We hypothesized that the difference in these amino acids across species would affect the in vivo pathogenicity of NMO-IgGs and that humanizing the AQP4 ECDs of rat AQP4 might increase the affinity and pathogenicity of patient-derived IgGs to induce severe lesions comparable to the human pathology of NMOSD. This evidence concerns the gene AQP4 and neuromyelitis optica.