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Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies

Abstract

Considerable clinical and molecular variations have been known in retinal blinding diseases in man and also in dogs. Different forms of retinal diseases occur in specific breed(s) caused by mutations segregating within each isolated breeding population. While molecular studies to find genes and mutations underlying retinal diseases in dogs have benefited largely from the phenotypic and genetic uniformity within a breed, within- and across-breed variations have often played a key role in elucidating the molecular basis. The increasing knowledge of phenotypic, allelic, and genetic heterogeneities in canine retinal degeneration has shown that the overall picture is rather more complicated than initially thought. Over the past 20 years, various approaches have been developed and tested to search for genes and mutations underlying genetic traits in dogs, depending on the availability of genetic tools and sample resources. Candidate gene, linkage analysis, and genome-wide association studies have so far identified 24 mutations in 18 genes underlying retinal diseases in at least 58 dog breeds. Many of these genes have been associated with retinal diseases in humans, thus providing opportunities to study the role in pathogenesis and in normal vision. Application in therapeutic interventions such as gene therapy has proven successful initially in a naturally occurring dog model followed by trials in human patients. Other genes whose human homologs have not been associated with retinal diseases are potential candidates to explain equivalent human diseases and contribute to the understanding of their function in vision.

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Acknowledgments

KM acknowledges The Kennel Club Charitable Trust (RG55218) for research funds; Fitzwilliam College, University of Cambridge, The University of Tokyo, British Council Japan Association for scholarships. Much of KM’s work is the result of the exceptional mentorship provided by Drs. David Sargan at the University of Cambridge, Cathryn Mellersh at the Animal Health Trust, Nobuo Sasaki and Kumiko Kato at The University of Tokyo, and Hiroyuki Ogawa at the Japan Animal Referral Medical Center. GMA and GDA acknowledge NEI/NIH grants EY-01244, EY06855, EY13132, and EY13729, The Foundation Fighting Blindness, The ONCE International Prize for Research & Development in Biomedicine and New Technologies for the Blind, and The Van Sloun Fund for Canine Genetic Research for their generous support. They are indebted to Sue Pearce-Kelling for her many contributions in all aspects of the research, to our scientific colleagues—research scientists, postdoctoral fellows, graduate students, and research technicians, and the staff of the RDSF—and to the dog owners for their participation in research. The authors thank Optigen LLC for disclosing unpublished data.

Disclosure

GMA and GDA are founding members and owners of OptiGen LLC, a company that carries out DNA testing for a large number of inherited eye diseases in dogs, and hold patents for some of these tests.

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Correspondence to Gustavo D. Aguirre.

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Miyadera, K., Acland, G.M. & Aguirre, G.D. Genetic and phenotypic variations of inherited retinal diseases in dogs: the power of within- and across-breed studies. Mamm Genome 23, 40–61 (2012). https://doi.org/10.1007/s00335-011-9361-3

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Keywords

  • Retinitis Pigmentosa
  • Retinal Disease
  • Positional Candidate Gene
  • Labrador Retriever
  • Golden Retriever