Nephrogenic Syndrome of Inappropriate Antidiuresis

MONDO:0010356 Pathograph 36 Show in embeddings browser inherited renal tubular disease X-linked disease

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is the gain-of-function mirror of X-linked nephrogenic diabetes insipidus. Constitutively activating missense variants in AVPR2, which encodes the arginine vasopressin V2 receptor of the renal collecting duct, make the receptor signal without its hormone. The principal cell therefore runs its Gs/adenylyl cyclase/cAMP/protein-kinase-A cascade, phosphorylates aquaporin-2 and shuttles it to the apical membrane, and reabsorbs free water even when circulating vasopressin is low or undetectable. The clinical picture reproduces the syndrome of inappropriate antidiuretic hormone secretion (SIADH) - hypotonic hyponatremia with inappropriately concentrated urine - but with suppressed rather than inappropriate hormone secretion, which is the feature that distinguishes it. It was first described by Feldman and colleagues in 2005 in two male infants with undetectable vasopressin who carried missense changes at codon 137 of the receptor, the same codon whose loss-of-function allele (R137H) causes nephrogenic diabetes insipidus. The disorder is X-linked: hemizygous males present in infancy with symptomatic hyponatremia - hypotonia, irritability, vomiting and seizures - while female carriers are variably affected. Because the lesion is a fixed inability to excrete free water rather than hormone excess, hyponatremia appears only with a water load and is managed with fluid restriction and oral urea.

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1
Mappings
1
Inheritance
12
Pathophys.
13
Phenotypes
36
Pathograph
1
Genes
5
Variants
4
Medical Actions
2
Differentials
1
Models
9
References
1
Deep Research
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Classifications

Harrison's Part
KIDNEY URINARY TRACT ENDOCRINOLOGY METABOLISM GENETICS ENVIRONMENT DISEASE
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Mappings

MONDO
MONDO:0010356 nephrogenic syndrome of inappropriate antidiuresis
skos:exactMatch MONDO
Primary disease term for this entry.
👪

Inheritance

1
X-linked recessive inheritance HP:0001419
X-linked disorder of AVPR2 on Xq28. Hemizygous males present in infancy; carrier females are variably affected; de novo variants occur. The "recessive" label is imperfect: symptomatic female probands are described, and carrier females can have episodic, usually incidentally found hyponatremia, so the distinction between carrier and affected is blurred.
X-linked recessive inheritance
Show evidence (2 references)
PMID:29472987 SUPPORT Human Clinical
"Female carriers may present with episodes of hyponatremia, usually found incidentally."
Carrier females are not reliably asymptomatic - they can have episodic hyponatremia.
PMID:15872203 SUPPORT Human Clinical
"DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations in both, with resultant changes in codon 137 from arginine to cysteine or leucine."
The X-linked AVPR2 gene underlying the inheritance pattern.
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Pathophysiology

