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A Transgenic Mouse Model for Human Autosomal Dominant Cataract

¹From the Departments of Ophthalmology and Visual Sciences and ³Genetics, and the ²Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri.

PURPOSE. To characterize lenses from transgenic mice designed to express mutant and wild-type A-crystallin subunits.

METHODS. A series of transgenic mouse strains was created to express mutant (R116C) and wild-type human 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 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 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 A-crystallin subunits are expressed on the background of wild-type endogenous mouse -crystallins. Low levels of R116C A-crystallin subunits are sufficient to induce lens opacities and sutural defects.

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