CRB2 acts as a modifying factor of CRB1-related retinal dystrophies in mice
Lucie P Pellissier1, Ditte M S Lundvig1, Naoyuki Tanimoto2
1Department of Neuromedical Genetics.
Abstract:
Mutations in the CRB1 gene lead to retinal dystrophies ranging from Leber congenital amaurosis (LCA) to early-onset retinitis pigmentosa (RP), due to developmental defects or loss of adhesion between photoreceptors and Müller glia cells, respectively. Whereas over 150 mutations have been found, no clear genotype-phenotype correlation has been established. Mouse Crb1 knockout retinas show a mild phenotype limited to the inferior quadrant, whereas Crb2 knockout retinas display a severe degeneration throughout the retina mimicking the phenotype observed in RP patients associated with CRB1 mutations. Crb1Crb2 double mutant retinas have severe developmental defects similar to the phenotype observed in LCA patients associated with CRB1 mutations. Therefore, CRB2 is a candidate modifying gene of human CRB1-related retinal dystrophy. In this study, we studied the cellular localization of CRB1 and CRB2 in human retina and tested the influence of the Crb2 gene allele on Crb1-retinal dystrophies in mice. We found that in contrast to mice, in the human retina CRB1 protein was expressed at the subapical region in photoreceptors and Müller glia cells, and CRB2 only in Müller glia cells. Genetic ablation of one allele of Crb2 in heterozygote Crb1(+/-) retinas induced a mild retinal phenotype, but in homozygote Crb1 knockout mice lead to an early and severe phenotype limited to the entire inferior retina. Our data provide mechanistic insight for CRB1-related LCA and RP.
Insights
Mutations in the CRB1 gene cause retinal dystrophies. The CRB2 gene influences these conditions, with its absence exacerbating CRB1-related Leber congenital amaurosis and retinitis pigmentosa in mice.
Area of Science:
- Ophthalmology
- Genetics
- Cell Biology
Background:
- Mutations in the CRB1 gene are linked to retinal dystrophies like Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP).
- Over 150 CRB1 mutations exist, but a clear genotype-phenotype correlation remains elusive.
- Mouse models show varying phenotypes for Crb1 and Crb2 knockouts, suggesting a modifying role for CRB2 in human CRB1-related retinal diseases.
Purpose of the Study:
- To investigate the cellular localization of CRB1 and CRB2 proteins in the human retina.
- To determine the influence of the CRB2 gene on CRB1-related retinal dystrophies using mouse models.
Main Methods:
- Immunohistochemical analysis of CRB1 and CRB2 protein localization in human retinal tissue.
- Generation and analysis of mouse models with specific Crb1 and Crb2 gene alterations (heterozygous and homozygous knockouts).
Main Results:
- In human retinas, CRB1 protein is localized to the subapical region of photoreceptors and Müller glia cells, while CRB2 is found only in Müller glia cells.
- Genetic ablation of one Crb2 allele in Crb1(+/-) mice induced a mild retinal phenotype.
- Complete Crb1 knockout in mice lacking Crb2 function resulted in an early-onset, severe retinal degeneration affecting the entire inferior retina.
Conclusions:
- CRB2 acts as a modifier gene in CRB1-related retinal dystrophies.
- The findings provide mechanistic insights into CRB1-related Leber congenital amaurosis and retinitis pigmentosa.
- Differential expression and function of CRB1 and CRB2 in human versus mouse retinas are highlighted.
