Journal article
Bestrophinopathy: An RPE-photoreceptor interface disease
Progress in Retinal and Eye Research, Vol.58, pp.70-88
05/2017
DOI: 10.1016/j.preteyeres.2017.01.005
PMCID: PMC5441932
PMID: 28111324
Abstract
Bestrophinopathies, one of the most common forms of inherited macular degenerations, are caused by mutations in the BEST1 gene expressed in the retinal pigment epithelium (RPE). Both human and canine BEST1-linked maculopathies are characterized by abnormal accumulation of autofluorescent material within RPE cells and bilateral macular or multifocal lesions; however, the specific mechanism leading to the formation of these lesions remains unclear. We now provide an overview of the current state of knowledge on the molecular pathology of bestrophinopathies, and explore factors promoting formation of RPE-neuroretinal separations, using the first spontaneous animal model of BEST1-associated retinopathies, canine Best (cBest). Here, we characterize the nature of the autofluorescent RPE cell inclusions and report matching spectral signatures of RPE-associated fluorophores between human and canine retinae, indicating an analogous composition of endogenous RPE deposits in Best Vitelliform Macular Dystrophy (BVMD) patients and its canine disease model. This study also exposes a range of biochemical and structural abnormalities at the RPE-photoreceptor interface related to the impaired cone-associated microvillar ensheathment and compromised insoluble interphotoreceptor matrix (IPM), the major pathological culprits responsible for weakening of the RPE-neuroretina interactions, and consequently, formation of vitelliform lesions. These salient alterations detected at the RPE apical domain in cBest as well as in BVMD- and ARB-hiPSC-RPE model systems provide novel insights into the pathological mechanism of BEST1-linked disorders that will allow for development of critical outcome measures guiding therapeutic strategies for bestrophinopathies. [Display omitted] •Fresh perspective on the development of macular lesions in BEST1-linked disorders.•Novel insights into BEST1 pathogenesis derived from canine model and hiPSC-RPE.•Underdeveloped RPE apical domain underlies lesion formation in bestrophinopathies.•New disease aspects for guidance of therapeutic strategies for bestrophinopathies.•Advances in understanding of the molecular pathology of bestrophinopathies.
Details
- Title: Subtitle
- Bestrophinopathy: An RPE-photoreceptor interface disease
- Creators
- Karina E Guziewicz - Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, PA 19104, USADivya Sinha - Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USANéstor M Gómez - Department of Anatomy & Cell Biology, School of Dental Medicine, University of Pennsylvania, PA 19104, USAKathryn Zorych - Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, PA 19104, USAEmily V Dutrow - Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, PA 19104, USAAnuradha Dhingra - Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, PA 19104, USARobert F Mullins - Department of Ophthalmology & Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USAEdwin M Stone - Department of Ophthalmology & Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USADavid M Gamm - Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USAKathleen Boesze-Battaglia - Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, PA 19104, USAGustavo D Aguirre - Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, PA 19104, USA
- Resource Type
- Journal article
- Publication Details
- Progress in Retinal and Eye Research, Vol.58, pp.70-88
- DOI
- 10.1016/j.preteyeres.2017.01.005
- PMID
- 28111324
- PMCID
- PMC5441932
- NLM abbreviation
- Prog Retin Eye Res
- ISSN
- 1350-9462
- eISSN
- 1873-1635
- Publisher
- Elsevier Ltd
- Language
- English
- Date published
- 05/2017
- Academic Unit
- Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
- Record Identifier
- 9983980087602771
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