Increased susceptibility to light damage in an arrestin knockout mouse model of Oguchi disease (stationary night blindness)

PURPOSE To determine whether constitutive signal flow arising from defective rhodopsin shut-off causes photoreceptor cell death in arrestin knockout mice. METHODS The retinas of cyclic-light-reared, pigmented arrestin knockout mice and wild-type littermate control mice were examined histologically for photoreceptor cell loss from 100 days to 1 year of age. In separate experiments, to determine whether constant light would accelerate the degeneration in arrestin knockout mice, these animals and wild-type control mice were exposed for 1, 2, or 3 weeks to fluorescent light at an intensity of 115 to 150 fc. The degree of photoreceptor cell loss was quantified histologically by obtaining a mean outer nuclear layer thickness for each animal. RESULTS In arrestin knockout mice maintained in cyclic light, photoreceptor loss was evident at 100 days of age, and it became progressively more severe, with less than 50% of photoreceptors surviving at 1 year of age. The photoreceptor degeneration appeared to be caused by light, because when these mice were reared in the dark, the retinal structure was indistinguishable from normal. When exposed to constant light, the retinas of wild-type pigmented mice showed no light-induced damage, regardless of exposure duration. By contrast, the retinas of arrestin knockout mice showed rapid degeneration in constant light, with a loss of 30% of photoreceptors after 1 week of exposure and greater than 60% after 3 weeks of exposure. CONCLUSIONS The results indicate that constitutive signal flow due to arrestin knockout leads to photoreceptor degeneration. Excessive light accelerates the cell death process in pigmented arrestin knockout mice. Human patients with naturally occurring mutations that lead to nonfunctional arrestin and rhodopsin kinase have Oguchi disease, a form of stationary night blindness. The present findings suggest that such patients may be at greater risk of the damaging effects of light than those with other forms of retinal degeneration, and they provide an impetus to restrict excessive light exposure as a protective measure in patients with constitutive signal flow in phototransduction.

[1]  Joe G. Hollyfield,et al.  Retinal degeneration : experimental and clinical studies , 1985 .

[2]  T. Dryja,et al.  Transgenic mice with a rhodopsin mutation (Pro23His): A mouse model of autosomal dominant retinitis pigmentosa , 1992, Neuron.

[3]  Sidney Lerman,et al.  Radiant Energy and the Eye , 1979 .

[4]  D. Organisciak,et al.  Retinal light damage: Practical and theoretical considerations , 1994, Progress in Retinal and Eye Research.

[5]  M. Tamai,et al.  Arrestin gene mutations in autosomal recessive retinitis pigmentosa. , 1998, Archives of ophthalmology.

[6]  W. Noell,et al.  Possible mechanisms of photoreceptor damage by light in mammalian eyes , 1980, Vision Research.

[7]  M. Lavail,et al.  Protection from light damage by ocular pigmentation: analysis using experimental chimeras and translocation mice. , 1987, Experimental eye research.

[8]  M. Lavail,et al.  Influence of eye pigmentation and light deprivation on inherited retinal dystrophy in the rat. , 1975, Experimental eye research.

[9]  R. Anderson,et al.  A comparative study of methods of photoreceptor morphometry. , 1991, Investigative ophthalmology & visual science.

[10]  T. Dryja,et al.  Missense mutation in the gene encoding the α subunit of rod transducin in the Nougaret form of congenital stationary night blindness , 1996, Nature Genetics.

[11]  M. Lavail,et al.  Strain differences in sensitivity to light-induced photoreceptor degeneration in albino mice. , 1987, Current eye research.

[12]  C. Sung,et al.  The Cytoplasmic Tail of Rhodopsin Acts as a Novel Apical Sorting Signal in Polarized MDCK Cells , 1998, The Journal of cell biology.

[13]  M. Tso,et al.  Amelioration of photic injury in rat retina by ascorbic acid: a histopathologic study. , 1985, Investigative ophthalmology & visual science.

[14]  S. Sanyal,et al.  Development and degeneration of retina inrds mutant mice: Effects of light on the rate of degeneration in albino and pigmented homozygous and heterozygous mutant and normal mice , 1986, Vision Research.

[15]  J. Lisman,et al.  Photoreceptor degeneration in vitamin A deprivation and retinitis pigmentosa: the equivalent light hypothesis. , 1993, Experimental eye research.

[16]  D. Oprian,et al.  Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness , 1993, Nature Genetics.

[17]  D. Oprian,et al.  Rhodopsin mutation G90D and a molecular mechanism for congenital night blindness , 1994, Nature.

[18]  Denis A. Baylor,et al.  Prolonged photoresponses in transgenic mouse rods lacking arrestin , 1997, Nature.

[19]  J. Lisman,et al.  Support for the equivalent light hypothesis for RP , 1995, Nature Medicine.

[20]  T. Dryja,et al.  Constitutive activation of phototransduction by K296E opsin is not a cause of photoreceptor degeneration. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[21]  P. Sternberg,et al.  Retinal phototoxicity. , 1999, International ophthalmology clinics.

[22]  M. Lavail,et al.  Light-induced retinal degeneration in albino mice and rats: strain and species differences. , 1987, Progress in clinical and biological research.

[23]  T. Williams,et al.  The role of ocular pigmentation in protecting against retinal light damage , 1980, Vision Research.

[24]  M. Tamai,et al.  A homozygous 1–base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese , 1995, Nature Genetics.

[25]  D. Baylor,et al.  A rhodopsin gene mutation responsible for autosomal dominant retinitis pigmentosa results in a protein that is defective in localization to the photoreceptor outer segment , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[26]  C. Graymore.  Biochemistry of the retina , 1966 .

[27]  M. Silverman,et al.  Photoreceptor transplants increase host cone survival in the retinal degeneration (rd) mouse. , 1997, Ophthalmic research.

[28]  M. Naash,et al.  Expression of a mutant opsin gene increases the susceptibility of the retina to light damage , 1997, Visual Neuroscience.

[29]  D. Oprian,et al.  Constitutively active mutants of rhodopsin , 1992, Neuron.

[30]  M. Lavail,et al.  Genetic regulation of light damage to photoreceptors. , 1987, Investigative ophthalmology & visual science.

[31]  M. Alpern,et al.  Dark-light: model for nightblindness from the human rhodopsin Gly-90-->Asp mutation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J B Hurley,et al.  Abnormal photoresponses and light-induced apoptosis in rods lacking rhodopsin kinase. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[33]  David J. Baylor,et al.  Mechanisms of rhodopsin inactivation in vivo as revealed by a COOH-terminal truncation mutant , 1995, Science.

[34]  M. Lavail,et al.  Increased susceptibility to constant light in nr and pcd mice with inherited retinal degenerations. , 1999, Investigative ophthalmology & visual science.

[35]  T. Williams,et al.  A Parametric Study of Retinal Light Damage in Albino and Pigmented Rats , 1980 .

[36]  S. Brodie.  Degenerative retinal disorders: Clinical and laboratory investigations , 1988 .

[37]  T. Dryja,et al.  Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness , 1997, Nature Genetics.