Abstract
Progressive retinal atrophy (PRA) in dogs is characterised by the degeneration of the photoreceptor cells of the retina, resulting in vision loss and eventually complete blindness. The condition affects more than 100 dog breeds and is known to be genetically heterogeneous between breeds. Around 19 mutations have now been identified that are associated with PRA in around 49 breeds, but for the majority of breeds the mutation(s) responsible have yet to be identified. Using genome-wide association with 22 Tibetan Spaniel PRA cases and 10 controls, we identified a novel PRA locus, PRA3, on CFA10 (praw = 2.01×10−5, pgenome = 0.014), where a 3.8 Mb region was homozygous within 12 cases. Using targeted next generation sequencing, a short interspersed nuclear element insertion was identified near a splice acceptor site in an intron of a provocative gene, FAM161A. Analysis of mRNA from an affected dog revealed that the SINE causes exon skipping, resulting in a frame shift, leading to a downstream premature termination codon and possibly a truncated protein product. This mutation segregates with the disease in 22 out of 35 cases tested (63%). Of the PRA controls, none are homozygous for the mutation, 15% carry the mutation and 85% are homozygous wildtype. This mutation was also identified in Tibetan Terriers, although our results indicate that PRA is genetically heterogeneous in both Tibetan Spaniels and Tibetan Terriers.
Highlights
Progressive retinal atrophy (PRA) in animals is the term used for a group of inherited retinal diseases characterised by progressive retinal degeneration resulting in loss of vision
Two single nucleotide polymorphisms (SNPs) markers 1.86 Mb apart (BICF2P729624 at 62.0 Mb and BICF2S23250878 at 63.86 Mb) were the most associated with PRA
Identity-by-state (IBS) clustering confirmed the presence of population stratification with a high genomic inflation factor, l = 1.69
Summary
Progressive retinal atrophy (PRA) in animals is the term used for a group of inherited retinal diseases characterised by progressive retinal degeneration resulting in loss of vision. Rod photoreceptor responses are lost first followed by cone photoreceptor responses [1]. While several disease-causing genes have been reported for some forms of PRA [3], many remain undefined. Retinitis Pigmentosa (RP), the human equivalent of PRA, is the collective name for a group of inherited human retinal disorders that lead to progressive loss of vision in approximately 1 in 4000 people [4,5,6]. As in PRA, rod photoreceptor cells are predominantly affected, resulting in clinical symptoms that typically include night blindness and loss of peripheral vision. At least 192 genes have been shown to cause a wide spectrum of retinal disease, including RP
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