September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Bestrophinopathy is an RPE-photoreceptor interface disease
Author Affiliations & Notes
  • Karina E Guziewicz
    University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • William A Beltran
    University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Simone Iwabe
    University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Artur V Cideciyan
    University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Samuel G Jacobson
    University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Anuradha Dhingra
    University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Kathleen Battaglia
    University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Gustavo D Aguirre
    University of Pennsylvania, Philadelphia, Pennsylvania, United States
  • Footnotes
    Commercial Relationships   Karina Guziewicz, None; William Beltran, None; Simone Iwabe, None; Artur Cideciyan, None; Samuel Jacobson, None; Anuradha Dhingra, None; Kathleen Battaglia, None; Gustavo Aguirre, None
  • Footnotes
    Support  FFB-Center and FFB-TRAP grant, MVRF, NEI/NIH EY06855, EY17549, EY10420, Van Sloun Fund, Hope for Vision
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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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.

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Abstract

Purpose : 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.

Methods : 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.

Results : 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.

Conclusions : 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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