Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium

Best Disease (BD), also known as Best Vitelliform Macular Dystrophy (BVMD), represents an inherited autosomal dominant macular dystrophy with a juvenile age of onset [1]. It is a phenotypically heterogeneous, bilateral condition that affects the retina and Retinal Pigment Epithelium (RPE) caused by pathogenic variants in the BEST1 gene located on chromosome 11q12-13 [2,3]. Typical fundus findings in BD are egg yolk-like, round or oval, lesions seen in the macula, and affected eyes may demonstrate various clinical stages, ranging from the previtelliform stage to Choroidal Neovascularization (CNV) [4]. The macular appearance in all stages is deceptive, as most patients maintain relatively good visual acuity throughout the course of the disease. Patients commonly experience visual compromise in early adulthood, although the age of onset can range from childhood to late adulthood [3] and most patients with BD maintain good vision in at least one eye. The presence of subretinal fluid or CNV has been associated with a poorer visual prognosis [4]. In this case report, we describe a patient with clinical features suggestive of Best disease. We discuss the differential diagnosis and we present the multimodal imaging of the retina used for both the diagnosis and follow up. We also report a genetic study that demonstrates more evidence on a novel genetic variant in the BEST1 gene. The same genetic mutation has been recently reported as a novel variant in a single patient with BVMD [5].

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Pathogenicity of new BEST1 variants identified in Italian patients with best vitelliform macular dystrophy assessed by computational structural biology

Journal of Translational Medicine ◽

10.1186/s12967-019-2080-3 ◽

2019 ◽

Vol 17 (1) ◽

Author(s):

Vladimir Frecer ◽

Giancarlo Iarossi ◽

Anna Paola Salvetti ◽

Paolo Enrico Maltese ◽

Giulia Delledonne ◽

...

Keyword(s):

Amino Acid ◽

Structural Biology ◽

Tertiary Structure ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Macular Dystrophy ◽

Vitelliform Macular Dystrophy ◽

Best Vitelliform Macular Dystrophy ◽

Potential Pathogenicity ◽

Computational Structural Biology

Abstract Background Best vitelliform macular dystrophy (BVMD) is an autosomal dominant macular degeneration. The typical central yellowish yolk-like lesion usually appears in childhood and gradually worsens. Most cases are caused by variants in the BEST1 gene which encodes bestrophin-1, an integral membrane protein found primarily in the retinal pigment epithelium. Methods Here we describe the spectrum of BEST1 variants identified in a cohort of 57 Italian patients analyzed by Sanger sequencing. In 13 cases, the study also included segregation analysis in affected and unaffected relatives. We used molecular mechanics to calculate two quantitative parameters related to calcium-activated chloride channel (CaCC composed of 5 BEST1 subunits) stability and calcium-dependent activation and related them to the potential pathogenicity of individual missense variants detected in the probands. Results Thirty-six out of 57 probands (63% positivity) and 16 out of 18 relatives proved positive to genetic testing. Family study confirmed the variable penetrance and expressivity of the disease. Six of the 27 genetic variants discovered were novel: p.(Val9Gly), p.(Ser108Arg), p.(Asn179Asp), p.(Trp182Arg), p.(Glu292Gln) and p.(Asn296Lys). All BEST1 variants were assessed in silico for potential pathogenicity. Our computational structural biology approach based on 3D model structure of the CaCC showed that individual amino acid replacements may affect channel shape, stability, activation, gating, selectivity and throughput, and possibly also other features, depending on where the individual mutated amino acid residues are located in the tertiary structure of BEST1. Statistically significant correlations between mean logMAR best-corrected visual acuity (BCVA), age and modulus of computed BEST1 dimerization energies, which reflect variations in the in CaCC stability due to amino acid changes, permitted us to assess the pathogenicity of individual BEST1 variants. Conclusions Using this computational approach, we designed a method for estimating BCVA progression in patients with BEST1 variants.

