September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
A quantitative trait locus on canine chromosome 31 influences disease severity phenotype of XLPRA1
Author Affiliations & Notes
  • Tatyana Appelbaum
    Department of Ophthalmology, U of Penn School Vet Med, Philadelphia, Pennsylvania, United States
  • Doreen Becker
    Department of Ophthalmology, U of Penn School Vet Med, Philadelphia, Pennsylvania, United States
  • Evelyn Santana
    Department of Ophthalmology, U of Penn School Vet Med, Philadelphia, Pennsylvania, United States
  • Gustavo D Aguirre
    Department of Ophthalmology, U of Penn School Vet Med, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Tatyana Appelbaum, None; Doreen Becker, None; Evelyn Santana, None; Gustavo Aguirre, None
  • Footnotes
    Support  EY-06855, -17549, the Foundation Fighting Blindness, the Macula Vision Research Foundation, the Van Sloun Fund for Canine Genetic Research, and Hope for Vision
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 6569. doi:
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    • Get Citation

      Tatyana Appelbaum, Doreen Becker, Evelyn Santana, Gustavo D Aguirre; A quantitative trait locus on canine chromosome 31 influences disease severity phenotype of XLPRA1. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6569.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Canine X-linked progressive retinal atrophy 1 (XLPRA1), caused by a 5 nt deletion in RPGR ORF15, shows extensive phenotypic variability in disease severity and progression. Previously we analyzed and further excluded 12 genes (RPGRIP1, RPGRIP1L, RANBP2, NPM1, PDE6D, NPHP5, ABCA4, RAB8A, CEP290, CC2D2A, DFNB31 and RAB11B) as genetic modifiers of XLPRA1. Here in search of the potential modifier(s) we performed a genome wide scan in XLPRA1-affected pedigree.

Methods : Phenotypes from a pedigree derived from XLPRA1 affected male dog were scored as mild, moderate and severe. Genome wide association study (GWAS) was performed using CanineHD Genotyping BeadChip. PHASE software was utilized for haplotype reconstruction. Fisher exact test was used for statistical analysis. Retinal gene expression was determined by qRT-PCR.

Results : GWAS identified a single locus on chromosome 31 with notable trend toward association with XLPRA1 phenotype. This 5 MB interval, containing ~6 predicted genes (ROBO1, ROBO2, TMED2, LIPI, NRIP1 and USP25), is not well characterized in canine genome. Number of informative SNPs per gene varied from n=1 (TMED2 and NRIP1) to n=50 (ROBO1). Here SNP data from GWAS for 4 candidate genes (ROBO1, ROBO2, LIPI and USP25) were re-analyzed as haplotypes and two XLPRA1 phenotypes (severe and moderate) were tested for association with each haplotype identified. We found significant association (p=0.02) of the major haplotype composed of 67 SNPs from 4 candidate genes with moderate XLPRA1 disease phenotype. Furthermore, the specific haplotype of the ROBO1, ROBO2 and USP25 was associated with the same phenotype (p=0.01). Indeed those gene-specific haplotypes were part of the major haplotype. To date we have examined expression and the mutational status of the ROBO1 gene that is functionally involved in inflammatory response and neovascularization process. We confirmed expression of the major ROBO1 isoform (30 exons) in retina. Two non-synonymous mutations (A982T and A1337V encoded by exon 21 and 26, respectively) found in ROBO1, were not associated with the XLPRA1 phenotype.

Conclusions : The significant association between the multigene haplotype on chromosome 31 with the moderate phenotype in XLPRA1-affected dogs implies potential protective role of this haplotype in the pathogenesis of canine XLPRA1. These results warrant further investigation.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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