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R. Guyon, S.E. Pierce–Kelling, C.J. Zeiss, G.M. Acland, G.D. Aguirre; Exclusion of Six Candidate Genes as Genetic Modifiers of Disease Expression in Canine XLPRA1, a Model for Human X–Linked Retinitis Pigmentosa 3 (RP3) . Invest. Ophthalmol. Vis. Sci. 2006;47(13):3256.
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© ARVO (1962-2015); The Authors (2016-present)
A stop mutation in RPGRORF15 causes XLPRA1. There is extensive phenotypic variability in the disease even though all colony dogs have inherited the same stable mutation derived from one mutant X–chromosome. We have investigated known (RPGRIP1, RANBP2, NPM1, PDE6D, NPHP5) and potential (ABCA4) RPGR interacting genes as possible genetic modifiers of the disease.
A pedigree derived from an affected male outcrossed to unrelated normal mix bred or purebred females was used. Morphologic examination revealed phenotypic variability in the affected dogs (1 mild, 9 moderate, 14 severe), possibly due to a secondary modifier gene acting as an autosomal semi–dominant trait. SNPs and indel–containing markers were designed based on the canine sequence and the Broad Institute SNP library. The segregation of the alleles was followed throughout the pedigree, and allelic phase was identified for each candidate gene, and their association with the level of severity of the disease estimated. Primers were derived from ESTs and predicted transcripts to assess the retinal expression of the 6 genes of interest in normal and affected retinas using semi–quantitative RT–PCR.
For each of the 6 genes, 4 to 7 informative SNPs and indel–containing markers were selected from upstream, downstream and intronic regions. These markers spanned a genomic region ranging from 57 to 111 kb, and covering the entire gene. The genotyping of these markers allowed the identification of 4 to 6 distinct allelic phases. None of these allelic phases co–segregates with the phenotype in a semi–dominant manner, excluding a modifying role of the genes investigated. No significant difference in the retinal expression levels of the candidate genes was seen between normal and affected dogs.
The phenotypic variability observed in XLPRA1 affected dogs having the same mutation inherited from a single mutant X–chromosome cannot be explained by one of the 6 candidate genes acting as a semi–dominant genetic modifier. The RPGRORF15 stop mutation does not affect the retinal expression of these genes.
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