Mutations in theCRB1gene 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. MouseCrb1knockout retinas show a mild phenotype limited to the inferior quadrant, whereasCrb2knockout retinas display a severe degeneration throughout the retina mimicking the phenotype observed in RP patients associated withCRB1mutations.Crb1Crb2double mutant retinas have severe developmental defects similar to the phenotype observed in LCA patients associated withCRB1mutations. Therefore,CRB2is a candidate modifying gene of humanCRB1-related retinal dystrophy. In this study, we studied the cellular localization of CRB1 and CRB2 in human retina and tested the influence of theCrb2gene allele onCrb1-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 ofCrb2in heterozygoteCrb1+/−retinas induced a mild retinal phenotype, but in homozygoteCrb1knockout mice lead to an early and severe phenotype limited to the entire inferior retina. Our data provide mechanistic insight forCRB1-related LCA and RP.