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Karina E Guziewicz, William A Beltran, Simone Iwabe, Artur V Cideciyan, Samuel G Jacobson, Anuradha Dhingra, Kathleen Battaglia, Gustavo D Aguirre; Bestrophinopathy is an RPE-photoreceptor interface disease. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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© 2017 Association for Research in Vision and Ophthalmology.
Bestrophinopathies are caused by mutations in the BEST1 gene expressed in the retinal pigment epithelium (RPE). Both human and canine bestrophinopathies are characterized by focal or multifocal separations of the retina from the RPE. The lesions can be macular or extramacular, and the specific pathomechanism leading to formation of these lesions remains unclear. We used the spontaneous dog BEST1 disease model, canine multifocal retinopathy (cmr), to explore factors contributing to the development of lesions.
Sixteen cmr dogs (age range 2mo - 6yr) with homozygous (R25X or P463fs) or compound heterozygous (R25X/P463fs) mutations in canine BEST1 were monitored clinically and imaged serially using cSLO/SD-OCT. Retinal structure was examined in cryosections by H&E, Oil Red O and filipin staining, WGA and PNA lectins labeling and immunohistochemistry. The sections were assessed using transmitted light microscopy, epifluorescence and confocal microscopy. All in vivo and ex vivo analyses were carried out in comparison to age-matched wild-type control eyes.
Misregulation of lipid metabolism and an indication of increased levels of oxidative stress within the photoreceptor layer of cmr-affected retinae were evidenced by Oil Red O, filipin, BODIPY 493/503 and anti-HNE staining. Immunolabeling with anti-EZR, anti-SLC16A1 and anti-RLBP1 revealed dramatic retraction of RPE apical cone sheath microvilli in all cmr samples. PNA staining confirmed compromised interphotoreceptor matrix (IPM) of cone outer segments. SD-OCT measurements of the distance between external limiting membrane and RPE showed greater than normal thickness in cmr implying elongated inner/outer segments. Histological evaluation revealed areas of subtle dissociation of the neural retina from RPE with accumulation of subretinal debris.
Compromised IPM and/or retraction of RPE apical processes that ensheath cones may contribute to the loss of retinal adhesiveness and lesion formation in bestrophinopathies by retinal detachment and subretinal deposit formation. These salient alterations detected at the RPE-photoreceptor interface in dogs, as well as abnormal electrooculogram light peak detected in many human patients could be reflecting the underlying pathophysiology resulting from abnormal volume regulation in mutant RPE cells.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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