12
AVPR2 Gain-of-Function Variant
A hemizygous germline missense variant in AVPR2 on Xq28, the gene encoding the arginine vasopressin V2 receptor. The reported alleles are a small set of activating substitutions: the two original codon-137 changes (arginine to cysteine, R137C, and to leucine, R137L), the transmembrane substitution F229V, and I130N. Codon 137 shows allelic opposition - R137H at the same residue is loss-of-function and causes X-linked nephrogenic diabetes insipidus, whereas R137C and R137L are gain-of-function.
Genetic context AVPR2 hgnc:897 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns AVPR2 (hgnc:897). hgnc:897 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: GAIN_OF_FUNCTION
Hemizygous in affected males. One original proband inherited R137C from a carrier mother and the other's R137L arose de novo. Heterozygous females are variably affected.
arginine vasopressin V2 receptor activity GO:0005000 ⇑ GAIN OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves arginine vasopressin V2 receptor activity, annotated with vasopressin receptor activity (GO:0005000), qualified as gain of function. GO:0005000 is a molecular function from the Gene Ontology.
Downstream
Ligand-Independent V2 Receptor Activation The activating substitutions let the receptor adopt an active conformation in the absence of vasopressin.
Show evidence (3 references)
PMID:15872203 SUPPORT Human Clinical
"DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations in both, with resultant changes in codon 137 from arginine to cysteine or leucine."
Reports the two founding AVPR2 gain-of-function alleles, R137C and R137L.
PMID:22956819 SUPPORT Human Clinical
"Here, we describe a 3-month-old hyponatremic infant found to have a phenylalanine 229 to valine (F229V) substitution in V2R."
Adds F229V as a third activating AVPR2 allele outside codon 137.
PMID:26131744 SUPPORT Human Clinical
"Here we present a newly identified I130N substitution in exon 2 of the V2R gene in a family, causing NSIAD."
Adds I130N as a fourth activating AVPR2 allele.
Ligand-Independent V2 Receptor Activation
The mutant V2 receptor is held in an active conformation and transduces signal without bound vasopressin. For F229V the active state is not locked - V2R-selective inverse agonists silence it - so the gain of function is a shifted equilibrium rather than an irreversible lock.
V2 vasopressin receptor activity GO:0005000 ⇑ GAIN OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves V2 vasopressin receptor activity, annotated with vasopressin receptor activity (GO:0005000), qualified as gain of function. GO:0005000 is a molecular function from the Gene Ontology.
Downstream
Constitutive Adenylyl Cyclase cAMP Generation The active receptor couples to Gs and stimulates adenylyl cyclase.
Constitutive V2 Receptor Internalization The biased active conformation also drives ligand-independent endocytosis of the receptor, a parallel consequence of the activating lesion.
Show evidence (1 reference)
PMID:22956819 SUPPORT In Vitro
"In contrast to R137C/L mutant receptors, F229V receptors do not undergo spontaneous desensitization, which results in sustained, high basal activity."
Distinguishes the receptor-regulation behaviour of the activating alleles - a sustained active state for F229V versus the desensitizing R137C/L receptors.
Constitutive V2 Receptor Internalization
The I130N receptor adopts a biased conformation whose basal activity does not recruit beta-arrestin, yet the receptor is constitutively internalized through a dynamin-dependent, beta-arrestin-independent route. This ligand-independent endocytosis lowers cell-surface receptor and is mechanistically separable from the cAMP output, and it is the receptor-trafficking counterpart of the misfolding retention seen with loss-of-function AVPR2 alleles.
constitutive G protein-coupled receptor internalization GO:0002031 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased constitutive G protein-coupled receptor internalization, annotated with G protein-coupled receptor internalization (GO:0002031). GO:0002031 is a biological process from the Gene Ontology.
Show evidence (2 references)
PMID:26131744 SUPPORT In Vitro
"The constitutive activity of the mutant receptor caused constitutive dynamin-dependent and β-arrestin-independent internalization."
Reports the ligand-independent internalization branch for the I130N receptor.
PMID:26131744 SUPPORT In Vitro
"The mutation causes a biased receptor conformation as the basal cAMP generation activity of I130N does not lead to interaction with β-arrestin."
Supports the biased-signalling character of the basal active state behind the beta-arrestin-independent internalization.
Constitutive Adenylyl Cyclase cAMP Generation
In the collecting-duct principal cell the constitutively active receptor drives Gs stimulation of adenylyl cyclase and raises intracellular cyclic AMP without vasopressin. This was demonstrated directly in transfected cells for the I130N and F229V receptors.
kidney collecting duct principal cell CL:1001431 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves kidney collecting duct principal cell (CL:1001431). CL:1001431 is a cell type from the Cell Ontology.
adenylate cyclase-activating G protein-coupled receptor signaling pathway GO:0007189 ⇑ GAIN OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), qualified as gain of function. GO:0007189 is a biological process from the Gene Ontology. cAMP biosynthetic process GO:0006171 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cAMP biosynthetic process (GO:0006171). GO:0006171 is a biological process from the Gene Ontology.
collecting duct of renal tubule UBERON:0001232 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in collecting duct of renal tubule (UBERON:0001232). UBERON:0001232 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
HEK293 cells expressing mutant V2 receptor CELL LINE Directly measures the ligand-independent cAMP output of the mutant receptor.
Downstream
PKA-Mediated Aquaporin-2 Phosphorylation Elevated cAMP activates protein kinase A.
Show evidence (2 references)
PMID:26131744 SUPPORT In Vitro
"This I130N mutation resulted in constitutive activity of the V2R with constitutive cyclic adenosine monophosphate (cAMP) generation in HEK293 cells."
Direct demonstration of ligand-independent cAMP generation by a mutant receptor.
PMID:22956819 SUPPORT In Vitro
"Characterization of this substitution in vitro revealed that it leads to high constitutive activity of the receptor, compatible with spontaneous antidiuresis."
A second activating allele showing high constitutive signalling, tied to spontaneous antidiuresis.
PKA-Mediated Aquaporin-2 Phosphorylation
Cyclic-AMP-activated protein kinase A phosphorylates aquaporin-2. This step is inferred from established V2-receptor physiology rather than shown in patient tissue, but it is the obligate link between the measured cAMP signal and water-channel trafficking.
cAMP-dependent protein kinase activity GO:0004691 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased cAMP-dependent protein kinase activity (GO:0004691). GO:0004691 is a molecular function from the Gene Ontology.
Downstream
Apical Aquaporin-2 Membrane Insertion Phosphorylated aquaporin-2 traffics to and is retained at the apical membrane.
Apical Aquaporin-2 Membrane Insertion
Phosphorylated aquaporin-2 redistributes from intracellular vesicles into the apical plasma membrane of the principal cell, the step that renders the membrane water-permeable.
positive regulation of renal water transport GO:2001153 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of renal water transport (GO:2001153). GO:2001153 is a biological process from the Gene Ontology.
apical plasma membrane GO:0016324 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves apical plasma membrane (GO:0016324). GO:0016324 is a cellular component from the Gene Ontology.
Downstream
Increased Collecting Duct Water Permeability Apical aquaporin-2 opens a transcellular water pathway.
Show evidence (1 reference)
PMID:20631022 SUPPORT INDIRECT Human Clinical
"Water loading was followed by a very slow and incomplete elimination in the asymptomatic hemizygous boy with no suppression of AQP2 excretion"
Urinary AQP2 excretion is a marker of apical AQP2 trafficking in the collecting duct; its failure to suppress after a water load in a hemizygous patient is the in-vivo sign that AQP2 stays in the apical membrane without vasopressin.
Increased Collecting Duct Water Permeability
With aquaporin-2 in the apical membrane the collecting duct epithelium becomes water-permeable, allowing water to follow the medullary osmotic gradient independently of hormonal command.
renal water absorption GO:0070295 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased renal water absorption (GO:0070295). GO:0070295 is a biological process from the Gene Ontology.
collecting duct of renal tubule UBERON:0001232 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in collecting duct of renal tubule (UBERON:0001232). UBERON:0001232 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Ligand-Independent Free Water Reabsorption The permeable duct reabsorbs free water from the tubular lumen.
Ligand-Independent Free Water Reabsorption
The kidney reabsorbs free water continuously, uncoupled from vasopressin, which is the whole-organ consequence of the fixed water permeability.
Downstream
Inappropriately concentrated urine Continuous water reabsorption leaves the urine concentrated despite plasma hypotonicity.
Free Water Retention Water that is not excreted is retained in the body.
Show evidence (1 reference)
PMID:22722264 SUPPORT Human Clinical
"gain-of-function mutation of arginine vasopressin receptor type 2 (AVPR2) resulting in free water reabsorption and episodes of hyponatremia"
States the disease-level consequence - free water reabsorption producing hyponatremia.
Free Water Retention
Retention of electrolyte-free water expands and dilutes total body water. Because sodium handling is intact, the result is dilutional rather than a sodium-deficit state.
Downstream
Hypotonic Hyponatremia Dilution of body sodium lowers serum sodium and osmolality.
Physiologic Suppression of Vasopressin Secretion Water retention and the fall in plasma osmolality appropriately suppress hypothalamic vasopressin release, which is why circulating hormone is low.
Physiologic Suppression of Vasopressin Secretion
The retained water and low plasma osmolality suppress hypothalamic vasopressin output normally. Hormone secretion is therefore appropriately low or undetectable - the opposite of SIADH - and the antidiuresis is driven entirely by the receptor.
Downstream
Decreased circulating antidiuretic hormone concentration The suppressed secretion is measured as low or undetectable plasma vasopressin.
Show evidence (1 reference)
PMID:15872203 SUPPORT Human Clinical
"We describe two infants whose clinical and laboratory evaluations were consistent with the presence of SIADH, yet who had undetectable arginine vasopressin (AVP) levels."
The undetectable vasopressin that distinguishes NSIAD from SIADH and reflects appropriate physiologic suppression.
Hypotonic Hyponatremia
Dilutional hyponatremia with low serum osmolality. It is water-load dependent - the genotype fixes an inability to excrete free water, so plasma sodium falls only when intake exceeds the reduced free-water excretory capacity.
Downstream
Hyponatremia The measured low serum sodium.
Low serum osmolality The accompanying fall in serum osmolality.
Hyponatremic Cerebral Water Shift Plasma hypotonicity drives water into brain cells.
Malaise Nonspecific later-life symptom of chronic/episodic hyponatremia.
Vertigo Dizziness as a later-life hyponatremic symptom.
Confusion Confusion as a later-life hyponatremic symptom.
Fatigue Tiredness as a later-life hyponatremic symptom.
Headache Headache as a later-life hyponatremic symptom.
Show evidence (1 reference)
PMID:22722264 SUPPORT Human Clinical
"gain-of-function mutation of arginine vasopressin receptor type 2 (AVPR2) resulting in free water reabsorption and episodes of hyponatremia"
The disease-level consequence this node models - episodic hyponatremia from free-water reabsorption.
Hyponatremic Cerebral Water Shift
The osmotic gradient created by plasma hypotonicity drives water into the brain, producing cerebral edema and the neurological manifestations seen in symptomatic infants.
Downstream
Seizure Cerebral edema and the hypotonic state lower the seizure threshold.
Irritability Non-specific neurological irritability of acute hyponatremia.
Hypotonia Hypotonia in symptomatic hyponatremic infants.
Vomiting Vomiting accompanying acute symptomatic hyponatremia.
Show evidence (1 reference)
PMID:26131744 SUPPORT Human Clinical
"These receptor mutations lead to hyponatremia, which may lead to clinical symptoms in infants."
States the step this node models: the hyponatremia, not the receptor lesion itself, is what produces symptoms in infants.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Nephrogenic Syndrome of Inappropriate Antidiuresis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Digestive 1
Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013), qualified as infantile onset. HP:0002013 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"Early clinical symptoms in infancy include hypotonia, irritability, vomiting and/or seizures."
Lists vomiting among the early infant presentations of NSIAD.
Ear 1
Vertigo HP:0002321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dizziness, annotated with Vertigo (HP:0002321), qualified as adult onset. HP:0002321 is a phenotype from the Human Phenotype Ontology.
Onset: ADULT
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"Symptoms in later life are often less specific and include malaise, dizziness, confusion, tiredness and headache."
Lists dizziness among the nonspecific later-life symptoms.
Endocrine 1
Decreased circulating antidiuretic hormone concentration HP:0034897 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating antidiuretic hormone concentration (HP:0034897). HP:0034897 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:15872203 SUPPORT Human Clinical
"yet who had undetectable arginine vasopressin (AVP) levels"
Direct report of undetectable circulating vasopressin.
Genitourinary 1
Inappropriately concentrated urine Abnormal urine osmolality HP:0033358 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inappropriately concentrated urine, annotated with Abnormal urine osmolality (HP:0033358). HP:0033358 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22154540 SUPPORT Human Clinical
"caused by activating mutations in arginine vasopressin receptor 2 (AVPR2), resulting in persistently concentrated urine"
States the persistently concentrated urine that defines the antidiuresis.
PMID:29472987 SUPPORT Human Clinical
"NSIAD is associated with hyponatremia, decreased serum osmolality and inappropriately increased urinary osmolality."
Names inappropriately increased urinary osmolality as a defining feature.
Metabolism 2
Hyponatremia HP:0002902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyponatremia (HP:0002902). HP:0002902 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:15872203 SUPPORT Human Clinical
"We describe two infants whose clinical and laboratory evaluations were consistent with the presence of SIADH, yet who had undetectable arginine vasopressin (AVP) levels."
The founding cases presented with the SIADH picture, of which hyponatremia is the defining abnormality.
PMID:22154540 SUPPORT Human Clinical
"The spectrum of symptoms varied markedly and ranged from infrequent voiding to incidentally noted hyponatremia to recurrent admissions with hyponatremic seizures."
Hyponatremia across an affected family, and the wide symptomatic range at similar sodium values.
Low serum osmolality HP:6000680 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low serum osmolality (HP:6000680). HP:6000680 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"NSIAD is associated with hyponatremia, decreased serum osmolality and inappropriately increased urinary osmolality."
Names decreased serum osmolality as one of the defining laboratory features.
Musculoskeletal 1
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252), qualified as infantile onset. HP:0001252 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"Early clinical symptoms in infancy include hypotonia, irritability, vomiting and/or seizures."
Lists hypotonia among the early infant presentations of NSIAD.
Nervous System 4
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250), qualified as infantile onset. HP:0001250 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (2 references)
PMID:20631022 SUPPORT Human Clinical
"Two hemizygous carriers presented with severe hyponatremia-induced seizures, and the repetition in one of them led to mental retardation."
Hyponatremic seizures in hemizygous NSIAD patients, with lasting harm after recurrence.
PMID:27355191 SUPPORT Human Clinical
"An L312S substitution in the seventh transmembrane domain was identified in a boy presenting with water-induced hyponatremic seizures"
A further case presenting with water-load-induced hyponatremic seizures.
Irritability HP:0000737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Irritability (HP:0000737), qualified as infantile onset. HP:0000737 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"Early clinical symptoms in infancy include hypotonia, irritability, vomiting and/or seizures."
Lists irritability among the early infant presentations of NSIAD.
Confusion HP:0001289 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Confusion (HP:0001289), qualified as adult onset. HP:0001289 is a phenotype from the Human Phenotype Ontology.
Onset: ADULT
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"Symptoms in later life are often less specific and include malaise, dizziness, confusion, tiredness and headache."
Lists confusion among the nonspecific later-life symptoms.
Headache HP:0002315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Headache (HP:0002315), qualified as adult onset. HP:0002315 is a phenotype from the Human Phenotype Ontology.
Onset: ADULT
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"Symptoms in later life are often less specific and include malaise, dizziness, confusion, tiredness and headache."
Lists headache among the nonspecific later-life symptoms; an adult proband presented with it.
Constitutional 2
Malaise HP:0033834 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malaise (HP:0033834), qualified as adult onset. HP:0033834 is a phenotype from the Human Phenotype Ontology.
Onset: ADULT
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"Symptoms in later life are often less specific and include malaise, dizziness, confusion, tiredness and headache."
Lists malaise among the nonspecific later-life symptoms.
Fatigue HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigue (HP:0012378), qualified as adult onset. HP:0012378 is a phenotype from the Human Phenotype Ontology.
Onset: ADULT
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"Symptoms in later life are often less specific and include malaise, dizziness, confusion, tiredness and headache."
Lists tiredness among the nonspecific later-life symptoms.
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Genetic Associations

1
AVPR2 activating variants
Gene: AVPR2 hgnc:897 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is AVPR2 (hgnc:897). hgnc:897 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
X-linked recessive inheritance
Variants (5)
R137C Pathogenic
Arginine-137-to-cysteine, one of the two founding alleles; constitutively activating. Reported inherited from a carrier mother in the original NSIAD family.
Show evidence (1 reference)
PMID:15872203 SUPPORT Human Clinical
"changes in codon 137 from arginine to cysteine or leucine"
Reports R137C as one of the two founding NSIAD alleles.
R137L Pathogenic
Arginine-137-to-leucine, the second founding allele; constitutively activating and de novo in the original report.
Show evidence (1 reference)
PMID:15872203 SUPPORT Human Clinical
"changes in codon 137 from arginine to cysteine or leucine"
Reports R137L as the second founding NSIAD allele.
F229V Pathogenic
Phenylalanine-229-to-valine, a transmembrane substitution found in a 3-month-old hyponatremic infant. In vitro it gives high constitutive activity without spontaneous desensitization, and is silenced by V2R inverse agonists.
Show evidence (1 reference)
PMID:22956819 SUPPORT In Vitro
"Characterization of this substitution in vitro revealed that it leads to high constitutive activity of the receptor, compatible with spontaneous antidiuresis."
Functional characterization of F229V as a gain-of-function allele.
I130N Pathogenic
Isoleucine-130-to-asparagine, identified in a family; constitutively active with a biased conformation and ligand-independent internalization, and sensitive to tolvaptan in cells.
Show evidence (1 reference)
PMID:26131744 SUPPORT In Vitro
"This I130N mutation resulted in constitutive activity of the V2R with constitutive cyclic adenosine monophosphate (cAMP) generation in HEK293 cells."
Functional characterization of I130N as a gain-of-function allele.
L312S Pathogenic
Leucine-312-to-serine in the seventh transmembrane domain, found in a boy with water-induced hyponatremic seizures and in his asymptomatic heterozygous mother. Constitutive cAMP without constitutive beta-arrestin recruitment, normal surface expression, and constitutive signalling reduced by tolvaptan.
Show evidence (1 reference)
PMID:27355191 SUPPORT In Vitro
"We show that, compared with wild-type V2R, the L312S mutation results in the constitutive production of cAMP, indicative of the gain-of-function NSIAD profile."
Functional characterization of L312S as a gain-of-function allele.
💊

