CRB1rd8 mutation influences the age-related macular degeneration phenotype of NRF2 knockout mice and favors choroidal neovascularization

Abstract

Purpose: We examined the influence of retinal degeneration 8 (rd8) mutation of crumbs homolog 1 (CRB1) gene on age-related macular degeneration (AMD) phenotype in nuclear factor E2-related factor 2 knock out (NRF2^-/-) mouse model.

Methods: CRB1^rd8 mutation genotype was determined by polymerase chain reaction from tail clips in 73 NRF2^-/- mice originating from C57BL/6J background on mixed C57BL/6J and C57BL/6N ancestry. The clinical grade of AMD-like fundus alterations was determined by funduscopy, optical coherence tomography (OCT) and fluorescein angiography (FLA) at the age of 9 or 12 months.

Results: Twelve NRF2^-/- mice were wildtype CRB1^+/+, 61 NRF2^-/- were homozygous CRB1^rd8/rd8. NRF2^-/-CRB1^rd8/rd8 mice had a significantly higher probability to show an advanced grade (grade 4 and 5) of AMD-like fundus alterations known to appear in NRF2^-/- mice. Choroidal neovascularization (CNV) was only detected in NRF2^-/-CRB1^rd8/rd8 homozygous mice.

Conclusions: Homozygous CRB1^rd8/rd8 mutation is common in commercial vendor mice strains of C57BL/6J origin if partly on C57BL/6N ancestry. The mutation has an influence on the extent of AMD-like retinal alterations in NRF2^-/- mice and favors CNV formation.

Keywords: Age related macular degeneration (AMD); Choroidal neovascularization (CNV); Crumbs homolog 1 (CRB1); Nuclear factor erythroid 2-related factor 2 (NRF2); Retinal degeneration 8 (rd8).