272 ◽

Cited By ~ 47

Author(s):

J. H. Robben ◽

N. V. A. M. Knoers ◽

P. M. T. Deen

Keyword(s):

Diabetes Insipidus ◽

Nephrogenic Diabetes Insipidus ◽

Transmembrane Domain ◽

Cell Model ◽

Basolateral Membrane ◽

Surface Expression ◽

Cell Surface Expression ◽

Intracellular Camp ◽

Vasopressin V2 Receptor ◽

V2 Receptor

X-linked nephrogenic diabetes insipidus (NDI) is caused by mutations in the gene encoding the vasopressin V2 receptor (V2R). For the development of a tailored therapy for NDI, knowledge of the cellular fate of V2R mutants is needed. It would be useful when this fate could be predicted from the location and type of mutation. To identify similarities and differences in localization, maturation, stability, and degradation of COOH-terminal GFP-tagged V2R mutants, we stably expressed nine mutants in polarized Madin-Darby canine kidney cells. The mutants V2R-L44P, -Δ62–64, -I130F, -S167T, -S167L, and -V206D were mainly expressed in the endoplasmic reticulum (ER) as immature proteins. These mutants had relatively short half-lives due to proteasomal degradation, except for V2R-Δ62–64. In contrast, V2R-R113W, -G201D, and -T204N were expressed in the ER and in the basolateral membrane as immature, high-mannose glycosylated, and mature complex-glycosylated proteins. The immature forms of V2R-R113W and -T204N, but not V2R-G201D, were rapidly degraded. The mature forms varied extensively in their stability and were degraded by only lysosomes (V2R-T204N and wild-type V2R) or lysosomes and proteasomes (V2R-G201D, -R113W). These data reveal that most missense V2R mutations lead to retention in the ER and suggest that mutations that likely distort a transmembrane domain or introduce a charged amino acid close to it make a V2R mutant more prone to ER retention. Because six of the mutants tested showed significant increases in intracellular cAMP levels on transient expression in COS cells, activation of these six receptors following rescue of cell-surface expression might provide a cure for NDI patients.

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