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A Non-Stop S-Antigen Gene Mutation Is Associated with Late Onset Hereditary Retinal Degeneration in Dogs Orly Goldstein

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A Non-Stop S-Antigen Gene Mutation Is Associated with Late Onset Hereditary Retinal Degeneration in Dogs Orly Goldstein University of Pennsylvania ScholarlyCommons Departmental Papers (Vet) School of Veterinary Medicine 8-2013 A Non-Stop S-Antigen Gene Mutation Is Associated With Late Onset Hereditary Retinal Degeneration in Dogs Orly Goldstein Julie Ann Jordan Gustavo D. Aguirre University of Pennsylvania, [email protected] Gregory M. Acland Follow this and additional works at: https://repository.upenn.edu/vet_papers Part of the Veterinary Medicine Commons Recommended Citation Goldstein, O., Jordan, J., Aguirre, G. D., & Acland, G. M. (2013). A Non-Stop S-Antigen Gene Mutation Is Associated With Late Onset Hereditary Retinal Degeneration in Dogs. Molecular Vision, 18 1871-1884. Retrieved from https://repository.upenn.edu/ vet_papers/77 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/vet_papers/77 For more information, please contact [email protected]. A Non-Stop S-Antigen Gene Mutation Is Associated With Late Onset Hereditary Retinal Degeneration in Dogs Abstract Purpose: To identify the causative mutation of canine progressive retinal atrophy (PRA) es gregating as an adult onset autosomal recessive disorder in the Basenji breed of dog. Methods: Basenji dogs were ascertained for the PRA hep notype by clinical ophthalmoscopic examination. Blood samples from six affected cases and three nonaffected controls were collected, and DNA extraction was used for a genome-wide association study using the canine HD Illumina single nucleotide polymorphism (SNP) array and PLINK. Positional candidate genes identified within the peak association signal region were evaluated. Results: The highest -Log10(P) value of 4.65 was obtained for 12 single nucleotide polymorphisms on three chromosomes. Homozygosity and linkage disequilibrium analyses favored one chromosome, CFA25, and screening of the S-antigen (SAG) gene identified a non-stop mutation (c.1216T>C), which would result in the addition of 25 amino acids (p.*405Rext*25). Conclusions: Identification of this non-stop SAG mutation in dogs affected with retinal degeneration establishes this canine disease as orthologous to Oguchi disease and SAG-associated retinitis pigmentosa in humans, and offers opportunities for genetic therapeutic intervention. Keywords progressive retinal atrophy, PRA, mutation, canine, Basenji dogs, s-antigen Disciplines Medicine and Health Sciences | Veterinary Medicine This journal article is available at ScholarlyCommons: https://repository.upenn.edu/vet_papers/77 Molecular Vision 2013; 19:1871-1884 <http://www.molvis.org/molvis/v19/1871> © 2013 Molecular Vision Received 7 June 2013 | Accepted 23 August 2013 | Published 27 August 2013 A non-stop S-antigen gene mutation is associated with late onset hereditary retinal degeneration in dogs Orly Goldstein,1 Julie Ann Jordan,1 Gustavo D. Aguirre,2 Gregory M. Acland1 1Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, NY; 2School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA Purpose: To identify the causative mutation of canine progressive retinal atrophy (PRA) segregating as an adult onset autosomal recessive disorder in the Basenji breed of dog. Methods: Basenji dogs were ascertained for the PRA phenotype by clinical ophthalmoscopic examination. Blood samples from six affected cases and three nonaffected controls were collected, and DNA extraction was used for a genome-wide association study using the canine HD Illumina single nucleotide polymorphism (SNP) array and PLINK. Positional candidate genes identified within the peak association signal region were evaluated. Results: The highest -Log10(P) value of 4.65 was obtained for 12 single nucleotide polymorphisms on three chromo- somes. Homozygosity and linkage disequilibrium analyses favored one chromosome, CFA25, and screening of the S-antigen (SAG) gene identified a non-stop mutation (c.1216T>C), which would result in the addition of 25 amino acids (p.