In vivo lens deficiency of the R49C alphaA-crystallin mutant.

The R49C mutation of alphaA-crystallin (alphaA-R49C) causes hereditary cataracts in humans; patients in a four-generation Caucasian family were found be heterozygous for this autosomal dominant mutation. We previously generated knock-in mouse models of this mutation and found that by 2 months of age, heterozygous mutant mice exhibited minor lens defects including reduced protein solubility, altered signaling in epithelial and fiber cells, and aberrant interactions between alphaA-crystallin and other lens proteins. In contrast, homozygous mutant alphaA-R49C knock-in mice displayed earlier and more extensive lens defects including small eyes and small lenses at birth, death of epithelial and fiber cells, and the formation of posterior, nuclear, and cortical cataracts in the first month of life. We have extended this study to now show that in alphaA-R49C homozygous mutant mice, epithelial cells failed to form normal equatorial bow regions and fiber cells continued to die as the mice aged, resulting in a complete loss of lenses and overall eye structure in mice older than 4 months. These results demonstrate that expression of the hereditary R49C mutant of alphaA-crystallin in vivo is sufficient to adversely affect lens growth, lens cell morphology, and eye function. The death of fiber cells caused by this mutation may ultimately lead to loss of retinal integrity and blindness.