Medical Actions

4
Fluid restriction
Platform: Behavioral / lifestyle
Long-term regulation of fluid intake is the mainstay and is well tolerated, since thirst is reduced in NSIAD relative to other causes of SIADH. Because the lesion is a fixed inability to excrete free water, limiting intake prevents the water load that precipitates hyponatremia.
Mechanism Target:
Free Water Retention — Reducing water intake keeps intake below the reduced free-water excretory capacity.
Show evidence (1 reference)
PMID:22722264 SUPPORT Human Clinical
"long-term fluid restriction (FR) and treatment with low doses of urea are efficient and well tolerated"
Reports fluid restriction as effective, well-tolerated long-term management.
Show evidence (1 reference)
PMID:22722264 SUPPORT Human Clinical
"NSIAD may differ from other causes of syndrome of inappropriate antidiuretic hormone secretion by reduction of thirst intensity due to lower levels of AVP"
Explains why fluid restriction is tolerated in NSIAD - thirst is reduced because vasopressin, which stimulates thirst, is low.
Oral urea
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: urea CHEBI:16199 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses urea (CHEBI:16199). CHEBI:16199 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Low-dose oral urea induces an osmotic diuresis that offloads free water and corrects hyponatremia. It is effective in both children and adults, and episodic dosing suffices for some patients.
Mechanism Target:
Free Water Retention — Osmotic diuresis from urea increases free-water excretion.
Show evidence (1 reference)
PMID:22722264 SUPPORT Human Clinical
"Six of the patients received urea with no reported failure to correct hyponatremia"
Reports urea correcting hyponatremia across treated patients.
Show evidence (1 reference)
PMID:22722264 SUPPORT Human Clinical
"NSIAD is quite easy to treat with FR and urea in adults as well as in children, with good compliance and efficacy."
Reports urea plus fluid restriction as effective in children and adults.
Vasopressin receptor antagonists (vaptans)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: tolvaptan CHEBI:32246 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses tolvaptan (CHEBI:32246). CHEBI:32246 is a therapeutic agent from Chemical Entities of Biological Interest. satavaptan CHEBI:194402 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses satavaptan (CHEBI:194402). CHEBI:194402 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
V2R inverse agonists silence the constitutive signalling of some mutant receptors in vitro (tolvaptan and satavaptan fully silence F229V; tolvaptan blocks I130N), making them a mechanistically targeted option. Clinical benefit is allele-dependent and not assured - the one clinical report in which vaptans were given (to patients not known to carry a vaptan-responsive allele) found no efficacy - so cellular reversibility should not be assumed to predict a response in every patient.
Mechanism Target:
Ligand-Independent V2 Receptor Activation — Inverse agonists shift the receptor equilibrium back toward the inactive state for alleles whose active conformation is not locked.
Show evidence (1 reference)
PMID:22956819 SUPPORT In Vitro
"the V2R-selective inverse agonists tolvaptan and satavaptan completely silenced the constitutive signaling activity of the F229V mutant receptor"
Demonstrates pharmacologic reversal of the activating lesion in vitro for F229V.
Show evidence (1 reference)
PMID:22722264 SUPPORT Human Clinical
"The AVPR2 antagonists tolvaptan and satavaptan (prescribed before the diagnosis of NSIAD was made) showed no efficacy in 1 patient."
The one clinical datum on vaptans in NSIAD, a non-response, tempering the in-vitro promise.
Furosemide with sodium chloride supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: furosemide CHEBI:47426 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses furosemide (CHEBI:47426). CHEBI:47426 is a therapeutic agent from Chemical Entities of Biological Interest. sodium chloride CHEBI:26710 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sodium chloride (CHEBI:26710). CHEBI:26710 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Proposed for refractory cases by analogy with its use in SIADH; loop diuresis with salt replacement increases free-water clearance.
Show evidence (3 references)
PMID:22722264 SUPPORT Human Clinical
"furosemide (associated with NaCl supplementation) would represent a valuable therapeutic option"
Reports furosemide plus NaCl as a proposed option for refractory cases.
PMID:22722264 SUPPORT Human Clinical
"5 received NaCl supplementation with varying efficacy"
NaCl supplementation alone had inconsistent effect across reported patients.
PMID:29472987 SUPPORT Human Clinical
"Due to lack of consistent improvement, she underwent a trial of demeclocycline, but again with limited sustained benefit."
Demeclocycline, tried in an adult proband, gave limited benefit.
🌍

Environmental Factors

1
Free water load (excess hypotonic fluid intake)
An exogenous water load - heavy drinking in hot weather or during sport, hypotonic feeds in infants, or excessive intravenous hypotonic fluid in hospital - is the precipitant that turns the fixed antidiuretic defect into measured hyponatremia. The genotype sets the inability to excrete free water; the load supplies the water.
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"It is important to counsel patients on appropriate daily fluid volume intake and to ensure that episodes of fluid overload can be avoided, such as increased fluid intake in summertime or during sports activities or excessive intravenous fluid administration during hospital admissions."
Names the fluid-overload situations that precipitate hyponatremia in NSIAD.
Mechanism Target:
EXACERBATES Free Water Retention — A water load exceeding the reduced free-water excretory capacity is what converts the ongoing antidiuresis into net water retention and hyponatremia.
Show evidence (1 reference)
PMID:20631022 SUPPORT Human Clinical
"it induced hyponatremia in all NSIAD patients"
Water loading induced hyponatremia across NSIAD patients, establishing the load as the precipitant.
🔬

Diagnosis

2
Water load test with AVP or copeptin measurement (PRESENT)
The functional test that separates NSIAD from SIADH: an oral water load that the patient cannot normally excrete, with a plasma AVP (or copeptin, as a surrogate) that is low or undetectable rather than inappropriately present. A diagnostic pitfall is that persistent AVPR2 activation can desensitize the downstream pathway, so urine osmolality after water deprivation can be as low as 241 mOsm/kg and may obscure the picture.
Show evidence (2 references)
PMID:29472987 SUPPORT Human Clinical
"A water load test may be informative, and measurement of co-peptin levels may be considered, in substitution for direct measurement of AVP, to aid diagnosis and guide diagnostic sequencing of AVPR2."
The diagnostic test and the copeptin surrogate, as the source frames them.
PMID:22154540 SUPPORT Human Clinical
"Urine osmolality was as low as 241 mOsm/kg (241 mmol/kg) in patients, which could obfuscate the diagnosis."
The desensitization pitfall - urine osmolality can fall low enough to mislead.
AVPR2 sequencing (PRESENT)
Molecular confirmation. A water load test consistent with nephrogenic antidiuresis guides sequencing of AVPR2 to identify the activating variant.
Show evidence (1 reference)
PMID:29472987 SUPPORT Human Clinical
"A water load test demonstrated an inability to dilute urine and gene sequencing confirmed a recurrent activating mutation in AVPR2."
Sequencing of AVPR2 as the confirmatory step after the functional test.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Nephrogenic Syndrome of Inappropriate Antidiuresis:

Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Overlapping Features The acquired phenocopy. SIADH shows the same hypotonic hyponatremia with concentrated urine, but vasopressin is inappropriately present rather than suppressed; NSIAD has low or undetectable vasopressin. A water load test with AVP or copeptin measurement is the reported way to distinguish them (see diagnosis).
🧫

Experimental Models

1
HEK293 cells expressing mutant V2 receptor CELL_LINE
Transfected human embryonic kidney (HEK293) cells expressing the I130N, F229V or R137C/L mutant V2 receptor, the system in which constitutive cAMP generation, biased signalling, ligand-independent internalization, and inverse-agonist responsiveness were measured.
Pathograph links
Constitutive Adenylyl Cyclase cAMP Generation recapitulates fidelity: moderate observes: molecular Directly measures the ligand-independent cAMP output of the mutant receptor.
Limitations: A heterologous cell line overexpressing the receptor; it reports receptor signalling but not the collecting-duct water handling or whole-body osmoregulation that produce the clinical phenotype.
Readouts
Basal intracellular cAMP
Direction: INCREASED
Interpretation: Constitutive cAMP generation by the mutant receptor without agonist.
Show evidence (1 reference)
PMID:26131744 SUPPORT In Vitro
"This I130N mutation resulted in constitutive activity of the V2R with constitutive cyclic adenosine monophosphate (cAMP) generation in HEK293 cells."
The cAMP measurement grounding the readout.
Show evidence (1 reference)
PMID:26131744 SUPPORT In Vitro
"This basal activity could be blocked by the inverse agonist tolvaptan"
The cell system is where the constitutive activity and its pharmacologic reversal were established.
{ }

