A transgenic mouse model for human autosomal dominant cataract

PURPOSE. To characterize lenses from transgenic mice designed to express mutant and wild-type alpha A-crystallin subunits. METHODS. A series of transgenic mouse strains was created to express mutant (R116C) and wild-type human alpha A-crystallin in fiber cells of the lens. Dissected lenses were phenotypically scored for the presence and extent of opacities, fiber cell morphology, and posterior suture morphology. Gene transcripts derived from integrated transgenes were detected by reverse transcriptase-PCR. Distribution of expressed transgenic protein was determined by immunohistochemical staining of lens tissue sections. The abundance of endogenous and transgenic lens proteins was estimated by quantitative Western blot analysis. RESULTS. Expression of R116C mutant alpha A-crystallin subunits resulted in posterior cortical cataracts and abnormalities associated with the posterior suture. The severity of lens abnormalities did not increase between the ages of 9 and 30 weeks. With respect to opacities and morphologic abnormalities, lenses from transgenic mice that express wild-type human alpha A-crystallin subunits were indistinguishable from age-matched nontransgenic control mice. Similar phenotypes were observed in different independent lines of R116C transgenic mice that differed by at least two orders of magnitude in the expression level of the mutant transgenic protein. CONCLUSIONS. The results show that lens opacities and posterior sutural defects occur when mutant R116C alpha A-crystallin subunits are expressed on the background of wild-type endogenous mouse alpha-crystallins. Low levels of R116C alpha A-crystallin subunits are sufficient to induce lens opacities and sutural defects.