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S.H. Tsang, M.L. Woodruff, C.K. Yamashita, W. Lee, S.P. Goff, P. Gouras, G.L. Fain, D.B. Farber; A New Animal Model of Congenital Stationary Night Blindness (CSNB) . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4515.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Many heredity retinal dystrophies manifest as retinitis pigmentosa (RP) or congenital stationary night blindness (CSNB). One of the initial symptoms of RP is night blindness, but the disease later progresses to apoptotic cell death and complete blindness. In contrast, CSNB features only nonprogressing night blindness without loss of cone (day light) vision. These 2 diseases can be caused by different mutations in the same gene, i.e. the ß subunit of cGMP phosphodiesterase (PDE). Individuals with CSNB in the "Rambusch pedigree" were found to have the His258Asn (Exon 4) mutation; a similar mutation has not been found in RP patients. Codon 258 is located in a conserved region of PDEß, between two non-catalytic cGMP binding domains, adjacent to the PDE-gamma interacting domain. Our purpose was to make an animal model carrying His258Asn in PDEß to investigate why this mutation does not lead to retinal degeneration. Methods: The murine opsin promoter was used to direct expression of wild-type PDEß and His258Asn PDEß transgenes to the photoreceptors. These constructs were injected into normal oocytes. The resulting founder mice were then crossed with rd1/rd1mice that lack PDEß to generate progeny that could only synthesize transgenic PDEß . Results: While rd1/rd1mice have severe photoreceptor degeneration resembling RP, His258Asn mice display features of CSNB, as diagnosed by morphological and physiological studies. The His258Asn mutant construct rescued the rd1/rd1retinal degeneration. However, the His258Asn increased the rate of cGMP hydrolysis, and slightly reduced the light sensitivity of rods. cGMP-PDE activity was 319.2 nmol x min-1 x nmol rhodopsin in the mutant animals compared with 130.1 nmol x min-1 x nmol rhodopsin in wild-type controls. The intensity response function of the rescued rods was shifted rightward by 0.25-0.5 log units. Conclusions: Comparison between rd1/rd1 and His258Asn PDEß mutant mice should allow the dissection of how different genetic, biochemical and physiological abnormalities in photoreceptor signaling lead to divergent phenotypes such as those of RP and CSNB. In His258Asn mice, higher than normal PDE activity may not be sufficient to close the cGMP gated channels and desensitize the rod photoreceptors. Analyses of possible compensatory mechanisms in response to the His258Asn genetic insult may allow the understanding of the plasticity of the photoresponse
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