March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Canine Bestrophinopathies: Lesion Morphology and Molecular Pathology
Author Affiliations & Notes
  • Karina E. Guziewicz
    Clinical Studies,
    University of Pennsylvania, Philadelphia, Pennsylvania
  • Artur V. Cideciyan
    Scheie Eye Institute, Philadelphia, Pennsylvania
  • William A. Beltran
    Clinical Studies,
    University of Pennsylvania, Philadelphia, Pennsylvania
  • Barbara Zangerl
    Clinical Studies,
    University of Pennsylvania, Philadelphia, Pennsylvania
  • Julianna Slavik
    Clinical Studies,
    University of Pennsylvania, Philadelphia, Pennsylvania
  • Simone Iwabe
    Clinical Studies,
    University of Pennsylvania, Philadelphia, Pennsylvania
  • Kathleen Boesze-Battaglia
    Biochemistry,
    University of Pennsylvania, Philadelphia, Pennsylvania
  • Robert F. Mullins
    Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa
  • Samuel G. Jacobson
    Scheie Eye Institute, Philadelphia, Pennsylvania
  • Gustavo D. Aguirre
    Clinical Studies,
    University of Pennsylvania, Philadelphia, Pennsylvania
  • Footnotes
    Commercial Relationships  Karina E. Guziewicz, None; Artur V. Cideciyan, None; William A. Beltran, None; Barbara Zangerl, None; Julianna Slavik, None; Simone Iwabe, None; Kathleen Boesze-Battaglia, None; Robert F. Mullins, None; Samuel G. Jacobson, None; Gustavo D. Aguirre, None
  • Footnotes
    Support  FFB, NEI/NIH EY06855, EY17549, Van Sloun Fund, Hope for Vision, RPB;
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 6888. doi:
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      Karina E. Guziewicz, Artur V. Cideciyan, William A. Beltran, Barbara Zangerl, Julianna Slavik, Simone Iwabe, Kathleen Boesze-Battaglia, Robert F. Mullins, Samuel G. Jacobson, Gustavo D. Aguirre; Canine Bestrophinopathies: Lesion Morphology and Molecular Pathology. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6888.

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Abstract

Purpose: : Mutations in the BEST1 gene cause human and canine bestrophinopathies, but the molecular mechanisms underlying the phenotypic variation in disease and the pathological nature of the lesions remain largely unknown. We used the spontaneous dog BEST1-disease model, canine multifocal retinopathy (cmr), to characterize the phenotypic and morphologic features of cmr1 (R25X/R25X) and cmr1/cmr3 (R25X/P463fs) dogs, and to assess the molecular pathology of the cmr lesions.

Methods: : Clinical and SD-OCT analyses were carried out in cmr1 and cmr1/cmr3 affected dogs. The cmr1 lesion architecture was analyzed in cryosections by IHC and lectin labeling with a Nikon confocal microscope; tissue samples were also examined by electron microscopy (EM) and energy-dispersive X-ray spectroscopy (EDAX).

Results: : The cmr lesions develop as early as 3-4 months of age as a single focal detachment in the area centralis that can be considered the canine macula. In cmr1, disease progresses slowly into multifocal bullous retinal lesions, often in close proximity to the optic nerve and more diffusely in the superior half of the fundus. Some lesions apparent on SD-OCT demonstrate distinct hyperautofluorescence with short-wavelength illumination, whereas others do not. In the only cmr1/cmr3 compound heterozygote studied to date, disease has remained limited to the canine macular region similar to the classic presentation of a unifocal lesion in Best vitelliform macular dystrophy. Histology and IHC revealed separation between RPE and photoreceptor outer segments with accumulation of autofluorescent debris on the apical RPE membranes. Furthermore, hypertrophy of endoplasmic reticulum and increased levels of calcium ions were detected in the cmr1-affected RPE cells by EM and EDAX, respectively.

Conclusions: : Canine multifocal retinopathy recapitulates the major features of human bestrophinopathies, establishing cmr as an important model of macular degeneration and setting the stage for testing experimental therapies. Analysis of autofluorescent structures on the RPE apical membranes will help explain the disease mechanism and define an optimal window for therapeutic intervention.

Keywords: retinal pigment epithelium • macula/fovea • retinal degenerations: hereditary 
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