Source YAML

click to show 
name: Nephrogenic Syndrome of Inappropriate Antidiuresis
creation_date: "2026-10-15T00:00:00Z"
description: >-
  Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is the gain-of-function
  mirror of X-linked nephrogenic diabetes insipidus. Constitutively activating
  missense variants in AVPR2, which encodes the arginine vasopressin V2 receptor of
  the renal collecting duct, make the receptor signal without its hormone. The
  principal cell therefore runs its Gs/adenylyl cyclase/cAMP/protein-kinase-A
  cascade, phosphorylates aquaporin-2 and shuttles it to the apical membrane, and
  reabsorbs free water even when circulating vasopressin is low or undetectable. The
  clinical picture reproduces the syndrome of inappropriate antidiuretic hormone
  secretion (SIADH) - hypotonic hyponatremia with inappropriately concentrated urine
  - but with suppressed rather than inappropriate hormone secretion, which is the
  feature that distinguishes it. It was first described by Feldman and colleagues in
  2005 in two male infants with undetectable vasopressin who carried missense changes
  at codon 137 of the receptor, the same codon whose loss-of-function allele (R137H)
  causes nephrogenic diabetes insipidus. The disorder is X-linked: hemizygous males
  present in infancy with symptomatic hyponatremia - hypotonia, irritability,
  vomiting and seizures - while female carriers are variably affected. Because the lesion is a
  fixed inability to excrete free water rather than hormone excess, hyponatremia
  appears only with a water load and is managed with fluid restriction and oral urea.
categories:
- Mendelian
- Renal Tubular Disorder
synonyms:
- NSIAD
- nephrogenic syndrome of inappropriate antidiuresis, X-linked recessive
- nephrogenic SIAD
- AVPR2-related nephrogenic syndrome of inappropriate antidiuresis
parents:
- inherited renal tubular disease
- X-linked disease
disease_term:
  preferred_term: nephrogenic syndrome of inappropriate antidiuresis
  term:
    id: MONDO:0010356
    label: nephrogenic syndrome of inappropriate antidiuresis
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0010356
      label: nephrogenic syndrome of inappropriate antidiuresis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary disease term for this entry.
classifications:
  harrisons_chapter:
  - classification_value: KIDNEY_URINARY_TRACT
  - classification_value: ENDOCRINOLOGY_METABOLISM
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
pathophysiology:
- name: AVPR2 Gain-of-Function Variant
  description: >-
    A hemizygous germline missense variant in AVPR2 on Xq28, the gene encoding the
    arginine vasopressin V2 receptor. The reported alleles are a small set of
    activating substitutions: the two original codon-137 changes (arginine to
    cysteine, R137C, and to leucine, R137L), the transmembrane substitution F229V,
    and I130N. Codon 137 shows allelic opposition - R137H at the same residue is
    loss-of-function and causes X-linked nephrogenic diabetes insipidus, whereas
    R137C and R137L are gain-of-function.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: arginine vasopressin V2 receptor activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0005000
      label: vasopressin receptor activity
  genetic_context:
    gene:
      preferred_term: AVPR2
      term:
        id: hgnc:897
        label: AVPR2
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Hemizygous in affected males. One original proband inherited R137C from a
      carrier mother and the other's R137L arose de novo. Heterozygous females are
      variably affected.
  downstream:
  - target: Ligand-Independent V2 Receptor Activation
    causal_link_type: DIRECT
    description: >-
      The activating substitutions let the receptor adopt an active conformation in
      the absence of vasopressin.
    evidence:
    - reference: PMID:15872203
      reference_title: Nephrogenic syndrome of inappropriate antidiuresis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These novel mutations cause constitutive activation of the receptor and are
        the likely cause of the patients' SIADH-like clinical picture
      explanation: >-
        Establishes that the codon-137 variants activate the receptor
        constitutively, the molecular lesion that initiates the chain.
  evidence:
  - reference: PMID:15872203
    reference_title: Nephrogenic syndrome of inappropriate antidiuresis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations
      in both, with resultant changes in codon 137 from arginine to cysteine or
      leucine.
    explanation: Reports the two founding AVPR2 gain-of-function alleles, R137C and R137L.
  - reference: PMID:22956819
    reference_title: Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a 3-month-old hyponatremic infant found to have a
      phenylalanine 229 to valine (F229V) substitution in V2R.
    explanation: Adds F229V as a third activating AVPR2 allele outside codon 137.
  - reference: PMID:26131744
    reference_title: Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we present a newly identified I130N substitution in exon 2 of the V2R gene
      in a family, causing NSIAD.
    explanation: Adds I130N as a fourth activating AVPR2 allele.
- name: Ligand-Independent V2 Receptor Activation
  description: >-
    The mutant V2 receptor is held in an active conformation and transduces signal
    without bound vasopressin. For F229V the active state is not locked - V2R-selective
    inverse agonists silence it - so the gain of function is a shifted equilibrium
    rather than an irreversible lock.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: V2 vasopressin receptor activity
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0005000
      label: vasopressin receptor activity
  downstream:
  - target: Constitutive Adenylyl Cyclase cAMP Generation
    causal_link_type: DIRECT
    description: The active receptor couples to Gs and stimulates adenylyl cyclase.
  - target: Constitutive V2 Receptor Internalization
    causal_link_type: DIRECT
    description: >-
      The biased active conformation also drives ligand-independent endocytosis of
      the receptor, a parallel consequence of the activating lesion.
  evidence:
  - reference: PMID:22956819
    reference_title: Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In contrast to R137C/L mutant receptors, F229V receptors do not undergo
      spontaneous desensitization, which results in sustained, high basal activity.
    explanation: >-
      Distinguishes the receptor-regulation behaviour of the activating alleles - a
      sustained active state for F229V versus the desensitizing R137C/L receptors.
- name: Constitutive V2 Receptor Internalization
  description: >-
    The I130N receptor adopts a biased conformation whose basal activity does not
    recruit beta-arrestin, yet the receptor is constitutively internalized through a
    dynamin-dependent, beta-arrestin-independent route. This ligand-independent
    endocytosis lowers cell-surface receptor and is mechanistically separable from the
    cAMP output, and it is the receptor-trafficking counterpart of the misfolding
    retention seen with loss-of-function AVPR2 alleles.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: constitutive G protein-coupled receptor internalization
    modifier: INCREASED
    term:
      id: GO:0002031
      label: G protein-coupled receptor internalization
  evidence:
  - reference: PMID:26131744
    reference_title: Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The constitutive activity of the mutant receptor caused constitutive
      dynamin-dependent and β-arrestin-independent internalization.
    explanation: Reports the ligand-independent internalization branch for the I130N receptor.
  - reference: PMID:26131744
    reference_title: Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The mutation causes a biased receptor conformation as the basal cAMP generation
      activity of I130N does not lead to interaction with β-arrestin.
    explanation: >-
      Supports the biased-signalling character of the basal active state behind the
      beta-arrestin-independent internalization.
- name: Constitutive Adenylyl Cyclase cAMP Generation
  description: >-
    In the collecting-duct principal cell the constitutively active receptor drives Gs
    stimulation of adenylyl cyclase and raises intracellular cyclic AMP without
    vasopressin. This was demonstrated directly in transfected cells for the I130N and
    F229V receptors.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: adenylate cyclase-activating G protein-coupled receptor signaling pathway
    modifier: GAIN_OF_FUNCTION
    term:
      id: GO:0007189
      label: adenylate cyclase-activating G protein-coupled receptor signaling pathway
  - preferred_term: cAMP biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0006171
      label: cAMP biosynthetic process
  cell_types:
  - preferred_term: kidney collecting duct principal cell
    term:
      id: CL:1001431
      label: kidney collecting duct principal cell
  locations:
  - preferred_term: collecting duct of renal tubule
    term:
      id: UBERON:0001232
      label: collecting duct of renal tubule
  downstream:
  - target: PKA-Mediated Aquaporin-2 Phosphorylation
    causal_link_type: DIRECT
    description: Elevated cAMP activates protein kinase A.
  evidence:
  - reference: PMID:26131744
    reference_title: Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This I130N mutation resulted in constitutive activity of the V2R with
      constitutive cyclic adenosine monophosphate (cAMP) generation in HEK293 cells.
    explanation: Direct demonstration of ligand-independent cAMP generation by a mutant receptor.
  - reference: PMID:22956819
    reference_title: Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Characterization of this substitution in vitro revealed that it leads to high
      constitutive activity of the receptor, compatible with spontaneous antidiuresis.
    explanation: >-
      A second activating allele showing high constitutive signalling, tied to
      spontaneous antidiuresis.
- name: PKA-Mediated Aquaporin-2 Phosphorylation
  description: >-
    Cyclic-AMP-activated protein kinase A phosphorylates aquaporin-2. This step is
    inferred from established V2-receptor physiology rather than shown in patient
    tissue, but it is the obligate link between the measured cAMP signal and
    water-channel trafficking.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: cAMP-dependent protein kinase activity
    modifier: INCREASED
    term:
      id: GO:0004691
      label: cAMP-dependent protein kinase activity
  downstream:
  - target: Apical Aquaporin-2 Membrane Insertion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Phosphorylated aquaporin-2 traffics to and is retained at the apical membrane.
- name: Apical Aquaporin-2 Membrane Insertion
  description: >-
    Phosphorylated aquaporin-2 redistributes from intracellular vesicles into the
    apical plasma membrane of the principal cell, the step that renders the membrane
    water-permeable.
  biological_scale: CELLULAR
  cellular_components:
  - preferred_term: apical plasma membrane
    term:
      id: GO:0016324
      label: apical plasma membrane
  biological_processes:
  - preferred_term: positive regulation of renal water transport
    modifier: INCREASED
    term:
      id: GO:2001153
      label: positive regulation of renal water transport
  downstream:
  - target: Increased Collecting Duct Water Permeability
    causal_link_type: DIRECT
    description: Apical aquaporin-2 opens a transcellular water pathway.
  evidence:
  - reference: PMID:20631022
    reference_title: "Familial nephrogenic syndrome of inappropriate antidiuresis: dissociation between aquaporin-2 and vasopressin excretion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Water loading was followed by a very slow and incomplete elimination in the
      asymptomatic hemizygous boy with no suppression of AQP2 excretion
    explanation: >-
      Urinary AQP2 excretion is a marker of apical AQP2 trafficking in the collecting
      duct; its failure to suppress after a water load in a hemizygous patient is the
      in-vivo sign that AQP2 stays in the apical membrane without vasopressin.
- name: Increased Collecting Duct Water Permeability
  description: >-
    With aquaporin-2 in the apical membrane the collecting duct epithelium becomes
    water-permeable, allowing water to follow the medullary osmotic gradient
    independently of hormonal command.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: renal water absorption
    modifier: INCREASED
    term:
      id: GO:0070295
      label: renal water absorption
  locations:
  - preferred_term: collecting duct of renal tubule
    term:
      id: UBERON:0001232
      label: collecting duct of renal tubule
  downstream:
  - target: Ligand-Independent Free Water Reabsorption
    causal_link_type: DIRECT
    description: The permeable duct reabsorbs free water from the tubular lumen.
- name: Ligand-Independent Free Water Reabsorption
  description: >-
    The kidney reabsorbs free water continuously, uncoupled from vasopressin, which is
    the whole-organ consequence of the fixed water permeability.
  biological_scale: ORGANISM
  downstream:
  - target: Inappropriately concentrated urine
    causal_link_type: DIRECT
    description: Continuous water reabsorption leaves the urine concentrated despite plasma hypotonicity.
  - target: Free Water Retention
    causal_link_type: DIRECT
    description: Water that is not excreted is retained in the body.
  evidence:
  - reference: PMID:22722264
    reference_title: "Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gain-of-function mutation of arginine vasopressin receptor type 2 (AVPR2)
      resulting in free water reabsorption and episodes of hyponatremia
    explanation: States the disease-level consequence - free water reabsorption producing hyponatremia.
- name: Free Water Retention
  description: >-
    Retention of electrolyte-free water expands and dilutes total body water. Because
    sodium handling is intact, the result is dilutional rather than a sodium-deficit
    state.
  biological_scale: ORGANISM
  downstream:
  - target: Hypotonic Hyponatremia
    causal_link_type: DIRECT
    description: Dilution of body sodium lowers serum sodium and osmolality.
  - target: Physiologic Suppression of Vasopressin Secretion
    causal_link_type: DIRECT
    description: >-
      Water retention and the fall in plasma osmolality appropriately suppress
      hypothalamic vasopressin release, which is why circulating hormone is low.
- name: Physiologic Suppression of Vasopressin Secretion
  description: >-
    The retained water and low plasma osmolality suppress hypothalamic vasopressin
    output normally. Hormone secretion is therefore appropriately low or undetectable -
    the opposite of SIADH - and the antidiuresis is driven entirely by the receptor.
  biological_scale: ORGANISM
  downstream:
  - target: Decreased circulating antidiuretic hormone concentration
    causal_link_type: DIRECT
    description: The suppressed secretion is measured as low or undetectable plasma vasopressin.
  evidence:
  - reference: PMID:15872203