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Bilateral Macular Holes in Adult Vitelliform Macular Dystrophy

Journal of VitreoRetinal Diseases ◽

10.1177/2474126420903544 ◽

2020 ◽

Vol 4 (4) ◽

pp. 340-343

Author(s):

Kathleen A. Regan ◽

Justin L. Gottlieb

Keyword(s):

Retinal Pigment Epithelium ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Vitreomacular Traction ◽

Macular Dystrophy ◽

Retrospective Case ◽

Vitelliform Macular Dystrophy ◽

Gas Tamponade ◽

Macular Holes ◽

The Right

Purpose: This report describes a case of bilateral macular holes (MHs) in adult vitelliform macular dystrophy (AVMD). Methods: A retrospective case report of a patient with AVMD and sequential onset of bilateral MHs is presented. Results: Bilateral MHs were observed after vitreomacular traction was identified on optical coherence tomography. Holes in both eyes were repaired with pars plana vitrectomy (PPV) with C3F8 (perfluoropropane) gas tamponade; only the right eye underwent internal limiting membrane peeling. In the right eye, 2 PPVs were required for hole closure. In both eyes, long-term atrophy of the retina and retinal pigment epithelium was observed. Conclusions: MHs in AVMD may be preceded by vitreomacular traction. Surgical repair with PPV and gas tamponade was successful. Retinal and retinal pigment epithelium atrophy developed postoperatively, but the patient’s vision still improved.

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TRP Channels Localize to Subdomains of the Apical Plasma Membrane in Human Fetal Retinal Pigment Epithelium

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.14-15738 ◽

2015 ◽

Vol 56 (3) ◽

pp. 1916 ◽

Cited By ~ 18

Author(s):

Peter Y. Zhao ◽

Geliang Gan ◽

Shaomin Peng ◽

Shao-Bin Wang ◽

Bo Chen ◽

...

Keyword(s):

Plasma Membrane ◽

Retinal Pigment Epithelium ◽

Trp Channels ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Apical Plasma Membrane

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Multimodal imaging of Hypotrichosis with juvenile macular dystrophy: a case report

BMC Ophthalmology ◽

10.1186/s12886-021-02037-8 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Giovanna Carnovale Scalzo ◽

Adriano Carnevali ◽

Gabriele Piccoli ◽

Domenico Ceravolo ◽

Donatella Bruzzichessi ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Multimodal Imaging ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Unknown Origin ◽

Clinical Findings ◽

Macular Dystrophy ◽

Photoreceptor Layer ◽

Inherited Retinal Dystrophies ◽

Italian Case

Abstract Background To report the first Italian case of hypotrichosis with juvenile macular dystrophy complicated by macular neovascularization diagnosed through multimodal imaging. Case presentation An 11-year-old boy was referred to our Institution for bilateral maculopathy of unknown origin. Multimodal imaging helps the diagnosis of Juvenile Macular Dystrophy with Hypotrichosis (HJMD). Fundus examination showed several alterations of the retinal pigment epithelium and circular pigmented area of chorioretinal atrophy. Structural spectral domain optical coherence tomography (OCT) showed some backscattering phenomenon with several alterations of retinal pigment epithelium and photoreceptor layer in both eyes. Moreover, OCT showed hyperreflective lesion beneath the neuroepithelium in left eye. OCT angiography (OCT-A) revealed a pathologic neovascular network in choriocapillaris plexus, probably the result of a fibrovascular membrane. Multifocal electroretinograms (MfERGs) showed functional alterations in 12.22° of the central retina. In order to confirm the suspicion of HJMD, the child and both parents underwent genetic testing. Both parents resulted to be heterozygous healthy carriers of a single variation. Conclusion Multimodal imaging, in particular OCT-A, is a useful aid, along to clinical findings and genetics, for the diagnosis of inherited retinal dystrophies.

