Bestrophin 1 – Phenotypes and Functional Aspects in Bestrophinopathies

Pasquay, Caroline; Wang, Lufei; Lorenz, Birgit; Preising, Markus N.

doi:10.3109/13816810.2013.863945

Cited by 19 publications

(21 citation statements)

References 132 publications

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“…S1). 1,2 Although the exact function of BEST1 is still not clear, it is generally believed to act as a chloride ion channel and has been shown to regulate voltagegated Ca 2þ channels in RPE cells, thus possibly having a dual function as a channel and a channel regulator.…”

Section: Resultsmentioning

confidence: 99%

“…Unlike the situation with Best disease, no patient with ARB has been shown to demonstrate vitelliform lesions in a typical ''egg yolk'' shape in the center of the macula; rather, the main characteristics of ARB are multifocal vitelliform lesions with subretinal fluid or macular edema. 2,[6][7][8][9][10][11][12][13] Other associated clinical features of ARB include hyperopia, a shallow anterior chamber, and increased incidence of angle-closure glaucoma. 7,9,12 Electrophysiology tests tend to demonstrate normal or abnormal eletroretinogram (ERG) with absent light rise in electrooculogram (EOG).…”

Section: Resultsmentioning

confidence: 99%

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A NovelBEST1Mutation in Autosomal Recessive Bestrophinopathy

Lee

Jun

Choi

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Lee CS, Jun I, Choi S, et al. A novel BEST1 mutation in autosomal recessive bestrophinopathy. Invest Ophthalmol Vis Sci. 2015;56:8141-8150. DOI:10.1167/iovs.15-18168 PURPOSE. To describe the clinical characteristics associated with a newly identified mutant of autosomal recessive bestrophinopathy (ARB) and confirm the associated physiological functional defects.METHODS. Two patients with ARB from one family underwent a full ophthalmic examination, including dilated fundus examination, fundus photography, fluorescein angiography, fundus autofluorescence imaging, spectral-domain optical coherence tomography (OCT), electroretinography (ERG), and electrooculography (EOG). Subsequently, genetic analysis for bestrophin-1 (BEST1) mutations was conducted through direct Sanger sequencing. The effect of ARB-associated mutations of BEST1 on the cellular localization was determined by in vitro experiments. Whole-cell patch clamping was conducted to measure the chloride conductance of wild-type BEST1 and the identified BEST1 mutants in transfected HEK293T cells. RESULTS.Two related patients (66-year-old brother and 52-year-old sister) presented with reduced visual acuity and bilateral symmetrical subretinal deposits of hyperautofluorescent materials in the posterior pole. Spectral-domain OCT showed macular thinning with submacular fluid. The female patient had a concomitant macular edema associated with branched retinal vein occlusion in the left eye, which responded well to intravitreal bevacizumab injections. Genetic analysis demonstrated that both patients were compound heterozygous for one novel (Leu40Pro) and one previously identified (Ala195Val) BEST1 variant. HEK293T cells transfected with the identified BEST1 mutant showed significantly small currents compared to those transfected with the wild-type gene, whereas cells cotransfected with mutant and wild-type BEST1 showed good chloride conductance. Cellular localization of BEST1 was well conserved to the plasma membrane in the mutants.CONCLUSIONS. We have identified and described the phenotype and in vitro functional aspects of a new BEST1 mutation causing ARB. Clinically suspected ARB cases warrant genetic confirmation to confirm the diagnosis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A NovelBEST1Mutation in Autosomal Recessive Bestrophinopathy

Lee

Jun

Choi

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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“…The BEST1 mutational spectrum underlying these retinopathies varies greatly, and involves over 200 distinct mutations (Boon et al, 2009a; Pasquay et al, 2015; Yang et al, 2015). Additionally, a considerable variability in age at onset, rate of disease progression and phenotypic expression has been reported, not only between unrelated patients harboring the same mutation, but also among affected individuals within a single family (Kramer et al, 2000; Kinnick et al, 2011; Bitner et al, 2012; MacDonald et al, 2012; Boon et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…BVMD (a.k.a. VMD2, OMIM#153700), inherited as an autosomal dominant trait with incomplete penetrance, and the recessive form (ARB; OMIM#611809) are the most common and best explored juvenile macular dystrophies among bestrophinopathies, characterized by a markedly abnormal electrooculogram (EOG) accompanied by an excessive accumulation of lipofuscin material within RPE cells, formation of focal and multifocal subretinal lesions, and consequently, loss of central vision (Pianta et al, 2003; Boon et al, 2009b; Pasquay et al, 2015; Fung et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Bestrophinopathy: An RPE-photoreceptor interface disease

Guziewicz

Sinha

Gómez

et al. 2017

Progress in Retinal and Eye Research

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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.

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“…1 The exact function of bestrophin 1 is still not unequivocally characterized, but it is linked to transepithelial chloride flow possibly by controlling Ca 2+ channels in the RPE. 1–3 Mutations in BEST1 therefore affect RPE metabolism, and by consequence outer retinal function with which the RPE is intimately associated. Over 200 mutations in BEST1 have been identified and published.…”

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confidence: 99%

New Best1 Mutations in Autosomal Recessive Bestrophinopathy

Fung

Yzer

Goldberg

et al. 2015

Retina

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Purpose To report the ocular phenotype in patients with autosomal recessive bestrophinopathy and carriers, and to describe novel BEST1 mutations. Methods Patients with clinically suspected and subsequently genetically proven autosomal recessive bestrophinopathy underwent full ophthalmic examination and investigation with fundus autofluorescence imaging, spectral domain optical coherence tomography, electroretinography, and electrooculography. Mutation analysis of the BEST1 gene was performed through direct Sanger sequencing. Results Five affected patients from four families were identified. Mean age was 16 years (range, 6–42 years). All affected patients presented with reduced visual acuity and bilateral, hyperautofluorescent subretinal yellowish deposits within the posterior pole. Spectral domain optical coherence tomography demonstrated submacular fluid and subretinal vitelliform material in all patients. A cystoid maculopathy was seen in all but one patient. In 1 patient, the location of the vitelliform material was seen to change over a follow-up period of 3 years despite relatively stable vision. Visual acuity and fundus changes were unresponsive to topical and systemic carbonic anhydrase inhibitors and systemic steroids. Carriers had normal ocular examinations including normal fundus autofluorescence. Three novel mutations were detected. Conclusion Three novel BEST1 mutations are described, suggesting that many deleterious variants in BEST1 resulting in haploinsufficiency are still unknown. Mutations causing autosomal recessive bestrophinopathy are mostly located outside of the exons that usually harbor vitelliform macular dystrophy–associated dominant mutations.

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Bestrophin 1 – Phenotypes and Functional Aspects in Bestrophinopathies

Cited by 19 publications

References 132 publications

A NovelBEST1Mutation in Autosomal Recessive Bestrophinopathy

A NovelBEST1Mutation in Autosomal Recessive Bestrophinopathy

Bestrophinopathy: An RPE-photoreceptor interface disease

New Best1 Mutations in Autosomal Recessive Bestrophinopathy

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