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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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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.
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).
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.
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.
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