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A Frameshift Mutation in Golden Retriever Dogs with Progressive Retinal Atrophy Endorses SLC4A3 as a Candidate Gene for Human Retinal Degenerations

Downs, LM; Wallin-Håkansson, B; Boursnell, M; Marklund, S; Hedhammar, Å; Truvé, K; Hübinette, L; ... Mellersh, CS; + view all (2011) A Frameshift Mutation in Golden Retriever Dogs with Progressive Retinal Atrophy Endorses SLC4A3 as a Candidate Gene for Human Retinal Degenerations. PLoS ONE , 6 (6) , Article e21452. 10.1371/journal.pone.0021452. Green open access

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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.

Type: Article
Title: A Frameshift Mutation in Golden Retriever Dogs with Progressive Retinal Atrophy Endorses SLC4A3 as a Candidate Gene for Human Retinal Degenerations
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0021452
Publisher version: http://dx.doi.org/10.1371/journal.pone.0021452
Language: English
Additional information: © 2011 Downs et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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/1409154
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