Overexpression of Na(+)-dependent myo-inositol transporter gene in mouse lens led to congenital cataract.

PURPOSE Maintaining appropriate osmotic pressure is essential for maintaining lens transparency. This study was performed to investigate whether high levels of myo-inositol, one of the major organic osmolytes in the lens, would lead to cataract development. METHODS Transgenic mouse lines carrying the bovine Na(+)-dependent myo-inositol transporter (bSMIT) cDNA under the control of the mouse alphaA-crystallin promoter were generated. RESULTS. Increased bSMIT expression was accompanied by increased myo-inositol level in the lens and increased uptake of (3H) myo-inositol by the lens in culture. The transgenic mice developed observable cataract under normal rearing conditions beginning at 2 to 8 weeks of age, and the severity of cataract development was correlated to the level of bSMIT gene expression and lens myo-inositol accumulation. For transgenic mouse line 3352, heterozygous mice did not develop cataract, whereas homozygous ones did. Prenatal feeding of heterozygous 3352 mice with high myo-inositol diet led to cataract development, indicating that cataract development was not merely due to a nonspecific effect of SMIT overexpression. Introducing aldose reductase overexpressing transgene into heterozygous 3352 mice also led to cataract development, indicating that this type of cataract is primarily due to osmotic stress. CONCLUSIONS The present results indicate that high levels of myo-inositol and sorbitol in the lens contribute to cataract development. This is a useful model to study the role of osmotic stress in cataractogenesis during lens development.