| Summary: | <p>Abstract</p> <p>Background</p> <p>αA-crystallin (CRYAA/HSPB4), a major component of all vertebrate eye lenses, is a small heat shock protein responsible for maintaining lens transparency. The R49C mutation in the αA-crystallin protein is linked with non-syndromic, hereditary human cataracts in a four-generation Caucasian family.</p> <p>Methods</p> <p>This study describes a mouse cataract model generated by insertion of a neomycin-resistant (neo<sup>r</sup>) gene into an intron of the gene encoding mutant R49C αA-crystallin. Mice carrying the neo<sup>r </sup>gene and wild-type <it>Cryaa </it>were also generated as controls. Heterozygous knock-in mice containing one wild type gene and one mutated gene for αA-crystallin (WT/R49C<sup>neo</sup>) and homozygous knock-in mice containing two mutated genes (R49C<sup>neo</sup>/R49C<sup>neo</sup>) were compared.</p> <p>Results</p> <p>By 3 weeks, WT/R49C<sup>neo </sup>mice exhibited large vacuoles in the cortical region 100 μm from the lens surface, and by 3 months posterior and nuclear cataracts had developed. WT/R49C<sup>neo </sup>mice demonstrated severe posterior cataracts at 9 months of age, with considerable posterior nuclear migration evident in histological sections. R49C<sup>neo</sup>/R49C<sup>neo </sup>mice demonstrated nearly complete lens opacities by 5 months of age. In contrast, R49C mice in which the neo<sup>r </sup>gene was deleted by breeding with CreEIIa mice developed lens abnormalities at birth, suggesting that the neo<sup>r </sup>gene may suppress expression of mutant R49C αA-crystallin protein.</p> <p>Conclusion</p> <p>It is apparent that modification of membrane and cell-cell interactions occurs in the presence of the αA-crystallin mutation and rapidly leads to lens cell pathology <it>in vivo</it>.</p>
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