The vitelliform macular dystrophy protein defines a new family of chloride channels.
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ABSTRACT:
SUBMITTER: Sun H
PROVIDER: S-EPMC122639 | biostudies-literature | 2002 Mar
REPOSITORIES: biostudies-literature
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The vitelliform macular dystrophy protein defines a new family of chloride channels.
Sun Hui H Tsunenari Takashi T Yau King-Wai KW Nathans Jeremy J
Proceedings of the National Academy of Sciences of the United States of America 20020301 6
Vitelliform macular dystrophy (VMD/Best disease; MIM*153700) is an early-onset autosomal dominant disorder in which accumulation of lipofuscin-like material within and beneath the retinal pigment epithelium is associated with a progressive loss of central vision. Bestrophin, the protein product of the VMD gene, has four predicted transmembrane domains. There are multiple bestrophin homologues in the human, Drosophila, and Caenorhabditis elegans genomes, but no function has previously been ascrib ...[more]
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Project description:Adult-onset vitelliform macular dystrophy (AVMD) is a common and benign macular degeneration which can be caused by BEST1 mutation. Here, we investigated the clinical characteristics associated with a newly identified BEST1 mutation, p.Ile38Ser and confirmed the associated physiological functional defects. The 51-year-old patient presented bilateral small subretinal yellow deposits. Consistent with AVMD, the corresponding lesions showed hyperautofluorescence, late staining in fluorescein angiography, and subretinal hyper-reflective materials in spectral-domain optical coherence tomography. Genetic analysis demonstrated that the patient presented with a heterozygous p.Ile38Ser BEST1 mutation. Surface biotinylation and patch clamp experiments were performed in transfected HEK293T cells. Although, the identified BEST1 mutant maintains normal membrane expression, p.Ile38Ser mutant showed significantly smaller currents than wild type (WT). However, it showed larger currents than other BEST1 mutants, p.Trp93Cys, causing autosomal dominant best vitelliform macular dystrophy (BVMD), and p.Ala195Val, causing autosomal recessive bestrophinopathy (ARB). The cells expressing both WT and each BEST1 mutant showed that the functional defect of p.Ile38ser was milder than that of p.Trp93Cys, whereas combination of p.Ala195Val with WT showed good current. We identified and described the phenotype and in vitro functions of a novel BEST1 mutation causing AVMD. AVMD induced by p.Ile38Ser BEST1 mutation is a mild form of BVMD.
| S-EPMC5567297 | biostudies-literature
Project description:PurposeIn patients diagnosed with Best vitelliform macular dystrophy (BVMD), quantitative fundus autofluorescence (qAF), near-infrared fundus autofluorescence (NIR-AF), and spectral-domain optical coherence tomography (SD-OCT) were used to elucidate pathogenic mechanisms.MethodsFourteen patients heterozygous for BEST1 mutations were recruited. qAF was analyzed using short-wavelength fundus autofluorescence (SW-AF) images. Mean gray levels (GL) were determined in nonlesion areas (7 to 9° eccentricity) and adjusted by GL measured in an internal fluorescent reference. NIR-AF images (787 nm; sensitivity of 96) were captured and saved in non-normalized mode. Horizontal SD-OCT images also were acquired and BVMD was staged according to the OCT findings.ResultsIn the pre-vitelliform stage, NIR-AF imaging revealed an area of reduced fluorescence, whereas in the vitelliruptive stage, puncta of elevated NIR-AF signal were present. In both SW-AF and NIR-AF images, the vitelliform lesion in the atrophic stage was marked by reduced signal. At all stages of BVMD, nonlesion qAF was within the 95% confidence intervals for healthy eyes. Similarly, the NIR-AF intensity measurements outside the vitelliform lesion were comparable to the healthy control eye. SD-OCT scans revealed a fluid-filled detachment between the ellipsoid zone and the hyperreflectivity band attributable to RPE/Bruch's membrane.ConclusionsNIR-AF imaging can identify the pre-vitelliform stage of BVMD. Mutations in BEST1 are not associated with increased levels of SW-AF outside the vitelliform lesion. Elevated SW-AF within the fluid-filled lesion likely reflects the inability of RPE to phagocytose outer segments due to separation of RPE from photoreceptor cells, together with progressive photoreceptor cell impairment.
