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Y. Tang, R. K. Zoltoski, J. R. Kuszak, N. M. Kumar; Disruption of Calpain 3 Gene Prevents Cataracts, but Doesn't Correct Lens Growth Deficiency in 8Cx50-Knockout Mice. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3636.
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© ARVO (1962-2015); The Authors (2016-present)
Previous studies have demonstrated that Calpain 3 is necessary for formation of the severe nuclear cataract in α3Cx46-knockout mice. Deletion of α8Cx50 produces microphthalmia with a zonular pulverulent cataract. To determine whether these two traits are influenced by Calpain 3 gene, mice carrying both α8Cx50 deletion and calpain 3 disruption were generated, and the growth defect and severity of cataracts were analyzed.
α8Cx50 and Calpain 3 double knockout mice were generated in the 129/C57 mixed background. To analyze the influence of calpain 3 disruption on the observed phenotype, postnatal lens growth, lens clarity, crystallin solubility, western blot analysis of major membrane proteins including MP 18, and lens histology were determined and compared between WT, α8Cx50 KO, CAPN3 KO and α8Cx50/CAPN3 dKO mice.
Calpain 3 disruption prevented cataractogenesis in α8Cx50/CAPN3 dKO mice (no cataract at least up to 9 months), but did not prevent lens growth deficiency. Calpain 3 disruption also differentially altered the solubility of crystallin proteins. Most interestingly, western blot analysis of lens homogenates for αB crystallin indicated that there were cleavage fragments of the αB crystallin that were unique to the α8Cx50(-/-) and α3Cx46(-/-) mice. However, while αB crystallin cleavage was detected in the lenses of dKO mice, the smallest cleaved form of the αB crystallin was not detected. Furthermore, quantitative western blot analysis indicated that the total amount of MP18 membrane protein were increased in α8Cx50(-/-) and α8Cx50/CAPN3 dKO mice compared to WT and calpain 3 KO mice.
These data show that intrinsic properties of α8Cx50 are required for cellular growth, and calpain 3 disruption prevents cataractogenesis in α8Cx50/Calpain 3 double KO mice. The cleavage of αB crystallin may be involved in the cataract formation in α8Cx50(-/-) mice.
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