    reference_title: Nephrogenic syndrome of inappropriate antidiuresis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe two infants whose clinical and laboratory evaluations were
      consistent with the presence of SIADH, yet who had undetectable arginine
      vasopressin (AVP) levels.
    explanation: >-
      The undetectable vasopressin that distinguishes NSIAD from SIADH and reflects
      appropriate physiologic suppression.
- name: Hypotonic Hyponatremia
  description: >-
    Dilutional hyponatremia with low serum osmolality. It is water-load dependent -
    the genotype fixes an inability to excrete free water, so plasma sodium falls only
    when intake exceeds the reduced free-water excretory capacity.
  biological_scale: ORGANISM
  downstream:
  - target: Hyponatremia
    causal_link_type: DIRECT
    description: The measured low serum sodium.
  - target: Low serum osmolality
    causal_link_type: DIRECT
    description: The accompanying fall in serum osmolality.
  - target: Hyponatremic Cerebral Water Shift
    causal_link_type: DIRECT
    description: Plasma hypotonicity drives water into brain cells.
  - target: Malaise
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Nonspecific later-life symptom of chronic/episodic hyponatremia.
  - target: Vertigo
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Dizziness as a later-life hyponatremic symptom.
  - target: Confusion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Confusion as a later-life hyponatremic symptom.
  - target: Fatigue
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Tiredness as a later-life hyponatremic symptom.
  - target: Headache
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Headache as a later-life hyponatremic symptom.
  evidence:
  - reference: PMID:22722264
    reference_title: "Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      gain-of-function mutation of arginine vasopressin receptor type 2 (AVPR2)
      resulting in free water reabsorption and episodes of hyponatremia
    explanation: The disease-level consequence this node models - episodic hyponatremia from free-water reabsorption.
- name: Hyponatremic Cerebral Water Shift
  description: >-
    The osmotic gradient created by plasma hypotonicity drives water into the brain,
    producing cerebral edema and the neurological manifestations seen in symptomatic
    infants.
  biological_scale: ORGANISM
  downstream:
  - target: Seizure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Cerebral edema and the hypotonic state lower the seizure threshold.
  - target: Irritability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Non-specific neurological irritability of acute hyponatremia.
  - target: Hypotonia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Hypotonia in symptomatic hyponatremic infants.
  - target: Vomiting
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Vomiting accompanying acute symptomatic hyponatremia.
  evidence:
  - reference: PMID:26131744
    reference_title: Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These receptor mutations lead to hyponatremia, which may lead to clinical
      symptoms in infants.
    explanation: >-
      States the step this node models: the hyponatremia, not the receptor lesion
      itself, is what produces symptoms in infants.
phenotypes:
- name: Hyponatremia
  category: Laboratory
  description: Low serum sodium, the core biochemical abnormality, dilutional in origin.
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: PMID:15872203
    reference_title: Nephrogenic syndrome of inappropriate antidiuresis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe two infants whose clinical and laboratory evaluations were
      consistent with the presence of SIADH, yet who had undetectable arginine
      vasopressin (AVP) levels.
    explanation: >-
      The founding cases presented with the SIADH picture, of which hyponatremia is
      the defining abnormality.
  - reference: PMID:22154540
    reference_title: A family with hyponatremia and the nephrogenic syndrome of inappropriate antidiuresis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The spectrum of symptoms varied markedly and ranged from infrequent voiding to
      incidentally noted hyponatremia to recurrent admissions with hyponatremic
      seizures.
    explanation: >-
      Hyponatremia across an affected family, and the wide symptomatic range at
      similar sodium values.
- name: Low serum osmolality
  category: Laboratory
  description: Reduced serum osmolality accompanying the dilutional hyponatremia.
  phenotype_term:
    preferred_term: Low serum osmolality
    term:
      id: HP:6000680
      label: Low serum osmolality
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NSIAD is associated with hyponatremia, decreased serum osmolality and
      inappropriately increased urinary osmolality.
    explanation: Names decreased serum osmolality as one of the defining laboratory features.
- name: Inappropriately concentrated urine
  category: Laboratory
  description: >-
    Urine osmolality is inappropriately high for the low plasma osmolality - the
    hallmark of ongoing antidiuresis.
  phenotype_term:
    preferred_term: Inappropriately concentrated urine
    term:
      id: HP:0033358
      label: Abnormal urine osmolality
  evidence:
  - reference: PMID:22154540
    reference_title: A family with hyponatremia and the nephrogenic syndrome of inappropriate antidiuresis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      caused by activating mutations in arginine vasopressin receptor 2 (AVPR2),
      resulting in persistently concentrated urine
    explanation: States the persistently concentrated urine that defines the antidiuresis.
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NSIAD is associated with hyponatremia, decreased serum osmolality and
      inappropriately increased urinary osmolality.
    explanation: Names inappropriately increased urinary osmolality as a defining feature.
- name: Decreased circulating antidiuretic hormone concentration
  category: Laboratory
  description: >-
    Plasma vasopressin is low or undetectable, which separates NSIAD from SIADH and
    reflects appropriate physiologic suppression.
  phenotype_term:
    preferred_term: Decreased circulating antidiuretic hormone concentration
    term:
      id: HP:0034897
      label: Decreased circulating antidiuretic hormone concentration
  evidence:
  - reference: PMID:15872203
    reference_title: Nephrogenic syndrome of inappropriate antidiuresis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      yet who had undetectable arginine vasopressin (AVP) levels
    explanation: Direct report of undetectable circulating vasopressin.
- name: Seizure
  category: Neurological
  description: Seizures in symptomatic hyponatremic infants.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:20631022
    reference_title: "Familial nephrogenic syndrome of inappropriate antidiuresis: dissociation between aquaporin-2 and vasopressin excretion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two hemizygous carriers presented with severe hyponatremia-induced seizures,
      and the repetition in one of them led to mental retardation.
    explanation: Hyponatremic seizures in hemizygous NSIAD patients, with lasting harm after recurrence.
  - reference: PMID:27355191
    reference_title: Mutations of Vasopressin Receptor 2 Including Novel L312S Have Differential Effects on Trafficking.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An L312S substitution in the seventh transmembrane domain was identified in a
      boy presenting with water-induced hyponatremic seizures
    explanation: A further case presenting with water-load-induced hyponatremic seizures.
- name: Irritability
  category: Neurological
  description: Non-specific neurological irritability of acute hyponatremia in infants.
  phenotype_term:
    preferred_term: Irritability
    term:
      id: HP:0000737
      label: Irritability
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early clinical symptoms in infancy include hypotonia, irritability, vomiting
      and/or seizures.
    explanation: Lists irritability among the early infant presentations of NSIAD.
- name: Hypotonia
  category: Neurological
  description: Hypotonia as an early presenting symptom in hyponatremic infants.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early clinical symptoms in infancy include hypotonia, irritability, vomiting
      and/or seizures.
    explanation: Lists hypotonia among the early infant presentations of NSIAD.
- name: Vomiting
  category: Constitutional
  description: Vomiting as a presenting feature of acute hyponatremia in infants.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early clinical symptoms in infancy include hypotonia, irritability, vomiting
      and/or seizures.
    explanation: Lists vomiting among the early infant presentations of NSIAD.
- name: Malaise
  category: Constitutional
  description: Malaise as a nonspecific later-life symptom; adults may learn to limit fluid to avoid it.
  phenotype_term:
    preferred_term: Malaise
    term:
      id: HP:0033834
      label: Malaise
    onset:
      onset_category: ADULT
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms in later life are often less specific and include malaise, dizziness,
      confusion, tiredness and headache.
    explanation: Lists malaise among the nonspecific later-life symptoms.
- name: Vertigo
  category: Neurological
  description: Dizziness as a nonspecific later-life hyponatremic symptom.
  phenotype_term:
    preferred_term: Dizziness
    term:
      id: HP:0002321
      label: Vertigo
    onset:
      onset_category: ADULT
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms in later life are often less specific and include malaise, dizziness,
      confusion, tiredness and headache.
    explanation: Lists dizziness among the nonspecific later-life symptoms.
- name: Confusion
  category: Neurological
  description: Confusion as a nonspecific later-life hyponatremic symptom.
  phenotype_term:
    preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
    onset:
      onset_category: ADULT
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms in later life are often less specific and include malaise, dizziness,
      confusion, tiredness and headache.
    explanation: Lists confusion among the nonspecific later-life symptoms.
- name: Fatigue
  category: Constitutional
  description: Tiredness as a nonspecific later-life hyponatremic symptom.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
    onset:
      onset_category: ADULT
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms in later life are often less specific and include malaise, dizziness,
      confusion, tiredness and headache.
    explanation: Lists tiredness among the nonspecific later-life symptoms.
- name: Headache
  category: Neurological
  description: Headache as a nonspecific later-life hyponatremic symptom; a presenting feature in adult probands.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
    onset:
      onset_category: ADULT
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms in later life are often less specific and include malaise, dizziness,
      confusion, tiredness and headache.
    explanation: Lists headache among the nonspecific later-life symptoms; an adult proband presented with it.
genetic:
- name: AVPR2 activating variants
  gene_term:
    preferred_term: AVPR2
    term:
      id: hgnc:897
      label: AVPR2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: X-linked recessive inheritance
    inheritance_term:
      preferred_term: X-linked recessive inheritance
      term:
        id: HP:0001419
        label: X-linked recessive inheritance
    description: >-
      Hemizygous males are affected and present in infancy; heterozygous female
      carriers are variably affected, from asymptomatic to symptomatic. De novo
      occurrence is documented (R137L in one of the two original probands).
    evidence:
    - reference: PMID:15872203
      reference_title: Nephrogenic syndrome of inappropriate antidiuresis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations
        in both, with resultant changes in codon 137 from arginine to cysteine or
        leucine.
      explanation: >-
        The X-linked AVPR2 gene and the founding codon-137 alleles in two affected
        males.
  variants:
  - name: R137C
    description: >-
      Arginine-137-to-cysteine, one of the two founding alleles; constitutively
      activating. Reported inherited from a carrier mother in the original NSIAD
      family.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:15872203
      reference_title: Nephrogenic syndrome of inappropriate antidiuresis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        changes in codon 137 from arginine to cysteine or leucine
      explanation: Reports R137C as one of the two founding NSIAD alleles.
  - name: R137L
    description: >-
      Arginine-137-to-leucine, the second founding allele; constitutively activating
      and de novo in the original report.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:15872203
      reference_title: Nephrogenic syndrome of inappropriate antidiuresis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        changes in codon 137 from arginine to cysteine or leucine
      explanation: Reports R137L as the second founding NSIAD allele.
  - name: F229V
    description: >-
      Phenylalanine-229-to-valine, a transmembrane substitution found in a 3-month-old
      hyponatremic infant. In vitro it gives high constitutive activity without
      spontaneous desensitization, and is silenced by V2R inverse agonists.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:22956819
      reference_title: Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Characterization of this substitution in vitro revealed that it leads to high
        constitutive activity of the receptor, compatible with spontaneous antidiuresis.
      explanation: Functional characterization of F229V as a gain-of-function allele.
  - name: I130N
    description: >-
      Isoleucine-130-to-asparagine, identified in a family; constitutively active with
      a biased conformation and ligand-independent internalization, and sensitive to
      tolvaptan in cells.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:26131744
      reference_title: Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This I130N mutation resulted in constitutive activity of the V2R with
        constitutive cyclic adenosine monophosphate (cAMP) generation in HEK293 cells.
      explanation: Functional characterization of I130N as a gain-of-function allele.
  - name: L312S
    description: >-
      Leucine-312-to-serine in the seventh transmembrane domain, found in a boy with
      water-induced hyponatremic seizures and in his asymptomatic heterozygous mother.
      Constitutive cAMP without constitutive beta-arrestin recruitment, normal surface
      expression, and constitutive signalling reduced by tolvaptan.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:27355191
      reference_title: Mutations of Vasopressin Receptor 2 Including Novel L312S Have Differential Effects on Trafficking.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show that, compared with wild-type V2R, the L312S mutation results in the
        constitutive production of cAMP, indicative of the gain-of-function NSIAD