| S-EPMC6735800 | biostudies-literature
Project description:Demonstrating the utility of adaptive optics scanning light ophthalmoscopy (AOSLO) to assess outer retinal structure in Best vitelliform macular dystrophy (BVMD).To characterize outer retinal structure in BVMD using spectral-domain optical coherence tomography (SD-OCT) and AOSLO.Prospective, observational case series. Four symptomatic members of a family with BVMD with known BEST1 mutation were recruited at the Advanced Ocular Imaging Program research lab at the Medical College of Wisconsin Eye Institute, Milwaukee.Thickness of 2 outer retinal layers corresponding to photoreceptor inner and outer segments was measured using SD-OCT. Photoreceptor mosaic AOSLO images within and around visible lesions were obtained, and cone density was assessed in 2 subjects.Photoreceptor structure.Each subject was at a different stage of BVMD, with photoreceptor disruption evident by AOSLO at all stages. When comparing SD-OCT and AOSLO images from the same location, AOSLO images allowed for direct assessment of photoreceptor structure. A variable degree of retained photoreceptors was seen within all lesions. The photoreceptor mosaic immediately adjacent to visible lesions appeared contiguous and was of normal density. Fine hyperreflective structures were visualized by AOSLO, and their anatomical orientation and size were consistent with Henle fibers.AND RELEVANCE: The AOSLO findings indicate that substantial photoreceptor structure persists within active lesions, accounting for good visual acuity in these patients. Despite previous reports of diffuse photoreceptor outer segment abnormalities in BVMD, our data reveal normal photoreceptor structure in areas adjacent to clinical lesions. This study demonstrates the utility of AOSLO for understanding the spectrum of cellular changes that occur in inherited degenerations such as BVMD. Photoreceptors are often significantly affected at various stages of inherited degenerations, and these changes may not be readily apparent with current clinical imaging instrumentation.
| S-EPMC3968428 | biostudies-literature
Project description:PurposeTo characterize outer retina structure in best vitelliform macular dystrophy (BVMD) and to determine the effect of macular lesions on overlying and adjacent photoreceptors.MethodsFive individuals with BVMD were followed prospectively with spectral domain optical coherence tomography and confocal and nonconfocal split-detector adaptive optics scanning light ophthalmoscopy (AOSLO). The AOSLO cone photoreceptor mosaic images were obtained within and around retinal lesions. Cone density was measured inside and outside lesions. In 2 subjects, densities were compared with published measurements acquired ∼2.5 years before. One subject was imaged 3 times over a 5-month period.ResultsThe AOSLO imaging demonstrated that photoreceptor morphology within BVMD retinal lesions was highly variable depending on the disease stage, with photoreceptor structure present even in advanced disease. The AOSLO imaging was repeatable even in severe disease over short-time and long-time intervals. Photoreceptor density was normal in retinal areas immediately adjacent to lesions and stable over ∼2.5 years. Mobile disk-like structures possibly representing subretinal macrophages were also observed.ConclusionCombined confocal and nonconfocal split-detector AOSLO imaging reveals substantial variability within clinical lesions in all stages of BVMD. Longitudinal cellular photoreceptor imaging could prove a powerful tool for understanding disease progression and monitoring emerging therapeutic treatment response in inherited degenerations such as BVMD.
| S-EPMC5362286 | biostudies-literature
Project description:PurposeTo analyze fixation location and stability in best vitelliform macular dystrophy (BVMD) and test their association with best-corrected visual acuity (BCVA).DesignObservational, cross-sectional study.ParticipantsThirty patients (55 eyes) affected by genetically confirmed BVMD were followed up at the Retinal Heredodystrophies Unit of IRCCS San Raffaele Scientific Institute, Milan.MethodsPatients underwent testing with macular integrity assessment (MAIA) microperimeter. Fixation location was measured as distance in degrees (°) between preferred retinal locus (PRL) and estimated fovea location (EFL); fixation was defined as eccentric when the distance between PRL and EFL exceeded 2°. Fixation stability was graded as stable, relatively unstable, or unstable and expressed as bivariate contour ellipse area (BCEA, °2).Main outcome measuresFixation location and stability.ResultsThe median distance of the PRL from the anatomic fovea was 0.7°, and fixation location was eccentric in 27% of eyes. Fixation was graded as stable in 64% of eyes, relatively unstable in 13%, and unstable in 24%, with a median 95% BCEA of 6.2°2. The atrophic/fibrotic stage was associated with worse fixation parameters (all P < 0.01). Both PRL eccentricity and fixation stability were linearly associated with BCVA: every 1° increase in PRL eccentricity was associated with a 0.07 logarithm of the minimum angle of resolution (logMAR) worse BCVA (P < 0.0001) while every 1°2 increase in 95% BCEA was associated with a 0.01 logMAR worse BCVA (P < 0.001). No significant intereye correlation was found for PRL eccentricity and fixation stability, as well as no association between the patient's age and fixation parameters.ConclusionsWe demonstrated that most eyes affected by BVMD retain a central stable fixation and provided evidence that both fixation eccentricity and stability are strongly associated with visual acuity in BVMD. These parameters may serve as secondary end points for future clinical trials.Financial disclosuresProprietary or commercial disclosure may be found after the references.
