Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
Aquaporin-2 (AQP2) is a vasopressin‐regulated water channel encoded by HGNC:634. Pathogenic variants in AQP2 underlie both autosomal recessive and rare autosomal dominant forms of nephrogenic diabetes insipidus (NDI; MONDO:0016383), characterized by polyuria, polydipsia, hypernatremic dehydration, and failure to thrive. Diagnosis of AQP2‐related NDI informs early genetic counseling, perinatal testing, and targeted interventions to prevent severe dehydration.
In autosomal recessive NDI, over 25 unique AQP2 variants have been identified in 30+ unrelated probands, often as compound heterozygotes or homozygotes in consanguineous families. Core‐glycosylation‐retained mutants (e.g., p.Thr125Met, p.Gly175Arg, p.Arg187Cys) demonstrate impaired water permeability and ER retention in Xenopus oocytes and mammalian cells ([PMID:8140421]; [PMID:9745427]; [PMID:9593782]). Carrier frequency is low, and variants are typically private, with no recurrent founder alleles reported.
Autosomal dominant NDI arises from C‐terminal AQP2 variants exhibiting dominant‐negative effects. The first reported E258K substitution (c.772G>A (p.Glu258Lys)) abolished Golgi exit and retained mixed tetramers with wild-type AQP2, reducing water permeability despite preserved S256 phosphorylation ([PMID:9649557]). Similarly, p.Arg254Gln impairs vasopressin‐induced trafficking by blocking S256 phosphorylation and apical insertion ([PMID:19585583]). Three additional families with frameshift mutations in exon 4 share extended C-terminal tails that misroute hetero-oligomers to endolysosomal compartments, establishing a general misrouting mechanism in dominant NDI ([PMID:11536078]).
Extensive functional work supports a loss‐of‐function mechanism mediated by protein misfolding, defective glycosylation, ER retention, and improper trafficking. Chemical chaperones such as glycerol, TMAO, and DMSO can rescue certain folding mutants (e.g., p.Thr126Met, p.Ala147Thr, p.Arg187Cys) to the plasma membrane and restore water permeability in CHO and MDCK cells ([PMID:9593782]; [PMID:9302264]). Mouse knock-in models of the T126M mutation recapitulate neonatal mortality and urinary concentrating defects, confirming in vivo relevance ([PMID:11035038]).
No major studies dispute the AQP2–NDI association. Genotype–phenotype correlations correlate residual channel activity with clinical severity; milder phenotypes correspond to partial water flux (e.g., p.Asp150Glu) and preserved plasma membrane targeting ([PMID:19458121]).
In summary, AQP2 has a Definitive ClinGen gene‐disease association with nephrogenic diabetes insipidus, supported by strong genetic evidence—including segregation in multiple families—and moderate functional evidence demonstrating pathogenic mechanisms. Genetic testing for AQP2 variants is clinically actionable for early diagnosis, management, and family counseling.
Gene–Disease AssociationDefinitiveOver 35 unrelated probands from >20 families with segregation and concordant functional studies Genetic EvidenceStrong35 probands with 27 unique variants in AQP2 including both AR and AD inheritance across multiple families ([PMID:7524315],[PMID:9649557]) Functional EvidenceModerateMultiple in vitro and in vivo studies demonstrating misfolding, retention, and dominant-negative effects rescued by chaperones ([PMID:9593782]; [PMID:8140421]) |