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Molecular characterisation of canine progressive retinal atrophies.

Downs, LM; (2013) Molecular characterisation of canine progressive retinal atrophies. Doctoral thesis (PhD), UCL (University College London). Green open access

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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 breeds, and is known to be genetically heterogeneous between breeds. Fourteen genes have been identified that are associated with PRA in at least 45 breeds, but for the majority of breeds the mutation(s) responsible have yet to be identified. This project utilised a genome-wide association mapping approach followed by sequencing of candidate genes or associated loci to characterise the molecular basis of PRA in three breeds: Golden Retrievers (GR), Gordon Setters (GoS) and Tibetan Spaniels (TS). Homozygous recessive mutations in four genes were identified as disease causing: SLC4A3c.2601_2602insC and TTC8c.669delA in GRs (PRA-1 and PRA-2 respectively), C2ORF71c.3149_3150insC in GoSs (RCD4) and FAM161Ac.1758-15_1758-16ins238 in TSs (PRA-3). SLC4A3 is a novel retinal atrophy gene. Canine isoforms of each of the genes identified were confirmed by sequencing retinal messenger RNA. DNA genotyping tests for each of the mutations were used to determine disease allele frequencies in the affected breeds. PRA-1 and PRA-2 were found to be mainly restricted to the GR breed, with allele frequencies of 0.04 and 0.01 respectively. RCD4 and PRA-3, with allele frequencies of 0.36 and 0.15 respectively, were also identified as the cause of PRA in at least one other breed. While none of the SLC4A3 variants identified in DNA from 200 human patients with autosomal recessive retinal degeneration were considered to be disease-causing mutations, the gene remains a plausible candidate for rare forms of retinal degeneration in humans. This research has identified four new potential models for human retinal degeneration and has resulted in the development of diagnostic DNA tests for each of the canine diseases, which will facilitate the elimination of PRA from affected breeds.

Type: Thesis (Doctoral)
Qualification: PhD
Title: Molecular characterisation of canine progressive retinal atrophies.
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: PRA, Progressive retinal Atrophy
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/1409041
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