        profile.
      explanation: Functional characterization of L312S as a gain-of-function allele.
  notes: >-
    MONDO:0010356 is AVPR2-defined, so AVPR2 is the sole causative gene recorded here.
    A separate germline gain-of-function cause has since been described in GNAS (Gsalpha):
    whole-exome sequencing of two families with dominantly inherited NSIAD, after
    excluding an AVPR2 variant, found GNAS-Gsalpha p.(F68_G70del) and p.(M255V), with
    effects milder than the somatic Gsalpha variants of McCune-Albright syndrome
    (PMID:30962325). Because Gsalpha is downstream of AVPR2 in the same cascade, the
    GNAS form produces the same antidiuretic phenotype through a shared mechanism; it is
    kept out of this AVPR2-defined entry and recorded as a differential cause. See
    differential_diagnoses.
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  description: >-
    X-linked disorder of AVPR2 on Xq28. Hemizygous males present in infancy; carrier
    females are variably affected; de novo variants occur. The "recessive" label is
    imperfect: symptomatic female probands are described, and carrier females can have
    episodic, usually incidentally found hyponatremia, so the distinction between carrier
    and affected is blurred.
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Female carriers may present with episodes of hyponatremia, usually found
      incidentally.
    explanation: Carrier females are not reliably asymptomatic - they can have episodic hyponatremia.
  - reference: PMID:15872203
    reference_title: Nephrogenic syndrome of inappropriate antidiuresis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA sequencing of each patient's V2R gene (AVPR2) identified missense mutations
      in both, with resultant changes in codon 137 from arginine to cysteine or
      leucine.
    explanation: The X-linked AVPR2 gene underlying the inheritance pattern.
environmental:
- name: Free water load (excess hypotonic fluid intake)
  description: >-
    An exogenous water load - heavy drinking in hot weather or during sport,
    hypotonic feeds in infants, or excessive intravenous hypotonic fluid in hospital -
    is the precipitant that turns the fixed antidiuretic defect into measured
    hyponatremia. The genotype sets the inability to excrete free water; the load
    supplies the water.
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is important to counsel patients on appropriate daily fluid volume intake and
      to ensure that episodes of fluid overload can be avoided, such as increased fluid
      intake in summertime or during sports activities or excessive intravenous fluid
      administration during hospital admissions.
    explanation: Names the fluid-overload situations that precipitate hyponatremia in NSIAD.
  influences_mechanisms:
  - target: Free Water Retention
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      A water load exceeding the reduced free-water excretory capacity is what converts
      the ongoing antidiuresis into net water retention and hyponatremia.
    evidence:
    - reference: PMID:20631022
      reference_title: "Familial nephrogenic syndrome of inappropriate antidiuresis: dissociation between aquaporin-2 and vasopressin excretion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        it induced hyponatremia in all NSIAD patients
      explanation: Water loading induced hyponatremia across NSIAD patients, establishing the load as the precipitant.
diagnosis:
- name: Water load test with AVP or copeptin measurement
  presence: PRESENT
  description: >-
    The functional test that separates NSIAD from SIADH: an oral water load that the
    patient cannot normally excrete, with a plasma AVP (or copeptin, as a surrogate)
    that is low or undetectable rather than inappropriately present. A diagnostic
    pitfall is that persistent AVPR2 activation can desensitize the downstream pathway,
    so urine osmolality after water deprivation can be as low as 241 mOsm/kg and may
    obscure the picture.
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A water load test may be informative, and measurement of co-peptin levels may be
      considered, in substitution for direct measurement of AVP, to aid diagnosis and
      guide diagnostic sequencing of AVPR2.
    explanation: The diagnostic test and the copeptin surrogate, as the source frames them.
  - reference: PMID:22154540
    reference_title: A family with hyponatremia and the nephrogenic syndrome of inappropriate antidiuresis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urine osmolality was as low as 241 mOsm/kg (241 mmol/kg) in patients, which could
      obfuscate the diagnosis.
    explanation: The desensitization pitfall - urine osmolality can fall low enough to mislead.
- name: AVPR2 sequencing
  presence: PRESENT
  description: >-
    Molecular confirmation. A water load test consistent with nephrogenic antidiuresis
    guides sequencing of AVPR2 to identify the activating variant.
  evidence:
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A water load test demonstrated an inability to dilute urine and gene sequencing
      confirmed a recurrent activating mutation in AVPR2.
    explanation: Sequencing of AVPR2 as the confirmatory step after the functional test.
treatments:
- name: Fluid restriction
  description: >-
    Long-term regulation of fluid intake is the mainstay and is well tolerated, since
    thirst is reduced in NSIAD relative to other causes of SIADH. Because the lesion is
    a fixed inability to excrete free water, limiting intake prevents the water load
    that precipitates hyponatremia.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Fluid restriction
  target_mechanisms:
  - target: Free Water Retention
    description: Reducing water intake keeps intake below the reduced free-water excretory capacity.
    evidence:
    - reference: PMID:22722264
      reference_title: "Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        long-term fluid restriction (FR) and treatment with low doses of urea are
        efficient and well tolerated
      explanation: Reports fluid restriction as effective, well-tolerated long-term management.
  evidence:
  - reference: PMID:22722264
    reference_title: "Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NSIAD may differ from other causes of syndrome of inappropriate antidiuretic
      hormone secretion by reduction of thirst intensity due to lower levels of AVP
    explanation: >-
      Explains why fluid restriction is tolerated in NSIAD - thirst is reduced because
      vasopressin, which stimulates thirst, is low.
- name: Oral urea
  description: >-
    Low-dose oral urea induces an osmotic diuresis that offloads free water and
    corrects hyponatremia. It is effective in both children and adults, and episodic
    dosing suffices for some patients.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: urea
      term:
        id: CHEBI:16199
        label: urea
  target_mechanisms:
  - target: Free Water Retention
    description: Osmotic diuresis from urea increases free-water excretion.
    evidence:
    - reference: PMID:22722264
      reference_title: "Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Six of the patients received urea with no reported failure to correct hyponatremia
      explanation: Reports urea correcting hyponatremia across treated patients.
  evidence:
  - reference: PMID:22722264
    reference_title: "Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NSIAD is quite easy to treat with FR and urea in adults as well as in children,
      with good compliance and efficacy.
    explanation: Reports urea plus fluid restriction as effective in children and adults.
- name: Vasopressin receptor antagonists (vaptans)
  description: >-
    V2R inverse agonists silence the constitutive signalling of some mutant receptors
    in vitro (tolvaptan and satavaptan fully silence F229V; tolvaptan blocks I130N),
    making them a mechanistically targeted option. Clinical benefit is allele-dependent
    and not assured - the one clinical report in which vaptans were given (to patients
    not known to carry a vaptan-responsive allele) found no efficacy - so cellular
    reversibility should not be assumed to predict a response in every patient.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tolvaptan
      term:
        id: CHEBI:32246
        label: tolvaptan
    - preferred_term: satavaptan
      term:
        id: CHEBI:194402
        label: satavaptan
  target_mechanisms:
  - target: Ligand-Independent V2 Receptor Activation
    description: >-
      Inverse agonists shift the receptor equilibrium back toward the inactive state
      for alleles whose active conformation is not locked.
    evidence:
    - reference: PMID:22956819
      reference_title: Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        the V2R-selective inverse agonists tolvaptan and satavaptan completely silenced
        the constitutive signaling activity of the F229V mutant receptor
      explanation: Demonstrates pharmacologic reversal of the activating lesion in vitro for F229V.
  evidence:
  - reference: PMID:22722264
    reference_title: "Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The AVPR2 antagonists tolvaptan and satavaptan (prescribed before the diagnosis of
      NSIAD was made) showed no efficacy in 1 patient.
    explanation: The one clinical datum on vaptans in NSIAD, a non-response, tempering the in-vitro promise.
- name: Furosemide with sodium chloride supplementation
  description: >-
    Proposed for refractory cases by analogy with its use in SIADH; loop diuresis with
    salt replacement increases free-water clearance.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: furosemide
      term:
        id: CHEBI:47426
        label: furosemide
    - preferred_term: sodium chloride
      term:
        id: CHEBI:26710
        label: sodium chloride
  evidence:
  - reference: PMID:22722264
    reference_title: "Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      furosemide (associated with NaCl supplementation) would represent a valuable
      therapeutic option
    explanation: Reports furosemide plus NaCl as a proposed option for refractory cases.
  - reference: PMID:22722264
    reference_title: "Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      5 received NaCl supplementation with varying efficacy
    explanation: NaCl supplementation alone had inconsistent effect across reported patients.
  - reference: PMID:29472987
    reference_title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Due to lack of consistent improvement, she underwent a trial of demeclocycline,
      but again with limited sustained benefit.
    explanation: Demeclocycline, tried in an adult proband, gave limited benefit.
experimental_models:
- name: HEK293 cells expressing mutant V2 receptor
  experimental_model_type: CELL_LINE
  description: >-
    Transfected human embryonic kidney (HEK293) cells expressing the I130N, F229V or
    R137C/L mutant V2 receptor, the system in which constitutive cAMP generation,
    biased signalling, ligand-independent internalization, and inverse-agonist
    responsiveness were measured.
  modeled_mechanisms:
  - target: Constitutive Adenylyl Cyclase cAMP Generation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Directly measures the ligand-independent cAMP output of the mutant receptor.
    limitations: >-
      A heterologous cell line overexpressing the receptor; it reports receptor
      signalling but not the collecting-duct water handling or whole-body osmoregulation
      that produce the clinical phenotype.
    readouts:
    - name: Basal intracellular cAMP
      target: Constitutive Adenylyl Cyclase cAMP Generation
      direction: INCREASED
      interpretation: Constitutive cAMP generation by the mutant receptor without agonist.
      evidence:
      - reference: PMID:26131744
        reference_title: Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          This I130N mutation resulted in constitutive activity of the V2R with
          constitutive cyclic adenosine monophosphate (cAMP) generation in HEK293 cells.
        explanation: The cAMP measurement grounding the readout.
    evidence:
    - reference: PMID:26131744
      reference_title: Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This basal activity could be blocked by the inverse agonist tolvaptan
      explanation: >-
        The cell system is where the constitutive activity and its pharmacologic
        reversal were established.
differential_diagnoses:
- name: Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
  description: >-
    The acquired phenocopy. SIADH shows the same hypotonic hyponatremia with
    concentrated urine, but vasopressin is inappropriately present rather than
    suppressed; NSIAD has low or undetectable vasopressin. A water load test with AVP
    or copeptin measurement is the reported way to distinguish them (see diagnosis).
- name: GNAS-related inappropriate antidiuresis
  description: >-
    A distinct germline gain-of-function cause in GNAS (Gsalpha), downstream of AVPR2 in
    the same cascade, producing an indistinguishable antidiuretic phenotype with a
    normal AVPR2 sequence. Described as dominantly inherited (PMID:30962325). Kept
    separate from this AVPR2-defined entry.
references:
- reference: PMID:29472987
  title: Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
- reference: PMID:27355191
  title: Mutations of Vasopressin Receptor 2 Including Novel L312S Have Differential Effects on Trafficking.
- reference: PMID:20631022
  title: "Familial nephrogenic syndrome of inappropriate antidiuresis: dissociation between aquaporin-2 and vasopressin excretion."
- reference: PMID:22154540
  title: A family with hyponatremia and the nephrogenic syndrome of inappropriate antidiuresis.
- reference: PMID:15872203
  title: Nephrogenic syndrome of inappropriate antidiuresis.
- reference: PMID:22956819
  title: Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD.
- reference: PMID:26131744
  title: Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
- reference: PMID:22722264
  title: "Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports."
- reference: PMID:30962325
  title: Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis.
notes: >-
  NSIAD is the gain-of-function counterpart of X-linked nephrogenic diabetes insipidus
  (kb/disorders/X-Linked_Nephrogenic_Diabetes_Insipidus.yaml); both act at AVPR2 on
  Xq28 but in opposite directions, and codon 137 carries alleles of both signs (R137H
  loss-of-function causes NDI; R137C/R137L gain-of-function cause NSIAD). Lump/split:
  curated as a single AVPR2-defined disease at the MONDO:0010356 level. The recognized
  alleles (R137C, R137L, F229V, I130N) differ in receptor-regulation behaviour -
  R137C/L desensitize, F229V does not, I130N is biased and internalizes - but share one
  mechanism and one clinical picture, so they are carried as variants rather than as
  subtypes. The GNAS (Gsalpha) gain-of-function form (PMID:30962325) is a separate
  genetic cause of the same antidiuretic phenotype and is recorded as a differential
  rather than folded in, because the MONDO term is AVPR2-defined. No GeneReviews chapter
  exists for NSIAD (checked offline against the committed Bookshelf index).
📚

