Cat^Tohm Mutation Studies Identify AQP0 as a Modulator of Lens Transparency, Cell-to-Cell Adhesion, Biomechanics,...

This study was conducted to determine how Aquaporin 0 (AQP0) Cat^Tohm natural mutation, which causes congenital cataracts and smaller eyes (microphthalmia) in mice, affects eye development, lens clarity, physiology, and mechanics. Eyes of wild-type (WT) and Cat^Tohm heterozygous (Cat^+/Tohm) mutant mice were examined; Cat^+/Tohm showed significantly smaller eyes, indicating microphthalmia. Lenses from wild-type (WT), AQP0 heterozygous (AQP0^+/-), and Cat^+/Tohm mutant mice were imaged, and transparency was quantified. In Cat^+/Tohm, transparency was greatly reduced compared with that of WT and AQP0^+/- (P<0.0001). Cell-to-cell adhesion studies using a cell aggregation assay on L-cells transfected with either WT or Cat^+/Tohm AQP0 showed a significant decrease in cell aggregation with Cat^+/Tohm AQP0 compared with WT-expressing cells (P<0.0001). Lens stiffness was determined using compression stress testing, which revealed heterozygous Cat^+/Tohm lenses substantially less stiff than WT lenses (P<0.001). Gap Junction Coupling (GJC) and Hydrostatic Pressure (HP) were assessed to evaluate the physiological effects on lens microcirculation and homeostasis; Cat^+/Tohm lenses displayed significantly increased GJC (P<0.0001) and reduced HP (P<0.0001) relative to those in WT lenses. In summary, the results indicate that the mutation has altered cell-to-cell adhesion, biomechanics, GJC, and HP; together, these changes lead to the development of dominant cataracts and microphthalmia. AQP0 serves as a multifunctional protein in the lens, modulating transparency, fiber cell-to-fiber cell adhesion, GJC, HP, biomechanics, microcirculation, and homeostasis.