May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Bestrophin Gene Mutations Cause Canine Multifocal Retinopathy
Author Affiliations & Notes
  • K. E. Guziewicz
    Department of Clinical Studies-Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
  • B. Zangerl
    Department of Clinical Studies-Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
  • S. J. Lindauer
    Department of Clinical Studies-Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
  • R. F. Mullins
    Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa
  • L. S. Sandmeyer
    Department of Small Animal Clinical Sciences, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
  • B. H. Grahn
    Department of Small Animal Clinical Sciences, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
  • E. M. Stone
    Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, Iowa
    Howard Hughes Medical Institute, Iowa City, Iowa
  • G. M. Acland
    J.A. Baker Institute for Animal Health, Cornell University, Ithaca, New York
  • G. D. Aguirre
    Department of Clinical Studies-Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 2982. doi:
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    • Get Citation

      K. E. Guziewicz, B. Zangerl, S. J. Lindauer, R. F. Mullins, L. S. Sandmeyer, B. H. Grahn, E. M. Stone, G. M. Acland, G. D. Aguirre; Bestrophin Gene Mutations Cause Canine Multifocal Retinopathy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2982.

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

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Abstract

Purpose:: Canine multifocal retinopathy (cmr) is an autosomal recessive disorder of multiple dog breeds. The disease shares a number of clinical and pathological similarities with Best macular dystrophy (BMD), and we propose cmr as a new large animal model for Best disease.

Methods:: cmr was characterized by ophthalmoscopy and histopathology, and compared with BMD-affected patients. VMD2, the bestrophin gene causally associated with BMD, was evaluated in the dog. Canine ortholog cDNA sequence was verified using RPE/choroid 5'-and 3'-RACE and cloned. Expression of the canine gene transcripts and protein was analyzed by northern and western blotting, and immunocytochemistry. All exons and the flanking splice junctions were screened by direct sequencing.

Results:: The clinical phenotype and pathology of cmr closely resembles lesions of BMD. Canine VMD2 spans 13.7 kb of genomic DNA on CFA18, and shows a high level of conservation among eukaryotes. The transcript is predominantly expressed in RPE/choroid, and encodes bestrophin, a 580 amino acid protein of 66 kDa. Immunocytochemistry of normal canine retina demonstrated specific localization of protein to the RPE basolateral plasma membranes. Two disease-specific sequence alterations were identified in the canine VMD2 gene: a C73T stop mutation in cmr1, and a G482A missense mutation in cmr2.

Conclusions:: We propose these two spontaneous mutations in the canine VMD2 gene causing cmr as the first naturally occurring animal model of BMD. Further development of the cmr models will permit elucidation of the complex molecular mechanism of both cmr and BMD and will lead to a better understanding of the different modes of inheritance of these retinopathies, as well as providing a model system in which to explore the development of potential therapies.

Keywords: retinal degenerations: hereditary • retinal pigment epithelium • candidate gene analysis 
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