References & Deep Research

References

9
PMID:29472987
Adult female with symptomatic AVPR2-related nephrogenic syndrome of inappropriate antidiuresis (NSIAD).
No top-level findings curated for this source.
PMID:27355191
Mutations of Vasopressin Receptor 2 Including Novel L312S Have Differential Effects on Trafficking.
No top-level findings curated for this source.
PMID:20631022
Familial nephrogenic syndrome of inappropriate antidiuresis: dissociation between aquaporin-2 and vasopressin excretion.
No top-level findings curated for this source.
PMID:22154540
A family with hyponatremia and the nephrogenic syndrome of inappropriate antidiuresis.
No top-level findings curated for this source.
PMID:15872203
Nephrogenic syndrome of inappropriate antidiuresis.
No top-level findings curated for this source.
PMID:22956819
Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD.
No top-level findings curated for this source.
PMID:26131744
Mutation in the V2 vasopressin receptor gene, AVPR2, causes nephrogenic syndrome of inappropriate diuresis.
No top-level findings curated for this source.
PMID:22722264
Long-term treatment of hyponatremic patients with nephrogenic syndrome of inappropriate antidiuresis: personal experience and review of published case reports.
No top-level findings curated for this source.
PMID:30962325
Germline-Derived Gain-of-Function Variants of Gsα-Coding GNAS Gene Identified in Nephrogenic Syndrome of Inappropriate Antidiuresis.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Nephrogenic Syndrome of Inappropriate Antidiuresis · 2026-10-15T04:26:40Z · View source

De novo curation of NSIAD (MONDO:0010356), the AVPR2 gain-of-function mirror of X-linked nephrogenic diabetes insipidus. The claude_code deep-research report was thin (57s, 2 web searches, only 2 of its PMIDs self-verified) and used strictly as leads; all literature work was done independently via NCBI E-utilities. Backbone PMIDs: 15872203 (Feldman NEJM 2005, R137C/R137L constitutive activation, undetectable AVP, named the syndrome), 22956819 (Carpentier JASN 2012, F229V, no spontaneous desensitization, tolvaptan/satavaptan silence it), 26131744 (Erdelyi Kidney Int 2015, I130N, constitutive cAMP, biased conformation, beta-arrestin-independent internalization), 22722264 (Vandergheynst 2012, fluid restriction + urea, vaptan non-response, furosemide), 30962325 (Miyado JASN 2019, germline GNAS Gsalpha GOF as a separate NSIAD cause, recorded as differential not folded in since MONDO term is AVPR2-defined). 12-node atomic pathophysiology chain from germline AVPR2 variant through ligand-independent V2R activation, constitutive adenylyl-cyclase cAMP, PKA-AQP2 phosphorylation, apical AQP2 insertion, collecting-duct water permeability, free water reabsorption/retention, physiologic AVP suppression, hypotonic hyponatremia, to cerebral water shift; plus a receptor-internalization branch. All 9 phenotypes causally wired (100%). Validated: just validate PASS, validate-terms PASS, 29/29 snippets verified, entity-refs/causal-targets/dup-keys/qualifier-terms/coarse-phenotypes/block-scalar all clean, GeneReviews NO_CHAPTER confirmed offline. preflight-dr WARN only for GNAS second-gene mentions (expected; handled as differential). Coordinator review pass before the PR: replaced two evidence items that did not support their claims (the cerebral-water-shift node and the Hyponatremia phenotype), added cited evidence for seizure/irritability/vomiting from PMID:29472987, 20631022 and 27355191, replaced an unsourced Lethargy phenotype with Hypotonia (named in PMID:29472987), dropped an unsourced Cerebral edema phenotype, added the L312S variant (PMID:27355191), and added Decaux 2010 (PMID:20631022) urinary AQP2 non-suppression as in-vivo evidence on the apical AQP2 node. Final: 37/37 snippets verified, 8/8 phenotypes connected, just validate-disorders passed with 0 issues. Review round 1 (ai4c-reviewer, changes requested): added a diagnosis section (water-load test with AVP/copeptin pitfall at urine osm 241, and AVPR2 sequencing), an environmental free-water-load entry linked to Free Water Retention (EXACERBATES), evidence on the Low serum osmolality and Inappropriately concentrated urine phenotypes, five adult-onset symptoms (malaise, dizziness->Vertigo, confusion, fatigue, headache) wired off Hypotonic Hyponatremia with ADULT onset and INFANTILE onset tagged on the infant symptoms, a carrier-female hyponatremia line plus the blurred-recessive caveat on inheritance, furosemide/NaCl therapeutic_agent bindings with demeclocycline and NaCl-alone outcome evidence, the GO binding on the permeability node corrected to GO:0070295 renal water absorption, and node-level evidence on Hypotonic Hyponatremia. All sourced from papers already cached in the PR. Re-validated: 54/54 snippets, 13/13 phenotypes connected, just validate-disorders clean. CI fix: bound GO:0005000 vasopressin receptor activity (GAIN_OF_FUNCTION) on the AVPR2 variant node so the gene is grounded, matching the XNDI sibling; clears the check-gene-activity-grounding gate.

Claude Code ▸
Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD): Research Report
claude-haiku-5-5, claude-sonnet-5-5 7 citations 2026-10-15T03:59:12.957047

Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD): Research Report

Verification status. Only two PMIDs were confirmed in this session: PMID:15872203 (Feldman 2005, NEJM) and PMID:30962326 (the GNAS paper in the Bockenhauer record). The searches returned secondary sources (OMIM mirrors, DrugBank, UCSF, PubMed, institutional repositories). I did not read the NEJM full text. Everything marked [unverified] comes from memory or is thinly sourced, and a curator must check it before use. Abstract quotes below are limited to what the search results returned. No exact snippets from the original papers were obtained, so none should be used as evidence snippets without just fetch-reference.

