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M. Danciger, L. Handschumacher, D. Yasumura, M.T. Matthes, M.M. LaVail, H. Yang; The C57BL/6–c2J Albino Background Reduces the Severity of Light–Sensitive rd3 Disease but Not by Means of the RPE65 Met450 Variant . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3257.
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© ARVO (1962-2015); The Authors (2016-present)
Previously, we showed that rd3 disease progresses more slowly in the C57BL/6–c2J (B6al) albino mouse background than in BALB/c (BALB) and even more slowly in pigmented B6 retinas. In addition, we and others have shown that the met450 variant of RPE65 carried by B6al reduces constant light–induced retinal damage relative to the leu450 variant carried by BALB. Since rd3 disease is exacerbated by light, we asked if met450 also protects against this autosomal recessive retinal degeneration.
Starting with Rb4Bnr rd3/rd3 (a mixed strain background), the rd3 allele was bred into BALB or into B6al to N10. Starting with B6al, the met450 allele was bred into BALB to N10. The BALB congenics were crossed in such a way as to produce progeny that were N10, BALB, rd3/rd3 and met/met, met/leu or leu/leu. At P70, when rd3/rd3 retinal degeneration is significantly greater in BALB than B6al, the thickness of the outer nuclear layer (ONL) was measured in 12 places in the central superior, posterior retina and averaged.
At P70, control BALB rd3/rd3 (n=18) and B6al rd3/rd3 (n=22) ONL averaged 11.3 µm and 21.1 µm, respectively (P = 2 x 10–9; t–test). ONLs for N10, BALB rd3/rd3 met/met (n=7), leu/leu (n=9) and met/leu (n=12) retinas were 11.3, 10.7 and 13.0 µm, respectively. There were no significant differences among these values. After exposure to constant light of 70–150 ft–c. for 6 days, BALB(leu/leu) rd3/rd3 and B6al(met/met) rd3/rd3 retinas showed similar losses of ONL thickness. On the other hand, age–matched wild–type BALB mice lost significantly more ONL than B6al mice after this light exposure regimen.
Although rd3 disease is exacerbated by light and progresses more slowly in B6al than BALB, and the met450 variant of RPE65 protects the B6al retina from constant light induced damage, rd3 disease was not influenced by the met450 modifier because: 1) there was no significant difference in the degree of retinal degeneration among BALB rd3/rd3 mice with RPE65met/met, met/leu or leu/leu, and 2) both B6al rd3/rd3 and BALB rd3/rd3 retinas lost comparable amounts of ONL after light exposure. Therefore, just as in the case of age–related retinal degeneration, the RPE65met450 modifier is not responsible for the significant difference in rd3 disease between these two strains. This shows that there are new, yet to be discovered, gene modifiers that influence the course of monogenic inherited retinal degenerations.
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