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A non-stop S-antigen gene mutation is associated with late onset hereditary retinal degeneration in dogs.

ABSTRACT: 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.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.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).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.

SUBMITTER: Goldstein O

PROVIDER: S-EPMC3762564 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A non-stop S-antigen gene mutation is associated with late onset hereditary retinal degeneration in dogs.

Goldstein Orly O Jordan Julie Ann JA Aguirre Gustavo D GD Acland Gregory M GM

Molecular vision 20130827

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 24019744

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Project description:A spontaneous frameshift mutation, c.3481delC, in the Crb1 gene is the underlying cause of dysplasia and retinal degeneration in rd8 mice. The rd8 mutation is found in C57BL/6N but not in C57BL/6J mouse sub-strains. The development of ocular pathology in single knockout Ccl2-/-, Cx3cr1-/- and in double knockout Ccl2-/-, Cx3cr1-/- mice raised on a C57BL/6 background has been reported to depend on the presence of a rd8 mutation. In this study, we investigated the influence of the rd8 mutation on the retinal pathology that we previously described in the late-onset retinal degeneration (L-ORD) mouse model with a heterozygous S163R mutation in the C1q-tumor necrosis factor-related protein-5Ctrp5+/- gene that was generated on a C57BL/6J background.Mouse lines carrying the Ctrp5 S163R and rd8 mutations (Ctrp5+/-;rd8/rd8), corresponding controls without the rd8 mutation (Ctrp5+/-;wt/wt), and wild-type mice with and without the rd8 mutation (Wtrd8/rd8 and Wtwt/wt, respectively) were generated by systematic breeding of mice in our L-ORD mouse colony. Genotyping the mice for the rd8 (del C at nt3481 in Crb1) and Ctrp5 S163R mutations was performed with allelic PCR or sequencing. Retinal morphology was studied with fundus imaging, histology, light microscopy, electron microscopy, and immunohistochemistry.Genotype analysis of the mice in L-ORD mouse colony detected the rd8 mutation in the homozygous and heterozygous state. Fundus imaging of wild-type mice without the rd8 mutation (Wtwt/wt) revealed no autofluorescence (AF) spots up to 6-8 months and few AF spots at 21 months. However, the accumulation of AF lesions accelerated with age in the Ctrp5+/- mice that lack the rd8 mutation (Ctrp5+/-;wt/wt). The number of AF lesions was significantly increased (p<0.001), and they were small and uniformly distributed throughout the retina in the 21-month-old Ctrp5+/-;wt/wt mice when compared to the age-matched controls. Wild-type and Ctrp5+/- mice with the rd8 mutation (Wtrd8/rd8 and Ctrp5+/-;rd8/rd8, respectively) revealed an integrated retinal architecture with well-defined outer segments/inner segments (OS/IS), outer nuclear layer (ONL), outer plexiform layer (OPL), and inner nuclear layer (INL). The presence of pseudorosette structures reported in the rd8 mice between the ONL and the INL in the ventral quadrant of the retina was not observed in all genotypes studied. Further, the external limiting membrane was continuous in the Ctrp5+/-;rd8/rd8 and Wtrd8/rd8 mice. Evaluation of the retinal phenotype revealed that the Ctrp5+/-;wt/wt mice developed characteristic L-ORD pathology including age-dependent accumulation of AF spots, development of sub-retinal, sub-RPE, and basal laminar deposits, and Bruch's membrane abnormalities at older age, while these changes were not observed in the age-matched littermate WTwt/wt mice.The Wtrd8/rd8 and Ctrp5+/-;rd8/rd8 mice raised on C57BL/6J did not develop early onset retinal changes that are characteristic of the rd8 phenotype, supporting the hypothesis that manifestation of rd8-associated pathology depends on the genetic background. The retinal pathology observed in mice with the Ctrp5+/-;wt/wt genotype is consistent with the L-ORD phenotype observed in patients and with the phenotype we described previously. The lack of rd8-associated retinal pathology in the Ctrp5+/-;wt/wt mouse model raised on the C57BL/6J background and the development of the L-ORD phenotype in these mice in the presence and absence of the rd8 mutation suggests that the pathology observed in the Ctrp5+/-;wt/wt mice is primarily associated with the S163R mutation in the Ctrp5 gene.

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A non-stop S-antigen gene mutation is associated with late onset hereditary retinal degeneration in dogs.

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A non-stop S-antigen gene mutation is associated with late onset hereditary retinal degeneration in dogs.

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