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Qingling Huang, Linlin Ding, Kim B. Phan, Catherine Cheng, Chun-hong Xia, Xiaohua Gong, Joseph Horwitz; Mechanism of Cataract Formation in αA-crystallin Y118D Mutation. Invest. Ophthalmol. Vis. Sci. 2009;50(6):2919-2926. doi: 10.1167/iovs.08-3070.
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purpose. The aim of this study was to elucidate the molecular mechanisms that lead to a dominant nuclear cataract in a mouse harboring the Y118D mutation in the αA-crystallin gene.
methods. The physicochemical properties of α-crystallin obtained from mouse lenses with the Y118D mutation as well as a recombinant Y118D αA-crystallin were studied using gel filtration, two-dimensional (2D) gel electrophoresis, multi-angle light scattering, circular dichroism, fluorescence, and chaperone activities.
results. Both native α-crystallin from mutant lens and recombinant αA-Y118D displayed higher molecular mass distribution than the wild-type. Circular dichroism spectra indicated changes in the secondary structures of αA-Y118D. The αA-Y118D protein prevented nonspecific protein aggregation more effectively than wild-type αA-crystallin. The gel filtration and 2D gel electrophoresis analysis showed a significant reduction of Y118D mutant protein in comparison with wild-type αA protein of heterozygous mutant lenses. Quantitative RT-PCR results confirmed a decrease in αA and αB transcripts in the homozygous mutant α A(Y118D/Y118D) lenses.
conclusions. The αA-Y118D mutant protein itself displays an increased chaperone-like activity. However, the dominant nuclear cataract is associated with a significant decrease in the amount of αA-crystallin, leading to a reduction in total chaperone capacity needed for maintaining lens transparency.
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