Insight Into Sight: Deciphering The Heterogeneity Of Hereditary Retinal Degeneration In The Canine Population

As of October 2013, around 285 million people are visually impaired worldwide. For an important subset of these, this visual impairment is genetic. That is, they have inherited mutant genes that prevent sight by affecting an element critical for vision. Understanding the genetic basis of these diseases offers insight into the mechanisms involved in photoreceptor development, function, and maintenance as well as significant potential for therapies addressed at cure or prevention. In recent decades, understanding of the cellular and molecular mechanisms of vision has expanded dramatically. In particular, many genes have been discovered that are vital for normal function of the retina, the delicate, multilayered, light-sensitive layer at the back of the eye that connects by the optic nerve to the brain. Retinitis pigmentosa (RP) is a subgroup of inherited eye diseases causing retinal degeneration. In the U.S.A alone, an estimated 100,000 people have inherited RP, either as an autosomal dominant, autosomal recessive, or X-linked disease. Among these, about 50% of cases of autosomal recessive RP cannot be explained by so far identified genes, and for many of the known genes, their role in vision is unclear. The dog also suffers from inherited eye diseases. The canine disease homolog of RP is referred to as Progressive Retinal Atrophy (PRA). Because of the unique population structure and genetic differences within and among the various breeds of dogs, this animal model offers a remarkable tool for discovering genetic mechanisms in vision and serves as a therapeutic model for potential gene therapy. In the present work, we have investigated nine different canine diseases (OSD, erd, prcd, cd, crd1, crd2, crd3, Basenji PRA, and Italian Greyhound PRA), characterized them, discovered the genes responsible for their phenotype, and determined the broad spectrum of breeds affected by them. These studies utilized classical genetic methods such as linkage and candidate gene approaches, and were expanded to employ Linkage Disequilibrium and Association Studies. We discovered two novel genes, PRCD and STK38L, both of which cause PRA in dogs, but had not previously been recognized as involved in vision or visual disorders, and thereby identified novel pathways critical for vision, as well as genes potentially responsible for human RP. We also identified novel mutations in six known genes (COL9A2, COL9A3, ADAM9, PDE6B, IQCB1, and SAG) that cause five different diseases, and thereby established new animal models for potential gene therapy in their human counterparts. We identified the exact deletion points of the cd disease in a broad spectrum of breeds affected by this disease, showing that they are all inherited Identical By Descent (IBD). We discovered the potential involvement of a microRNA in retinal degeneration in the Italian greyhound PRA, the first such evidence in a large animal model, and the first suggestion that retinal degeneration can be caused by alteration in gene expression regulated by microRNA. We developed screening tests for all the above diseases so these diseases can be eliminated from affected breeding lines. We showed that, in the dog, pooled samples might be used for association studies, when research budgets are limited