March 2012
Volume 53, Issue 14
ARVO Annual Meeting Abstract  |   March 2012
GWAS Mapping and Evaluation of a Modifier Locus for the Age of Onset in Canine RPGRIP1–/– Cone-Rod Dystrophy
Author Affiliations & Notes
  • Keiko Miyadera
    School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  • Kumiko Kato
    Dept of Veterinary Medical Science, University of Tokyo, Tokyo, Japan
  • Cathryn S. Mellersh
    Animal Health Trust, Newmarket, United Kingdom
  • David R. Sargan
    Dept of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom
  • Gregory M. Acland
    James A Baker Institute, Cornell University, Ithaca, New York
  • Gustavo D. Aguirre
    School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  • Footnotes
    Commercial Relationships  Keiko Miyadera, None; Kumiko Kato, None; Cathryn S. Mellersh, None; David R. Sargan, None; Gregory M. Acland, None; Gustavo D. Aguirre, None
  • Footnotes
    Support  Kennel Club Charitable Trust, Fitzwilliam College, University of Cambridge, Foundation Fighting Blindness, NIH-EY 06855, 17549, Van Sloun Fund, Hope for Vision
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 1225. doi:
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      Keiko Miyadera, Kumiko Kato, Cathryn S. Mellersh, David R. Sargan, Gregory M. Acland, Gustavo D. Aguirre; GWAS Mapping and Evaluation of a Modifier Locus for the Age of Onset in Canine RPGRIP1–/– Cone-Rod Dystrophy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1225.

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

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Purpose: : A naturally-occurring recessive cone-rod dystrophy (CRD) in Miniature longhaired dachshund (MLHD) dogs has been studied in an inbred research colony. The disease is characterized by lack of cone ERG response as early as 6 weeks, progressing into blindness by 2 years of age. A whole genome scan has led to the identification of a 44bp insertion in exon 2 of RPGRIP1 and predicted to cause a premature stop codon. The homozygous mutation (RPGRIP1–/–) segregated completely with early-onset CRD. However, in the wider MLHD pet population, a much broader age of clinical onset (0.3-16 years) occurs; as well, some RPGRIP1–/– dogs appears to be unaffected. Our aim was to identify genetic modifiers underlying the variability in the age of onset in dogs with the RPGRIP1–/– background.

Methods: : GWAS was performed using Illumina canine SNP chips (22,362 SNPs) in 31 early-onset (0-4 years), 15 late-onset (5-16 years), and 34 normal (4-14 years) MLHDs that were all RPGRIP1–/–. Once a locus was mapped, positional candidate genes were sequenced by Sanger sequencing. Subsequently, the entire interval of association was sequenced by targeted capture and next-generation sequencing. Expression of positional candidate genes was examined by RT-PCR in canine retinas with different genotypes at the second locus.

Results: : Comparing the early-onset cases against the controls (late-onset and normal dogs combined), a single strong association was found on canine chromosome 15, ~40Mb from RPGRIP1 (p=5.05x10-13). Haplotype analysis defined a 1.49-Mb interval of homozygosity which corresponded highly to the early-onset phenotype in RPGRIP1–/– dogs. Sequencing of positional candidate genes and intergenic regions identified numerous polymorphisms. RNA expression levels of five positional candidate genes (CTSO, GUCY1A3, GUCY1B3, LRAT, MAP9) did not show experssion changes between the dogs with different second locus genotype as examined by RT-PCR.

Conclusions: : We have established a unique model of canine CRD involving two distinct genetic loci; concomitant homozygosity at RPGRIP1 and the newly mapped second locus leads to early-onset blindness whereas the onset is delayed or remains subclinical in dogs with RPGRIP1–/– alone. The positional candidate genes examined to date may be provisionally excluded, yet further study is under way to confirm the modifier mutation.

Keywords: gene modifiers • retina • gene mapping 

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