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Optical Coherence Tomography in Best Vitelliform Macular Dystrophy

European Journal of Ophthalmology ◽

10.5301/ejo.5000878 ◽

2017 ◽

Vol 27 (2) ◽

pp. 201-204 ◽

Cited By ~ 8

Author(s):

Maurizio Battaglia Parodi ◽

Pierluigi Iacono ◽

Francesco Romano ◽

Gianluigi Bolognesi ◽

Francesco Fasce ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Visual Acuity ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Macular Dystrophy ◽

Optical Coherence ◽

Vitelliform Macular Dystrophy ◽

Retinal Layers ◽

Hyperreflective Foci ◽

Sd Oct

Purpose To analyze spectral-domain optical coherence tomography (SD-OCT)-specific findings in the different stages of vitelliform macular dystrophy (VMD). Methods Thirty-seven patients were prospectively recruited. All the patients underwent a complete ophthalmologic examination, including best-corrected visual acuity (BCVA), biomicroscopy, and SD-OCT. The examined findings were vitelliform material, neurosensory detachment, intraretinal hyperreflective foci, and the status of external limiting membrane, ellipsoid zone, and retinal pigment epithelium. The primary outcome was the stratification of SD-OCT findings in each VMD stage. Secondary outcomes included the description of different characteristics related to intraretinal hyperreflective foci. Results Outer retinal layers were preserved almost exclusively in stage 1 (range 70%-100%), whereas their disruption and absence were typical of stages 2 to 4 (83%-100%) and stage 5 (67%-83%), respectively. Vitelliform material was found always in stages 2 and 3, 89% of stage 4, and rarely in stage 5 (33%). Neurosensory detachment was to some extent representative of stages 3 and 4 (80% and 72%, respectively) when compared with the other stages (p<0.001). Hyperreflective foci (16% of all eyes) demonstrated a progressive increase across stages 2 to 4, with slightly reduced figure in stage 5. These foci were located in the outer nuclear and plexiform layers, showed different sizes, and were not associated with a visual acuity reduction (p = 0.64). Conclusions A progressive deterioration of the outer retinal layers was noticeable in more advanced stages of VMD. The reduction of vitelliform material from stage 3 to 4 was paralleled by an increased evidence of neurosensory detachment. Although showing different size and location, hyperreflective foci did not correlate with worse BCVA.

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Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1418840112 ◽

2015 ◽

Vol 112 (20) ◽

pp. E2630-E2639 ◽

Cited By ~ 72

Author(s):

Andrea Milenkovic ◽

Caroline Brandl ◽

Vladimir M. Milenkovic ◽

Thomas Jendryke ◽

Lalida Sirianant ◽

...

Keyword(s):

Retinal Pigment Epithelium ◽

Volume Regulation ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Cell Swelling ◽

Macular Dystrophy ◽

Cell Physiology ◽

Rpe Cells ◽

Human Retinal Pigment Epithelium ◽

Molecular Identity

In response to cell swelling, volume-regulated anion channels (VRACs) participate in a process known as regulatory volume decrease (RVD). Only recently, first insight into the molecular identity of mammalian VRACs was obtained by the discovery of the leucine-rich repeats containing 8A (LRRC8A) gene. Here, we show that bestrophin 1 (BEST1) but not LRRC8A is crucial for volume regulation in human retinal pigment epithelium (RPE) cells. Whole-cell patch-clamp recordings in RPE derived from human-induced pluripotent stem cells (hiPSC) exhibit an outwardly rectifying chloride current with characteristic functional properties of VRACs. This current is severely reduced in hiPSC-RPE cells derived from macular dystrophy patients with pathologic BEST1 mutations. Disruption of the orthologous mouse gene (Best1−/−) does not result in obvious retinal pathology but leads to a severe subfertility phenotype in agreement with minor endogenous expression of Best1 in murine RPE but highly abundant expression in mouse testis. Sperm from Best1−/− mice showed reduced motility and abnormal sperm morphology, indicating an inability in RVD. Together, our data suggest that the molecular identity of VRACs is more complex—that is, instead of a single ubiquitous channel, VRACs could be formed by cell type- or tissue-specific subunit composition. Our findings provide the basis to further examine VRAC diversity in normal and diseased cell physiology, which is key to exploring novel therapeutic approaches in VRAC-associated pathologies.

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