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Elucidating the Genetic Basis of Canine Progressive Retinal Atrophies in Several Breeds of Dog



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Hitti-Malin, Rebekkah 


Canine progressive retinal atrophies (PRA) are a group of hereditary diseases characterised by rod and cone photoreceptor cell death in the retina. This study sought to elucidate novel PRA-associated variants of distinct forms of PRA in three breeds of dog: the Lhasa Apso (LA), Giant Schnauzer (GS) and Shetland Sheepdog (SS). A genome-wide association study identified a 1.3 Mb disease-associated region on canine chromosome 33 in LA dogs. Whole genome sequencing (WGS) analysis of a PRA-affected LA revealed a long interspersed nuclear element-1 (LINE-1) insertion in the predicted promoter region of the retinal candidate gene, IMPG2. Validation of the LINE-1 insertion determined it segregated with disease and was likely to be private to LA dogs. Comprehensive WGS analyses alone were utilised to determine PRA-associated mutations in a family of GS dogs, and in a single SS. For the GS breed, WGS was performed on two affected siblings and both non-affected parents. Successive filtering, for autosomal recessive deleterious variants, against 568 canine genomes identified a single nucleotide variant (SNV) in the gene encoding NECAP endocytosis associated 1 (NECAP1): c.544G>A (p.G182R). Screening 5,130 canids revealed only the three PRA-affected GS were homozygous for the SNV, yet heterozygotes were identified in the GS breed and in other breeds of German ancestry. NECAP1 has not previously been associated with retinal degeneration; however, these findings, in parallel with known gene function, indicate NECAP1 should be considered as a strong candidate for retinal degeneration research in other species. Following WGS analysis of the single SS against 176 controls of other breeds, a c.1222G>C (p.A408P) SNV in the Bardet-Biedl syndrome 2 gene (BBS2) was identified. In addition to PRA, homozygotes exhibited features including an upturned nose, unusual coat and dental defects, proposing a novel syndromic form of canine PRA. This research has elucidated three novel PRA-associated mutations for which diagnostic DNA tests have been developed, offering breeders the opportunity to avoid producing PRA-affected dogs. Since PRA shares clinical features to human retinitis pigmentosa (RP) and other phenotypically similar retinal diseases, this study may offer novel insights for consideration in human as well as canine retinal degeneration research and gene therapies.





Sargan, David
Mellersh, Cathryn


Canine, Progressive retinal atrophy, Retinal degeneration, PRA


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge