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Molecular and Cellular Biology, February 2007, p. 1433-1441, Vol. 27, No. 4
0270-7306/07/$08.00+0     doi:10.1128/MCB.01037-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Retinal Degeneration and Ionizing Radiation Hypersensitivity in a Mouse Model for Cockayne Syndrome

Theo G. M. F. Gorgels,^1,2, Ingrid van der Pluijm,^1, Renata M. C. Brandt,¹ George A. Garinis,¹ Harry van Steeg,³ Gerard van den Aardweg,¹ Gerard H. Jansen,⁴ Jan M. Ruijter,⁵ Arthur A. B. Bergen,^2,6 Dirk van Norren,⁷ Jan H. J. Hoeijmakers,¹ and Gijsbertus T. J. van der Horst^1*

MGC Department of Genetics, Center of Biomedical Genetics, Erasmus University Medical Center, Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands,¹ Department of Molecular Ophthalmogenetics, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands,² Laboratory of Toxicology, Pathology, and Genetics (TOX), National Institute of Public Health and the Environment, P.O. Box 1, 3720 BA Bilthoven, The Netherlands,³ Department of Pathology and Laboratory Medicine, Ottawa Hospital, Ottawa, Canada,⁴ Department of Anatomy and Embryology, Academic Medical Centre, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands,⁵ Department of Clinical Genetics, Amsterdam Medical Center, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands,⁶ Department of Ophthalmology, University Medical Center Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands⁷

Received 9 June 2006/ Returned for modification 5 July 2006/ Accepted 17 November 2006

Mutations in the CSB gene cause Cockayne syndrome (CS), a DNA repair disorder characterized by UV sensitivity and severe physical and neurological impairment. CSB functions in the transcription-coupled repair subpathway of nucleotide excision repair. This function may explain the UV sensitivity but hardly clarifies the other CS symptoms. Many of these, including retinopathy, are associated with premature aging. We studied eye pathology in a mouse model for CS. Csb^m/m mice were hypersensitive to UV light and developed epithelial hyperplasia and squamous cell carcinomas in the cornea, which underscores the importance of transcription-coupled repair of photolesions in the mouse. In addition, we observed a spontaneous loss of retinal photoreceptor cells with age in the Csb^m/m retina, resulting in a 60% decrease in the number of rods by the age of 18 months. Importantly, when Csb^m/m mice (as well as Csa^–/– mice) were exposed to 10 Gy of ionizing radiation, we noticed an increase in apoptotic photoreceptor cells, which was not observed in wild-type animals. This finding, together with our observation that the expression of established oxidative stress marker genes is upregulated in the Csb^m/m retina, suggests that (endogenous) oxidative DNA lesions play a role in this CS-specific premature-aging feature and supports the oxidative DNA damage theory of aging.

Published ahead of print on 4 December 2006.

T.G.M.F.G. and I.V.D.P. contributed equally.

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