AVPR2 – Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by renal tubular insensitivity to arginine vasopressin, leading to profound polyuria and polydipsia. The X-linked vasopressin V2 receptor (AVPR2) mediates antidiuretic hormone signaling in the collecting duct; loss-of-function mutations in AVPR2 underlie most congenital NDI cases. X-linked recessive inheritance results in hemizygous males presenting with severe polyuria, whereas heterozygous females may be asymptomatic or show variable skewed X-inactivation phenotypes.

Genetic evidence for AVPR2’s role in NDI is robust. Initial studies identified point mutations in 8 unrelated X-linked NDI probands, demonstrating co-segregation of non-conservative amino acid substitutions with disease across three multigenerational pedigrees (PMID:1303271). Subsequent comprehensive review documented 211 distinct AVPR2 mutations in 326 families world-wide, including missense (55.8%), nonsense, frameshift, splice-site, and in-frame deletion variants (PMID:18726898). Notable recurrent mutations include c.334T>C (p.Cys112Arg) and c.310C>T (p.Arg104Cys), each shown to abrogate receptor function and consistently segregate with affected males and carrier females (PMID:10694923).

Segregation analysis across multiple pedigrees confirms X-linked recessive transmission. Segregating AVPR2 variants were demonstrated in three multigenerational NDI families, where affected males and carrier mothers carried the same missense alleles, and no variants were found in unaffected relatives (PMID:10694923).

Functional assays uniformly demonstrate loss of receptor activity. In vitro studies of representative missense mutants (e.g., p.Arg137His, p.Arg202Cys) reveal impaired cell surface expression, diminished ligand affinity (20- to 60-fold shifts in EC₅₀), and reduced G_s-mediated cAMP generation (PMID:7984150; PMID:7560098). Rescue experiments using pharmacological chaperones (e.g., tolvaptan) restore maturation, trafficking, and signaling for select folding-defective variants such as p.Met272Arg (PMID:33009446).

In vivo support comes from a mouse model harboring a nonsense AVPR2 mutation (p.Glu242Ter) that recapitulates human NDI with polyuria, hyposthenuria, and early lethality, highlighting the essential role of AVPR2 in water homeostasis (PMID:11104789). Therapeutic studies demonstrate that V2R agonists (e.g., Val⁴-desmopressin) can bypass specific missense defects, offering genotype-tailored treatment strategies (PMID:24628417).

Conclusion: Definitive genetic and functional data establish AVPR2 loss-of-function as the cause of X-linked NDI. Identification of AVPR2 mutations enables precise diagnosis, genetic counseling, and the potential for targeted therapies such as pharmacological chaperones or receptor-specific agonists. Clinically, early molecular confirmation guides management to prevent dehydration-related complications.

References

• Nature Genetics • 1992 • Mutations in the vasopressin type 2 receptor gene (AVPR2) associated with nephrogenic diabetes insipidus. PMID:1303271
• Journal of Cellular Physiology • 2008 • AVPR2 variants and mutations in nephrogenic diabetes insipidus: review and missense mutation significance. PMID:18726898
• Human Mutation • 1998 • C112R, W323S, N317K mutations in the vasopressin V2 receptor gene in patients with nephrogenic diabetes insipidus. PMID:10694923
• The Journal of Clinical Investigation • 2000 • Generation and phenotype of mice harboring a nonsense mutation in the V2 vasopressin receptor gene. PMID:11104789
• Molecular Endocrinology • 2014 • Altered agonist sensitivity of a mutant v2 receptor suggests a novel therapeutic strategy for nephrogenic diabetes insipidus. PMID:24628417
• Scientific Reports • 2020 • Characterization of five novel vasopressin V2 receptor mutants causing nephrogenic diabetes insipidus reveals a role of tolvaptan for M272R-V2R mutation. PMID:33009446

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