AVPR2 – Nephrogenic Syndrome of Inappropriate Antidiuresis

Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) is a rare X-linked disorder characterized by hypotonic hyponatremia and persistently concentrated urine despite low or undetectable arginine vasopressin levels (PMID:15872203). Patients present in infancy with recurrent severe hyponatremia and may develop seizures, while adult-onset or symptomatic heterozygous females have also been reported (PMID:20148077).

Gain-of-function missense variants in AVPR2 encode constitutively active V2 receptors. To date, at least 12 unrelated hemizygous males and multiple symptomatic heterozygotes have been described, harboring R137C, R137L, R137G, F229V, L312S, Q96H, R104C and other substitutions (PMID:15872203; PMID:16843086; PMID:22325688; PMID:22956819; PMID:27355191). The most prevalent allele, c.409C>T (p.Arg137Cys), recurs across diverse populations and segregates with NSIAD in multiple families (PMID:20148077; PMID:25925274).

Segregation analysis across pedigrees confirms X-linked inheritance, with two additional male relatives affected in the original family (PMID:20148077). Overall, 12 probands have been molecularly confirmed, with genotype–phenotype concordance in each kindred.

Functional assays demonstrate that R137C/L variants elevate basal cAMP signaling 4- to 7.5-fold relative to wild-type receptor, recapitulating constitutive V2R activation (PMID:16843086). In vitro studies of F229V and L312S mutations reveal sustained high basal activity without desensitization, reversible by the inverse agonists tolvaptan and satavaptan (PMID:22956819; PMID:27355191). Clinically, NSIAD infants show persistent urinary aquaporin-2 excretion and failure to suppress free water excretion on water loading (PMID:22325688).

Structural modeling and targeted mutagenesis support a gain-of-function mechanism in which altered transmembrane domain interactions or disrupted hydrogen bonds stabilize the receptor’s active conformation (PMID:26715131). The concordance of genetic, functional, and clinical data establishes NSIAD as a definitive AVPR2 constitutive activation disorder.

Key Take-home: AVPR2 gain-of-function mutations reliably cause NSIAD, supporting targeted genetic testing, guided fluid restriction, and precision therapy with V2R inverse agonists.

References

• The New England Journal of Medicine • 2005 • Nephrogenic syndrome of inappropriate antidiuresis PMID:15872203
• International Journal of Pediatric Endocrinology • 2009 • Long-term outcomes in a family with nephrogenic syndrome of inappropriate antidiuresis. PMID:20148077
• The American Journal of Medicine • 2006 • Nephrogenic syndrome of inappropriate antidiuresis: a novel disorder in water balance in pediatric patients. PMID:16843086
• International Journal of Pediatric Endocrinology • 2012 • Persistent elevation of urine aquaporin-2 during water loading in a child with nephrogenic syndrome of inappropriate antidiuresis (NSIAD) caused by a R137L mutation in the V2 vasopressin receptor. PMID:22325688
• Journal of the American Society of Nephrology : JASN • 2012 • Identification and characterization of an activating F229V substitution in the V2 vasopressin receptor in an infant with NSIAD. PMID:22956819
• Molecular Endocrinology • 2016 • Mutations of Vasopressin Receptor 2 Including Novel L312S Have Differential Effects on Trafficking. PMID:27355191

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