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Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens

Abstract

The eye lens is composed of fibre cells, which develop from the epithelial cells on the anterior surface of the lens1,2,3. Differentiation into a lens fibre cell is accompanied by changes in cell shape, the expression of crystallins4 and the degradation of cellular organelles5,6. The loss of organelles is believed to ensure the transparency of the lens, but the molecular mechanism behind this process is not known. Here we show that DLAD (‘DNase II-like acid DNase’7, also called DNase IIβ8) is expressed in human and murine lens cells, and that mice deficient in the DLAD gene are incapable of degrading DNA during lens cell differentiation—the undigested DNA accumulates in the fibre cells. The DLAD-/- mice develop cataracts of the nucleus lentis, and their response to light on electroretinograms is severely reduced. These results indicate that DLAD is responsible for the degradation of nuclear DNA during lens cell differentiation, and that if DNA is left undigested in the lens, it causes cataracts of the nucleus lentis, blocking the light path.

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Figure 1: Expression of DLAD mRNA in the lens.
Figure 2: Targeted disruption of the DLAD gene.
Figure 3: No breakdown of nuclear DNA in DLAD-/- lens fibres.
Figure 4: Development of cataract in DLAD-/- mice.

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Acknowledgements

We thank E. Kominami for providing us with rabbit antibody against the subunit β of mitochondrial ATP synthase. We thank K. Miwa for cloning of mouse DLAD gene, Y. Seto for maintaining the mice, and M. Fujii and M. Harayama for secretarial assistance. This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports, and Culture in Japan.

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Correspondence to Shigekazu Nagata.

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Nishimoto, S., Kawane, K., Watanabe-Fukunaga, R. et al. Nuclear cataract caused by a lack of DNA degradation in the mouse eye lens. Nature 424, 1071–1074 (2003). https://doi.org/10.1038/nature01895

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