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Sarah El-Khazendar, Viviana M Berthoud, Eric C Beyer, Rebecca K Zoltoski; Expression of Cx46fs380 causes significant changes in lens fiber membrane structural organization. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2643.
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© ARVO (1962-2015); The Authors (2016-present)
Inherited human cataracts have been linked to mutations in connexin46 (Cx46) including Cx46fs380. Mice expressing Cx46fs380 (generated by a knock-in strategy) show anterior nuclear cataracts that are evident at 2 months in homozygotes and at ≥4 months in heterozygotes. These animals have substantially reduced levels of fiber cell connexins before cataracts become detectable. The experiments were designed to characterize the structural changes in the organization of lens fiber cell membranes that occur in these mice with age.
Lenses from young (≤ 3 months) and older (> 3 months) wild type (WT) and heterozygous (HT) and homozygous (HM) Cx46fs3880 mice were examined by scanning electron microscopy. Broad faces of fiber cells were classified by organization of interdigitations, ball and socket joints and furrows. Data are presented as the percentage of fiber cells showing organization of these features. Statistical significance was determined using nonparametric t-tests.
The percentages of fiber cells with organized interdigitations were significantly decreased in old HT and HM Cx46fs380 mice compared with WT animals (18.6 in HT and 19.3 in HM vs. 30.4 in WT; p<0.001). The percentages of fiber cells with organized ball and socket joints were reduced in both young and old HT and HM Cx46fs380 mice compared with WT values (33.7 in old HT and 29.8 in old HM vs. 78.3 in old WT; p<0.001). Organized ball and socket joints decreased with age in HT Cx46fs380 mice (young, 63.6 vs. old, 33.7; p=0.01). Interestingly, while furrows could be identified in all genotypes, the percentage of fiber cells showing a consistent pattern of membrane folds was dramatically reduced in both young and old HT and HM Cx46fs380 mice compared with WT (0 in old HT and HM vs. 17.4 in old WT; p<0.001).
Mouse lenses expressing Cx46fs380 show significant changes in the organization of fiber cell membrane structure compared with wild type lenses. Because formation of furrows has been associated with compaction, the lack of organized furrows in Cx46fs380 fiber cells suggests that compaction does not occur effectively in these lenses. The near absence of Cx46 in Cx46fs380 lenses (that precedes the appearance of cataracts) may cause these structural changes in fiber cell membranes contributing to cataract formation.
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