Abstract
Inherited retinal dystrophies generally lead to severe visual impairment early in life. Most genes involved in retinal dystrophies are expressed exclusively or predominantly in the retina or the RPE. To identify candidate genes for inherited retinal dystrophies, we isolated novel genes expressed preferentially in the retina or the RPE through suppression subtractive hybridization. We characterized the complete gene structure of one of these genes, CRB1, and showed that it is involved in RP12, a severe form of autosomal recessive retinitis pigmentosa (RP). We also identified CRB1 mutations in 7 (13%) of 52 patients with Leber congenital amaurosis (LCA), which causes blindness from birth. In addition, we showed that CRB1 mutations are an important risk factor for the development of Coats-like exudative vasculopathy, a relatively rare complication of RP. CRB1 is homologous to Drosophila Crumbs protein, which is essential for establishing and maintaining apico-basal polarity in epithelial cells. The cytoplasmic domain of Crumbs organizes an intracellular protein scaffold that defines the localization of the zonula adherens. Through rescuing and overexpression studies in Drosophila we showed that the cytoplasmic domains of CRB1 and Crumbs are functionally related between these distant species. This suggests that CRB1 may function as an anchor for an intracellular protein complex in the retina, and that it may be involved in the establishing and maintaining polarity of retinal cells. By in situ hybridizations in mice we showed that Crb1 is expressed exclusively in the eye and the brain. In the eye Crb1 expression is confined to the outer nuclear layer, the photoreceptors, some nuclei of the inner nuclear layer and the iris
