Congenital lens cataracts, the most common form of blindness in children worldwide (Evans et al., 1996; Lambert, 1994) appear as cloudiness, present at birth, or develop shortly after, as a major eye abnormality. About 30 % of childhood blindness is due to congenital cataracts (Arkin et al., 1992; Jensen and Goldschmidt, 1971), resulting from gene mutations that directly or indirectly affect lens development and function. Dr. Kasai's laboratory in Japan identified a spontaneous mutation causing lens cataracts and microphthalmia in DDI mouse strain and named it CatTohm. Mouse mutants with cataracts serve as important models for human hereditary cataracts and help to identify the genes responsible for normal eye development (review Graw, 1999a, Graw, 1999b).

The mammalian lens is avascular (Varadaraj et al., 2007); ion and water channels create a microcirculation (Mathias et al., 1997) to nourish and remove metabolic waste. The lens has a layer of anterior epithelial cells; many layers of fiber cells form the core. Aquaporin (AQP) water channels play a major role in maintaining lens homeostasis (Donaldson et al., 2023; Schey et al., 2014, 2022; Shiels et al., 2001; Varadaraj et al., 1999). Four lens aquaporins (AQPs) AQP0, AQP1, AQP3 and AQP5 have been identified and characterized (Grey et al., 2013; Hamann et al., 1998; Kumari et al., 2012; Kushmerick et al., 1995; Mulders et al., 1995; Petrova et al., 2024). Epithelial cells have AQP1, AQP3 and AQP5. When fiber cells differentiate from the epithelial cells at the lens equator, AQP1 is replaced by AQP0; AQP3 and AQP5 are also expressed in the fiber cells. AQP0 constitutes ∼45 % of the lens' total membrane protein. Compared to AQP1, AQP3 and AQP5, AQP0 has low water permeability, which is compensated by its profuse expression and distribution at the fiber cells (Petrova et al., 2024; Schey et al., 2017; Shiels et al., 2001; Varadaraj et al., 1999, 2005, 2007). AQP0 plays multiple roles; it functions as a water channel, peroxiporin, and cell-to-cell adhesion molecule, and is important for upholding lens transparency, refractive index gradient, and biomechanics (Amro et al., 2024; Kumari and Varadaraj, 2009, Kumari and Varadaraj, 2014; Li et al., 2022; Schey et al., 2017; Shiels et al., 2001; Sindhu Kumari et al., 2014, 2015; Varadaraj et al., 1999, 2024). AQP0 interacts with several lens proteins such as calmodulin, CP49, filensin, Connexin (Cx) 46, Cx50, vimentin, α-crystallin and γE-crystallin (review: O'Neale et al., 2024). AQP0 and Glutathione peroxidase 1 play a critical role in sustaining the lens redox balance; mutation(s) or knocking out of either one leads to accelerated oxidative damage and lens cataracts (Reddy et al., 2001; Varadaraj and Kumari, 2020; Varadaraj et al., 2021, 2022; Wang et al., 2009). Thirty-one natural AQP0 mutations in humans (Ni et al., 2024), three in mice (1. Cataract Fraser (CatFr; Muggleton-Harris et al., 1987; Shiels and Bassnett, 1996), 2. Cataract lens opacity (Catlop; Shiels and Griffin, 1993; Shiels and Bassnett, 1996), and 3. Cataract Tohoku (CatTohm; Okamura et al., 2003) and one in the rat (Watanabe et al., 2012) resulted in dominant lens cataracts. A 17-amino acid deletion mutation at the C-terminal end of AQP0 (Varadaraj et al., 2019), and knockout of AQP0 in mice caused lens cataracts (Shiels et al., 2001). Diabetes leads to glycation of AQP0 and accelerated lens cataractogenesis (Swamy-Mruthinti, 2001). These results point to the significance of the function(s) of AQP0 for lens transparency and homeostasis.

In the current investigation, we tried to unravel the possible causes for the formation of congenital dominant lens cataract, using two in vivo models such as the CatTohm mutant mouse and a transgenic mouse model expressing CatTohm mutant AQP0 (heterozygous: Tg4/0; homozygous: Tg4/Tg4); we also did in vitro expression of CatTohm mutant AQP0 in Xenopus oocytes and MDCK cells. We explored lens transparency, morphology, CatTohm mutant protein trafficking, localization, water and H2O2 permeabilities and cytotoxicity.