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Chun-hong Xia, Haiquan Liu, Bo Chang, Catherine Cheng, Debra Cheung, Meng Wang, Qingling Huang, Joseph Horwitz, Xiaohua Gong; Arginine 54 and Tyrosine 118 Residues of αA-Crystallin Are Crucial for Lens Formation and Transparency. Invest. Ophthalmol. Vis. Sci. 2006;47(7):3004-3010. doi: 10.1167/iovs.06-0178.
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purpose. To identify new mouse models for studying roles of αΑ-crystallin in vivo and to investigate why and how different mutations of the αΑ-crystallin gene lead to dominant or recessive cataracts.
methods. Using mouse genetic approaches and slit lamp screening, we identified two mouse cataractous mutant lines. Causative genes were mapped by a genome-wide linkage analysis. DNA sequencing verified missense mutations of αA-crystallin gene in both mutant lines. Histology, imaging of green fluorescent protein (GFP)–positive lenses, and protein 2-DE gel were used to determine the morphologic and biochemical properties of mutant lenses.
results. Two new αA-crystallin gene mutations were identified, αA-R54C (αA-Cys) and αA-Y118D, which cause recessive whole cataracts and dominant nuclear cataracts, respectively. In homozygous αA-Cys mutant mice, lens epithelial and fiber cells lost their characteristic cellular features and developed disrupted subcellular structures, such as actin filaments and mitochondria. The nuclear cataract caused by αA-Y118D mutation was associated with increased water-insoluble crystallins (α, β, and γ classes). These results suggest that the Arg54 residue in the N-terminal region is crucial for αA-crystallin to perform its roles in lens epithelial and fiber cells during development, whereas the Y118D mutation in the central α-crystallin domain impairs αA-crystallin’s ability to maintain the solubility of crystallin proteins in the lens.
conclusions. This work demonstrates that different regions of αA-crystallin mediate distinct functions in vivo. These two mutant mouse lines provide useful animal models for further investigating the multiple roles of αA-crystallin in the lens.
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