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Arginine 54 and Tyrosine 118 Residues of A-Crystallin Are Crucial for Lens Formation and Transparency

¹From the School of Optometry and Vision Science Program, University of California, Berkeley, Berkeley, California; ²The Jackson Laboratory, Bar Harbor, Maine; the ³UC Berkeley/UCSF Joint Bioengineering Graduate Program, University of California, Berkeley, Berkeley, California; and the ⁴Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, California.

PURPOSE. To identify new mouse models for studying roles of A-crystallin in vivo and to investigate why and how different mutations of the A-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 A-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 A-crystallin gene mutations were identified, A-R54C (A-Cys) and A-Y118D, which cause recessive whole cataracts and dominant nuclear cataracts, respectively. In homozygous A-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 A-Y118D mutation was associated with increased water-insoluble crystallins (, ß, and classes). These results suggest that the Arg⁵⁴ residue in the N-terminal region is crucial for A-crystallin to perform its roles in lens epithelial and fiber cells during development, whereas the Y118D mutation in the central -crystallin domain impairs A-crystallin’s ability to maintain the solubility of crystallin proteins in the lens.

CONCLUSIONS. This work demonstrates that different regions of A-crystallin mediate distinct functions in vivo. These two mutant mouse lines provide useful animal models for further investigating the multiple roles of A-crystallin in the lens.

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