1. Disease information

  • NSIAD is a rare disorder in which the kidney concentrates urine and retains free water despite undetectable or low arginine vasopressin (AVP). The result is a SIADH-like picture of hyponatremia, hypo-osmolality and inappropriately concentrated urine. It was first reported by Feldman et al. in two unrelated male infants who had no measurable AVP (PMID:15872203, NEJM 2005;352:1884-90; DrugBank citation record, OMIM AVPR2).
  • Identifiers:
  • MONDO:0010356 (from the template).
  • OMIM #300539, as it appears in the search results' OMIM mirror URL. I did not open it, so confirm it.
  • Orphanet code and ICD-10/ICD-11 mapping: not verified. ICD-10 E22.2 is the SIADH code and probably not NSIAD-specific.
  • MeSH: not verified.
  • Synonyms: nephrogenic SIAD; "NSIAD" (AVPR2 gain-of-function); X-linked nephrogenic SIAD. The GNAS-related form is a separate "GNAS-associated" presentation (see Section 4).
  • Data source: the information comes from published case reports and family series (individual patients), plus aggregated resources such as OMIM.

2. Etiology

  • Causal factor (genetic): constitutively activating missense variants in AVPR2 (X-linked), which drive antidiuresis without ligand. Gain-of-function germline GNAS variants have recently been reported as a second cause.
  • Risk factors:
  • Genetic: male hemizygosity for AVPR2. Heterozygous females are variably affected, with a range from asymptomatic to symptomatic (skewed X-inactivation is a proposed explanation [unverified]).
  • Environmental: free-water load, such as large fluid intake or hypotonic fluids, precipitates hyponatremia. Infants given formula or intravenous hypotonic fluids are especially vulnerable.
  • Protective factors: none identified apart from fluid restriction behavior.
  • Gene-environment interaction: the genotype sets a fixed inability to excrete free water. Hyponatremia appears only with a water load, and it is made worse by hypotonic intake.

3. Phenotypes

Phenotype Suggested HPO (verify via lookup) Notes
Hyponatremia HP:0002902 Core finding.
Hypoosmolality / decreased serum osmolality verify Core finding.
Inappropriately concentrated urine with high urine osmolality verify Despite low serum osmolality.
Low or undetectable plasma AVP verify Distinguishes NSIAD from SIADH.
Seizures HP:0001250 In symptomatic infants.
Irritability, lethargy, vomiting verify
Fluid-restriction-responsive course n/a
  • Frequency: quantitative frequencies are not available because of rarity. The case series are small.
  • Onset: in the first reports, onset was in infancy (symptomatic hyponatremia). Adult or late-onset presentation is reported, including an asymptomatic adult with the R137C variant who was identified through family screening [unverified]. Severity ranges from asymptomatic to seizures.
  • Quality of life: no data found.

4. Genetic and molecular information

  • AVPR2 (Xq28, HGNC symbol AVPR2; verify CURIE through lookup).
  • R137C and R137L (Feldman 2005): in functional assays both receptors showed constitutive activation with high cAMP (OMIM).
    • The R137C mother was a carrier, and R137L appeared to arise de novo (UCSF news summary). This is a secondary source.
    • Codon 137 shows allelic opposition. R137H is loss-of-function and causes nephrogenic diabetes insipidus (NDI), whereas R137C/R137L are gain-of-function.
  • F229V: a 3-month-old hyponatremic infant. The variant gives high constitutive activity in vitro. The inverse agonists tolvaptan and satavaptan completely silenced the constitutive signaling (PMC search hit, unverified link match).
  • I130N: found in a family. It has constitutive cAMP signaling, and tolvaptan blocks the basal activity in cells. The authors concluded tolvaptan could be used for treatment of hyponatremia in patients with this variant. This is a cell-based finding.
  • Other later-described variants, such as L312S and others [unverified], were not confirmed here.
  • GNAS: germline gain-of-function GNAS (Gsα) variants were found in NSIAD families, with effects milder than the somatic variants of McCune-Albright syndrome (PMID:30962326, "GNAS: A New Nephrogenic Cause of Inappropriate Antidiuresis"; PubMed). Variant details and the full phenotype were not retrieved. Possible extra features, such as hormone resistance, are [unverified].
  • Functional consequence is gain of function (constitutive). Variants are germline. Allele frequency, ClinVar classification and modifier genes were not researched.
  • Epigenetic changes and chromosomal abnormalities: none known.

5. Environmental information

  • No environmental cause. Hypotonic fluid load is a trigger. There are no known infectious agents, and lifestyle factors are not relevant.

6. Mechanism and pathophysiology (causal chain)

  1. A germline activating variant in AVPR2 (or GNAS, a Gsα variant) arises. The V2R variants are missense changes at codon 137 and other sites, and they cause the receptor to adopt an active conformation without ligand. (demonstrated in vitro; PMID:15872203)
  2. The constitutively active V2 receptor stimulates Gs-adenylyl cyclase signaling and raises intracellular cAMP in collecting-duct principal cells. (demonstrated in transfected cells)
  3. Elevated cAMP and PKA activity drive aquaporin-2 (AQP2) trafficking to the apical membrane. This step is inferred from V2R physiology and was not shown directly in these patients' tissue.
  4. AQP2 insertion increases water permeability of the collecting duct, so the kidney reabsorbs water independently of AVP. (inferred)
  5. Urine stays inappropriately concentrated and free water is retained, and this suppresses AVP physiologically. (supported by undetectable AVP in patients)

  6. Dilutional hyponatremia and hypo-osmolality follow. Water entering brain cells causes cerebral edema, which produces irritability, lethargy and seizures.

  7. Branch: in the GNAS form, the upstream step is increased Gsα activity (a G protein shared by many receptors), and its effects on kidney V2R signaling are inferred.

  8. GO suggestions (verify): adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), water transport / water homeostasis, and cellular response to vasopressin.
  9. CL suggestions (verify): renal collecting duct principal cell.
  10. Omics, single-cell and CRISPR data: none found.

7. Anatomical structures affected

  • Primary: kidney collecting duct (principal cells; UBERON for renal collecting duct, verify).
  • Secondary: brain, through hyponatremic edema.
  • Subcellular: the plasma membrane (V2R) and the apical membrane (AQP2).
  • Bilateral. Systemic hyponatremia is the downstream effect.

8. Temporal development

  • Onset may be in infancy, with later or milder presentations in some carriers [unverified]. The course is lifelong. Severity depends on fluid intake, and hyponatremia is episodic when water load varies.
  • There are no stages. Remission occurs only with fluid restriction (symptom control), not spontaneously. Infancy is a critical window for symptomatic hyponatremia.

9. Inheritance and population

  • Epidemiology: ultra-rare. No prevalence or incidence data were found. Orphanet prevalence: not verified.
  • AVPR2 form: X-linked, with male hemizygotes more severely affected and female carriers variably affected. De novo variants occur (R137L).
  • GNAS form: described in families (PMID:30962326). Autosomal dominant transmission is plausible, but the mode needs checking.
  • No data on penetrance, founder effects or anticipation. Some adult cases show lifelong asymptomatic or late presentation, so the phenotype is variable [unverified].

10. Diagnostics

  • Laboratory: low serum sodium and osmolality, inappropriately high urine osmolality, and undetectable AVP (or copeptin, as a surrogate [unverified]). Rule out SIADH (where AVP is detectable), adrenal insufficiency, hypothyroidism, renal disease and drugs.
  • Functional test: a V2 antagonist (such as tolvaptan) can help assess urinary dilution in suspected NSIAD (an editorial cited in the search results). Water loading showing failure to dilute urine was used in original reports [unverified].
  • Genetic testing: sequence AVPR2 (single gene, or panels for hyponatremia / SIADH-like disorders), and then GNAS if negative. Copy number or exome testing was not researched.
  • Differential diagnosis: SIADH, cerebral salt wasting, other causes of hyponatremia, and NDI (the opposite allele effect at codon 137).
  • Screening: cascade testing of family members when a variant is known.
  • LOINC codes were not looked up. Look them up through loinc-seed-cache and do not type labels by hand.

11. Outcome and prognosis

  • The prognosis is generally good if hyponatremia is recognized and water intake is controlled. Untreated severe hyponatremia risks seizures and neurologic injury. No long-term survival or quality-of-life data were found.
  • Prognostic factors: age at recognition and fluid-load control.

12. Treatment

  • Fluid restriction is the mainstay (NCIT: Dietary Intervention, NCIT:C15447, from the CLAUDE.md list). It is hard to maintain in infants because of their high fluid needs.
  • Urea (oral) is used for chronic management [unverified]. Searches found nothing on urea, so a curator should find a source. Furosemide plus salt is another reported approach [unverified].
  • Tolvaptan (V2 inverse agonist): the in vitro data (F229V, I130N) show that inverse agonists silence the constitutive activity (PMC links above). Clinical benefit for the AVPR2 variants should not be assumed from cell data. A clinical result for the R137 variants is not established here, and some variants may respond differently [unverified].
  • Therapeutic modality: SMALL_MOLECULE for tolvaptan and urea, BEHAVIORAL for fluid restriction. NCIT:C15986 (Pharmacotherapy) applies to the drug entries, with CHEBI terms for tolvaptan and urea, to be looked up.
  • Experimental: no clinical trial found. ClinicalTrials.gov was not searched.

13. Prevention

  • No primary prevention. Genetic counseling and cascade testing help families, since male relatives may need early diagnosis. Prenatal diagnosis is possible in principle. Early recognition lets clinicians avoid hypotonic fluids in affected infants.

14. Other species

  • No natural disease found. Not searched in OMIA.

15. Model organisms

  • None identified in the search results. Cell models are in HEK293-type cells expressing mutant V2R, where cAMP assays showed constitutive activity (PMID:15872203, in vitro). A curator should search MGI and other databases before stating that no mouse model exists. Hypothesis: cells are the main experimental system, with limited ability to model whole-body water balance.

Key gaps for curators

  1. Confirm PMIDs for the F229V, I130N and other variant papers, since only the Feldman 2005 and GNAS PMIDs are verified.
  2. Source the treatment claims (urea, tolvaptan, furosemide), since the searches did not return clinical data.
  3. Obtain Orphanet, ICD, GeneReviews and ClinVar data, and exact snippets.
  4. Verify every CURIE by lookup before binding.

Sources: - DrugBank citation record for Feldman 2005 (PMID 15872203) - OMIM AVPR2 entry (mirror) - UCSF news summary, 2005 - News-Medical, 2005 - GNAS: A New Nephrogenic Cause of Inappropriate Antidiuresis (PubMed 30962326) - PMC3458462 and PMC6493987, which carry the F229V and I130N material. Identify their PMIDs by fetching them.

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 4
On topic 2
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 6
Resolved 6
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 3
Terms named correctly 3
Terms named as a different term 0

Every term resolved, and every label the report gave matched.