*405Rext*25). Conclusions: Identification of this non-stop SAG mutation in dogs affected with retinal degeneration establishes this canine disease as orthologous to Oguchi disease and SAG-associated retinitis pigmentosa in humans, and offers op- portunities for genetic therapeutic intervention. The gene S-antigen (SAG), also known as arrestin, culminating in blindness. This is a highly heterogeneous encodes a major soluble rod outer segment protein that exem- group of diseases with more than 12 different causative plifies a family of inhibitory proteins that bind tyrosine-phos- gene mutations already identified in canine populations, phorylated receptors to block their interaction with specific causing either early or late onset disease, and inherited as G-proteins to terminate a signal chain. In the retina, arrestin autosomal dominant, autosomal recessive, or X-linked [for a binds to activated rhodopsin [1] in rod outer segments, to review, see 13]. These canine mutations result in phenotypes hinder G-protein binding and quench rhodopsin activity [2,3]. resembling orthologous human diseases and provide valuable Mutations in this gene in humans have been associated with large animal models for studying the molecular basis of the Oguchi disease, a rare form of autosomal recessive stationary diseases, and for preclinical trials of potential therapies. night blindness (HGMD). This disease has an unusual but In the Basenji breed, the adult onset of PRA was characteristic clinical feature, the Mizuo-Nakamura phenom- observed, with initial visual loss in dim light (night blind- enon, in which an unusual golden-yellow discoloration of the ness), which gradually progressed to total blindness. Initial fundus disappears in the dark-adapted condition and reap- visual loss affects the peripheral visual field, but unless the pears shortly after exposure to light [4]. Patients with Oguchi dog is used for high visual performance tasks such as agility disease usually have night blindness but normal color vision work, the reduction in the visual field (tunnel vision) may not and normal cone function [5,6]. Patients exhibiting Oguchi be apparent. Despite tunnel vision and night blindness, many disease may later develop retinitis pigmentosa (RP), and in Basenjis affected with PRA retain adequate forward daylight other cases, the presence of RP can mask signs of Oguchi vision for many years, sometimes for their entire natural disease [7-12]. life. This phenotype highly resembles progressive rod-cone Progressive retinal atrophy (PRA) comprises a group degeneration (prcd), late onset retinal degeneration affecting of genetically inherited diseases affecting dogs of various multiple breeds caused by a point mutation in the PRCD gene breeds. Similar to RP in humans, PRA is characterized by [14]. A complementary breeding test for dogs affected with photoreceptor degeneration causing progressive vision loss, prcd excluded allelism between these two similar diseases [15], and this has been confirmed with PRCD genotyping. Correspondence to: Orly Goldstein, Baker Institute for Animal Complicating this broadly recognizable clinical phenotype Health, Cornell University College of Veterinary Medicine, Ithaca, has been considerable heterogeneity in the disease manifesta- NY 14853; Phone: (607) 256-5691; FAX: (607) 256-5608; email: tion, and uncertainty about whether this clinical heterogeneity [email protected] represented a single protean disorder or an underlying genetic 1871 Molecular Vision 2013; 19:1871-1884 <http://www.molvis.org/molvis/v19/1871> © 2013 Molecular Vision heterogeneity. This problem has been further complicated by Phenotypic evaluation of study dogs: Ascertainment of the extremely small gene pool of Basenjis in the American disease phenotype was based entirely on indirect ophthal- breeding population and the multiple inbreeding loops moscopic examination by board-certified veterinary ophthal- apparent in pedigree analysis. mologists. In the minority of cases, the ophthalmoscopic Linkage disequilibrium (LD) enables genome-wide diagnosis was confirmed with clinical electroretinography. association mapping in populations even when the extended The cases studied in the present report include only dogs pedigree information normally required for linkage analysis examined and diagnosed by either or both of two of the is either incomplete or missing entirely. Furthermore, the authors (GMA, GDA), although in several cases the initial development of genome-wide single nucleotide polymorphism diagnostic examination was previously performed by other (SNP) chip arrays has made such mapping widely available veterinarians. for humans and several other species, including the dog. In Genome-wide association study: Of the 19 purebred Basenji humans, mapping has been particularly successful in isolated dogs diagnosed clinically as affected with PRA, six were populations [16-20]. In the broader canine population, each selected as cases for association analysis, based on confi- breed comprises such a genetically isolated population, with dence in the disease ascertainment (dogs affected with stage extensive LD blocks, making the association approach attrac- II PRA), consistency of the disease phenotype among the tive for mapping traits and disease-causative genes [21-25]. selected dogs, pedigree information supporting autosomal In this study, we report a genome-wide association recessive inheritance identical by descent (IBD), and choosing study (GWAS) to map a specific form of PRA in the Basenji the least closely related set of dogs affected with PRA avail- breed of
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