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Jan Tode, Elisabeth Richert, Alexa Klettner, Claus Christian von der Burchard, Stefan Otto Johannes Koinzer, Johann Roider; CRB-1 rd8 Mutation Influences the Extent of AMD-like Retinal Alterations in NRF2 Knock Out Mice and Favors CNV Formation. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1989.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal degeneration (rd)8 mutation of the human crumbs homolog (CRB)-1 gene is known to lead to neuroretinal degeneration. Rd8 mutation may confound retinal alterations in age related macular degeneration (AMD) mouse models with implications for AMD research. We tested the influence of the rd8 mutation on AMD-like alterations in the nuclear factor E2-related factor 2 knock out (NRF2-/-) AMD mouse model.
CRB-1 rd8 mutation genotype was determined by PCR from tail clips in 73 NRF2-/- mice originating from a C57BL/6J background purchased from Jackson Labs (Bar Harbor, ME USA). All mice were examined by funduscopy and optical coherence tomography (OCT) at the age of 9 or 12 months to evaluate the clinical score of AMD-like retinal alterations. Clinical score was determined by the number of drusen (1= physiological retina, 2= 1-14 drusen, 3= 15-100 drusen, 4= >100 drusen, 5= any number of drusen + choroidal neovascularization [CNV], retinal pigment epithelium (RPE)/retinal atrophy or hemorrhage) in a standardized manner. CNV was confirmed by fluorescein angiography (FLA).
Twelve NRF2-/- mice were heterozygote for CRB-1 rd8 mutation, 61 were homozygote. Drusen could be seen by funduscopy in most eyes and verified by OCT. Seventeen % (4/24 eyes) of the heterozygote mice had a physiological retina, 3 % (4/122 eyes) of the homozygote mice. Forty six % (11/24 eyes) of the heterozygote mice had grade 2 AMD-like alterations vs. 29 % (35/122) of the homozygote. Twelve % (3/24 eyes) of the heterozygote mice had grade 4 AMD-like fundus alterations vs. 36 % (44/122 eyes) of the homozygote mice. No CNV was detected in heterozygote mice, but in 16 eyes of the homozygote, thus significant, CNV was detected and confirmed by OCT and FLA. The pattern of drusen distribution across the retina did not follow a certain scheme, it was homogenous. There was no significant difference in AMD score concerning age (9 or 12 months).
Homozygote CRB-1 rd8 mutation can be found in a commercial vendor mice strain of C57BL/6J origin. The mutation has an influence on the extent of AMD-like retinal alterations in NRF2-/- mice. However, these alterations may develop independently of rd8 mutation. CRB-1 rd8 mutation may favor CNV formation.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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