title: Bestrophinopathy: An RPE-photoreceptor interface disease.
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.
authors.affiliation: Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, PA 19104, USA. Electronic address: karinag@vet.upenn.edu.
authors.forename: Karina E
authors.initials: KE
authors.lastname: Guziewicz
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: Divya
authors.initials: D
authors.lastname: Sinha
authors.affiliation: Department of Anatomy & Cell Biology, School of Dental Medicine, University of Pennsylvania, PA 19104, USA.
authors.forename: Néstor M
authors.initials: NM
authors.lastname: Gómez
authors.affiliation: Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, PA 19104, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Zorych
authors.affiliation: Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, PA 19104, USA.
authors.forename: Emily V
authors.initials: EV
authors.lastname: Dutrow
authors.affiliation: Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, PA 19104, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Dhingra
authors.affiliation: Department of Ophthalmology & Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Mullins
authors.affiliation: Department of Ophthalmology & Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Ophthalmology & Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Gamm
authors.affiliation: Department of Biochemistry, School of Dental Medicine, University of Pennsylvania, PA 19104, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Boesze-Battaglia
authors.affiliation: Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, PA 19104, USA.
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
mesh_terms: D000818:Animals; D000075002:Bestrophins / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D015785:Eye Diseases, Hereditary / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D012164:Retinal Diseases / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D055213:Retinal Pigment Epithelium / Q000378:metabolism / Q000473:pathology*
chemical_list: C113133:BEST1 protein, human; D000075002:Bestrophins; D004247:DNA
keywords: Bestrophinopathies; Canine model; Lipofuscin; Macula; RPE apical microvilli; RPE-Photoreceptor interface; hiPSC-RPE