Gene expression profiling in human age-related nuclear cataract.

Age-related cataract still represents the most frequent worldwide cause of visual impairment and, frequently, of blindness. Even though much is known about the environmental cues and biochemical changes associated with age-related loss of lens transparency, the sequence of events ultimately leading to cataract formation is far from being elucidated. One of the most popular hypotheses considers oxidative stress as a possible cause of age-related cataract, and evidence derived from in vitro analyses as well as from cataractous human eyes studies have been supportive of this possibility [1-3]. Other studies, however, came up with inconclusive or even negative results as to a critical involvement of oxidative stress in cataractogenesis [4]. The same is largely true for observational studies aimed at evaluating a possible role of the anti-oxidant status of human participants in preventing (or at least delaying) the development of age-related lens opacities [5-7]. The identification of genes differentially expressed in agerelated cataract compared with transparent adult human lenses is likely to provide important insights into the metabolic and protective processes that characterize the tissue response to the disease. Although the overall spectrum of gene modulation that characterizes the development of lens opacification is presently largely unknown, some information has been gained recently both in animal models of age-onset cataract and in the human age-related disease. RT-PCR differential display analysis of lens mRNAs has resulted in the identification of a limited number of transcripts that appear to be upor down-regulated in the lens epithelium of human lenses with age-related cataract (or corresponding animal disease models) as compared to epithelial samples from normal transparent lenses [8-11]. In the Emory mouse, a well-characterized model of age-dependent cataract, Sheets et al. [8] reported the downregulation of αAand βA3/A1-crystallin and the upregulation of the ARK receptor tyrosine kinase. In human lens epithelium derived from age-related cataracts, Kantorow et al. [9-11] observed abnormal changes in the expression levels of a few transcripts, including increased expression of metallothionein IIA and osteonectin, and decreased expression of the protein Phosphatase 2A regulatory subunit, as well as of the mRNAs for ribosomal proteins L21, L15, L13a, and L7a. A more comprehensive picture of the mRNA expression profile of a tissue and of the changes in expression levels that can take place during disease development (or maintenance, as in late onset chronic diseases such as age-related cataract) may be obtained with the use of DNA microarrays, a tech© 2003 Molecular Vision