Abstract
Progressive retinal atrophy (PRA) in dogs, the canine equivalent of retinitis pigmentosa (RP) in humans, is characterised by vision loss due to degeneration of the photoreceptor cells in the retina, eventually leading to complete blindness. It affects more than 100 dog breeds, and is caused by numerous mutations. RP affects 1 in 4000 people in the Western world and 70% of causal mutations remain unknown. Canine diseases are natural models for the study of human diseases and are becoming increasingly useful for the development of therapies in humans. One variant, prcd-PRA, only accounts for a small proportion of PRA cases in the Golden Retriever (GR) breed. Using genome-wide association with 27 cases and 19 controls we identified a novel PRA locus on CFA37 (praw = 1.94×10−10, pgenome = 1.0×10−5), where a 644 kb region was homozygous within cases. A frameshift mutation was identified in a solute carrier anion exchanger gene (SLC4A3) located within this region. This variant was present in 56% of PRA cases and 87% of obligate carriers, and displayed a recessive mode of inheritance with full penetrance within those lineages in which it segregated. Allele frequencies are approximately 4% in the UK, 6% in Sweden and 2% in France, but the variant has not been found in GRs from the US. A large proportion of cases (approximately 44%) remain unexplained, indicating that PRA in this breed is genetically heterogeneous and caused by at least three mutations. SLC4A3 is important for retinal function and has not previously been associated with spontaneously occurring retinal degenerations in any other species, including humans.
Highlights
Retinitis pigmentosa (RP) is the collective name for a group of inherited human retinal disorders that leads to progressive loss of vision in approximately 1 in 4000 people [1,2,3]
Several forms of progressive retinal atrophy (PRA) are present in the Golden Retriever (GR), including the prcd variant, but this mutation does not account for the majority of cases, in Europe
Using a genome-wide association (GWA) analysis approach, we have identified a novel candidate variant in the SLC4A3 gene that is likely to represent a major susceptibility locus for PRA in the GR
Summary
Retinitis pigmentosa (RP) is the collective name for a group of inherited human retinal disorders that leads to progressive loss of vision in approximately 1 in 4000 people [1,2,3]. Rod photoreceptor cells are predominantly affected and clinical symptoms typically include night blindness and loss of peripheral vision. With disease progression the cones degenerate resulting in central vision loss and eventually complete blindness is possible. Mutations in these genes currently only account for approximately 30% of recessive RP cases. In animals inherited and progressive retinal diseases are commonly referred to as progressive retinal atrophy (PRA) and as in humans PRA is characterised by progressive retinal degeneration resulting in loss of vision. Several diseasecausing genes have been reported for some forms of PRA [7,8,9,10,11,12,13,14,15,16], but many remain undefined
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