| S-EPMC10251068 | biostudies-literature
Project description:PURPOSE: To investigate the multimodal morphological features in the different stages of Best vitelliform macular dystrophy (VMD) in subjects harboring mutations in the BEST1 gene, and their changes during the progression of the disease. METHODS: In this retrospective observational study performed between January 2007 and December 2012, 21 patients (42 eyes) with Best VMD from eight families with the BEST1 mutation were included. Best-corrected visual acuity (BCVA), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SDOCT) were evaluated at study entry and at last visit. RESULTS: The mean age of patients was 26.3±17.4 years. Seven new missense mutations in BEST1 were identified. Mean follow-up was 41.1±18.5 months. Mean BCVA was 0.34±0.34 LogMAR at study entry and 0.32±0.33 LogMAR at last follow-up visit (p = 0.2). The overall lesion area on FAF increased from 6.62±4.9 mm² to 7.34±6.1 mm² (p = 0.05). At study entry, on SD-OCT, photoreceptor inner segment ellipsoid portion (ellipsoid zone, EZ) was normal in 15 eyes, disrupted in 14 eyes, and absent in 13 eyes. In two eyes, EZ changed from normal to disrupted during follow-up. Three eyes of three patients showing pseudohypopyon lesions at study entry progressed to vitelliruptive lesions at the last follow-up visit. Three eyes of three patients showing vitelliruptive lesion at study entry reverted to pseudohypopyon lesion with overall enlargement of the lesion size. CONCLUSIONS: Multimodal analysis allowed documenting a continuous material accumulation and reabsorption in Best VMD progression. Blue FAF and SD-OCT could represent noninvasive imaging techniques to monitor Best VMD.
| S-EPMC4000718 | biostudies-literature
Project description:PurposeTo determine the pupil response of Best vitelliform macular dystrophy (BVMD) patients for focal blue and red light stimuli presented at 76 test points in a 16.2° visual field (VF) using a chromatic pupilloperimeter.MethodsAn observational study was conducted in 16 participants: 7 BVMD patients with a heterozygous BEST1 mutation and 9 similar-aged controls. All participants were tested for best-corrected visual acuity, chromatic pupilloperimetry and Humphrey perimetry. Percentage of pupil contraction (PPC), maximal pupil contraction velocity (MCV) and latency of MCV (LMCV) were determined.ResultsThe mean PPC and MCV recorded in BVMD patients in response to red stimuli were lower by >2 standard errors (SEs) from the mean of controls in 47% and 43% of VF test points, respectively. The mean PPC and MCV recorded in the patients in response to blue stimuli were lower by >2 SEs from the mean of controls in 36% and 24% of VF test points, respectively. The patients' mean and median MCV recorded in response to red light correlated with their Humphrey mean deviation score (r=-0.714, P=0.071 and r=-0.821, P=0.023, respectively) and visual acuity (r=0.709, P=0.074 and r=0.655, P=0.111, respectively). A substantially shorter mean LMCV was recorded in BVMD patients compared to controls in 54% and 93% of VF test points in response to red and blue light, respectively. Receiver operating characteristic analysis for LMCV in response to red light identified a test point at the center of the VF with high diagnostic accuracy (area under the curve of 0.94).ConclusionChromatic pupilloperimetry may potentially be used for objective noninvasive assessment of rod and cone cell function in different locations of the retina in BVMD patients.
