Aquaporin-4 – Neuromyelitis Optica Spectrum Disorder

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a severe demyelinating disease characterized by recurrent optic neuritis and longitudinally extensive transverse myelitis. The presence of serum aquaporin-4 immunoglobulin G autoantibodies is both highly specific and pathogenic, defining NMOSD as an astrocytopathy mediated by anti-AQP4 antibodies, rather than a primary oligodendrocyte disease (PMID:21900637).

Genetic sequencing of AQP4 in 177 sporadic and 14 familial NMOSD cases identified two missense mutations at Arg19 (c.56G>C (p.Arg19Thr) and c.56G>A (p.Arg19Ile)) in three patients, including segregation in one pedigree, and a rare SNP (NC_000018.8:g.22695167T>A) with an odds ratio of 13.1 (PMID:21900637). No other coding variants were found in the majority of cohorts, and promoter polymorphisms showed inconsistent associations across ethnicities, suggesting a limited contribution of germline AQP4 variation to overall NMOSD susceptibility.

Functional assays using cell-based systems and mutagenesis have elucidated the critical role of AQP4 supramolecular assemblies (orthogonal arrays of particles, OAPs) in autoantibody binding. Mutation of extracellular loop residues such as Asp69 to His (c.205G>C (p.Asp69His)) abrogates NMO-IgG binding without altering channel water permeability or tetramerization, demonstrating a conformational epitope dependent on loop A integrity (PMID:25239624).

In vivo studies in Aqp4-A25Q knock-in mice, which disrupt OAP formation, show reduced astrocytic endfoot localization of AQP4, preserved blood–brain barrier integrity, and attenuated cerebral edema in models of water intoxication and focal ischemia, underscoring the pathogenic importance of OAPs in NMOSD-related astrocyte injury (PMID:36100398).

Some population studies report no significant association of common AQP4 SNPs with NMOSD risk in Korean and Chinese cohorts, reinforcing that autoantibody targeting of wild-type AQP4 rather than germline mutation underlies most disease cases (PMID:24361961).

Overall, AQP4 is the principal antigen in NMOSD with definitive functional evidence of autoantibody-mediated astrocyte damage, but only limited genetic evidence of Mendelian risk variants. AQP4 autoantibody testing remains the cornerstone for diagnosis, prognostication, and therapeutic targeting in NMOSD.

Key Take-home: AQP4 autoantibody assays are critical for NMOSD diagnosis and guide immunotherapy, whereas germline AQP4 variants contribute only marginally to disease risk.

References

• Neurology • 2011 • Genetic analysis of aquaporin-4 in neuromyelitis optica. PMID:21900637
• The Journal of Biological Chemistry • 2014 • Identification of a point mutation impairing the binding between aquaporin-4 and neuromyelitis optica autoantibodies. PMID:25239624
• The Journal of Neuroscience • 2022 • AQP4-A25Q Point Mutation in Mice Depolymerizes Orthogonal Arrays of Particles and Decreases Polarized Expression of AQP4 Protein in Astrocytic Endfeet at the Blood–Brain Barrier. PMID:36100398
• Gene • 2014 • Lack of association between AQP4 polymorphisms and risk of inflammatory demyelinating disease in a Korean population. PMID:24361961

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