Cataract Development and Water Transport in the Aquaporin 0 Mutant CatTohm Mouse Lens

Abstract

Abstract: : Purpose: Recently, Okamura et al. (Genomics 81: 361–368, 2003) reported that AQP0 mutation in a DDI mouse strain (Cat^Tohm) developed dominant bilateral cataracts. DNA sequence analysis of AQP0 showed deletion of four amino acids within the second transmembrane region of the protein. The mutated AQP0 protein did not traffic to the fiber cell plasma membrane. The present study was conducted to determine the lens morphology and water permeability of fiber cell membranes (Pw) from the Cat^Tohm mouse. Methods: Lenses from wild type and Cat^Tohm mice were dissected and photographed under a light microscope. Cortical fiber cell vesicles were prepared from wild type and Cat^Tohm mice and Pw was determined from the rate of volume change when the vesicle was immersed in hypertonic bathing solution. Results:Fiber cell membrane vesicles from wild type mice had a Pw of 37 µm/s, whereas those from Cat^Tohm heterozygous mice had a Pw of 16 µm/s and from homozygous mice had a Pw of 9 µm/s. Before birth, lenses from heterozygous and homozygous Cat^Tohm mice developed polymorphic nuclear opacities. In the adult Cat^Tohm, focusing power of lenses was significantly reduced. The heterozygous AQP0 knockout and Cat^Tohm lenses have about the same Pw, but the heterozygous knockout does not develop an equivalent cataract until much later in life.Conclusions: The effect of the AQP0 mutation on lens Pw is similar to that in AQP0 knockout mice, however the cataract phenotype is different. This may be due to defects in protein trafficking at different organelle levels, causing varying degrees of cytotoxicity. AQP0 natural mutations in mice and human, and AQP0 knockout studies suggest that cataract development is more severe due to cytotoxicity by gain of function than due to loss of membrane water permeability.

Keywords: cataract • gene/expression • immunohistochemistry