According to the 2014 National Health Survey, 22.5 million people in the US suffer from vision loss or blindness from many causes, including heritable retinal disorders, for which effective treatments are generally unavailable. CRB1 variants cause heritable retinal degenerative phenotypes ranging from Leber congenital amaurosis, characterized by congenital or early-onset blindness, to retinitis pigmentosa, a more slowly progressive disease. CRB1 RP variants are often associated with unique disease features, such as retinal telangiectasia with or without exudative retinal detachment (Coat's disease), a loss of RPE pigmentation except near arterioles (preservation of para-arteriolar RPE or PPRPE), pigment paravenous chorioretinal atrophy, cone-rod dystrophy, nanophthalmos with optic disc drusen, and macular dystrophic disease. Limited evidence for genotype-phenotype correlations in patients bearing CRB1 mutations has been detected. This suggests that interactions of mutant CRB1 with either environmental factors or genetic modifiers are the likely cause of the variability in disease phenotypes observed. In this proposal, we will specifically address the genetic complexities underlying CRB1-associated disease. Through a sensitized chemical mutagenesis screen, we have identified 12 novel mouse models bearing epistatic genetic modifiers associated with the Crb1rd8 mutation. These models on defined genetic backgrounds, raised in controlled environments will allow us to answer the following questions: 1) What are the genetic modifiers that interact with Crb1rd8 to cause the clinical phenotypes observed including retinal dysplasia, reduction in visual acuity and diminished electroretinographic response? 2) What cell types contribute to the disease phenotypes? 3) What are the pathogenic mechanisms that are induced by the genetic modifiers that lead to these phenotypes? 4) Can shared mechanisms be identified that might serve as a blueprint for future therapeutic intervention to delay, prevent, or reverse the disease? The goal of this proposal is to determine the molecular basis of the genetic modifiers and the pathogenic mechanisms underlying the disease phenotypes to which they contribute. These studies address a critical unmet need for developing effective therapies that can target the pre-symptomatic stage to prevent, delay onset or decrease severity of the disease. Animal models serve an important and unique role to further our understanding of the genetic underpinnings of disease and as a resource to examine tissue pathology, and to perform pre-clinical therapeutic tests that cannot be readily conducted in humans.

Public Health Relevance

There is an increasing recognition that the variability in human diseases caused by mutations within a single gene are influenced by genetic modifiers, which may alter disease onset, severity and clinical appearance. Identification of these modifiers promises to deepen our understanding of pathogenic mechanisms, yield new potential targets for therapeutic intervention, and enhance the use of precision medicine to improve treatments. In this application, we focus on the pathogenic mechanisms that underlie ocular disease phenotypes in CRB1- associated modifiers.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Shen, Grace L
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Jackson Laboratory
Bar Harbor
United States
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Kong, Yang; Naggert, J├╝rgen K; Nishina, Patsy M (2018) The Impact of Adherens and Tight Junctions on Physiological Function and Pathological Changes in the Retina. Adv Exp Med Biol 1074:545-551
Chang, Bo; FitzMaurice, Bernard; Wang, Jieping et al. (2018) Spontaneous Posterior Segment Vascular Disease Phenotype of a Mouse Model, rnv3, Is Dependent on the Crb1rd8 Allele. Invest Ophthalmol Vis Sci 59:5127-5139