| S-EPMC6407903 | biostudies-literature
Project description:PurposeTo analyze the spectrum of sequence variants in the BEST1 gene in a group of Italian patients affected by Best vitelliform macular dystrophy (VMD).MethodsThirty Italian patients with a diagnosis of VMD and 20 clinically healthy relatives were recruited. They belonged to 19 Italian families predominantly originating from central Italy. They received a standard ophthalmologic examination, OCT scan, and electrophysiological tests (ERG and EOG). Fluorescein and ICG angiographies and fundus autofluorescence imaging were performed in selected cases. DNA samples were analyzed for sequence variants of the BEST1 gene by direct sequencing techniques.ResultsNine missense variants and one deletion were found in the affected patients; each patient carried one mutation. Five variants [c.73C>T (p.Arg25Trp), c.652C>T (p.Arg218Cys), c.652C>G (p.Arg218Gly), c.728C>T (p.Ala243Val), c.893T>C (p.Phe298Ser)] have already been described in literature while another five variants [c.217A>C (p.Ile73Leu), c.239T>G (p.Phe80Cys), c.883_885del (p.Ile295del), c.907G>A (p.Asp303Asn), c.911A>G (p.Asp304Gly)] had not previously been reported. Affected patients, sometimes even from the same family, occasionally showed variable phenotypes. One heterozygous variant was also found in five clinically healthy relatives with normal fundus, visual acuity and ERG but with abnormal EOG.ConclusionsTen variants in the BEST1 gene were detected in a group of individuals with clinically apparent VMD, and in some clinically normal individuals with an abnormal EOG. The high prevalence of novel variants and the frequent report of a specific variant (p.Arg25Trp) that has rarely been described in other ethnic groups suggests a distribution of BEST1 variants peculiar to Italian VMD patients.
| S-EPMC3513188 | biostudies-literature
Project description:Best Vitelliform Macular Dystrophy (BVMD) is a dominantly inherited retinal disease caused by dominant variants in the BEST1 gene. The original classification of BVMD is based on biomicroscopy and color fundus photography (CFP); however, advancements in retinal imaging provided unique structural, vascular, and functional data and novel insights on disease pathogenesis. Quantitative fundus autofluorescence studies informed us that lipofuscin accumulation, the hallmark of BVMD, is unlikely to be a primary effect of the genetic defect. It could be due to a lack of apposition between photoreceptors and retinal pigment epithelium in the macula with subsequent accumulation of shed outer segments over time. Optical Coherence Tomography (OCT) and adaptive optics imaging revealed that vitelliform lesions are characterized by progressive changes in the cone mosaic corresponding to a thinning of the outer nuclear layer and then disruption of the ellipsoid zone, which are associated with a decreased sensitivity and visual acuity. Therefore, an OCT staging system based on lesion composition, thus reflecting disease evolution, has been recently developed. Lastly, the emerging role of OCT Angiography proved a greater prevalence of macular neovascularization, the majority of which are non-exudative and develop in late disease stages. In conclusion, effective diagnosis, staging, and clinical management of BVMD will likely require a deep understanding of the multimodal imaging features of this disease.
| S-EPMC10757402 | biostudies-literature
Project description:BackgroundTo perform a quantitative optical coherence tomography (OCT) angiography (OCTA) analysis of macular neovascularization (MNV) secondary to age-related macular degeneration (AMD), central serous chorioretinopathy (CSC) and best vitelliform macular dystrophy (BVMD), with the aim of highlighting quantitative features indicating different clinical entities.MethodsStudy design: prospective, interventional. We recruited patients affected by AMD, CSC or BVMD, complicated by naive MNV. All patients underwent complete ophthalmologic examination and multimodal imaging. They were treated with anti-VEGF injections, following a pro-re-nata regimen. The ensuing follow-up lasted 1 year. Quantitative dye-based angiography, OCT, and OCTA parameters were analysed to obtain cutoff values able to distinguish two clinically different patient subgroups for each retinal disease. The main outcome measures were best-corrected visual acuity (BCVA), central macular thickness, vessel density of superficial, deep and choriocapillaris plexa, vessel tortuosity (VT) of MNV, vessel dispersion of MNV, number of injections, MNV/leakage ratio, MNV size, speckled fluorescence, and outer retinal atrophy.ResultsNinety-eight eyes affected by MNV (98 patients) were analysed. These included 66 eyes affected by AMD, 18 displaying CSC, and 14 eyes with BVMD. BCVA was alike in the three groups, both at baseline and after 1 year (p > 0.05). An MNV VT cutoff of 8.40 at baseline detected two patient subgroups differing significantly in terms of morpho-functional features, found both at baseline and at the end of the follow-up.ConclusionsQuantitative OCTA suggested that the MNV's VT might be able to provide a better characterization of two different morpho-functional manifestations in AMD, CSC and BVMD.
| S-EPMC8602382 | biostudies-literature