scholarly journals The Light Peak of the Electroretinogram Is Dependent on Voltage-gated Calcium Channels and Antagonized by Bestrophin (Best-1)

2006 ◽  
Vol 127 (5) ◽  
pp. 577-589 ◽  
Author(s):  
Lihua Y. Marmorstein ◽  
Jiang Wu ◽  
Precious McLaughlin ◽  
John Yocom ◽  
Mike O. Karl ◽  
...  
Keyword(s):  
Recent Observation ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Macular Dystrophy ◽  
Significant Shift ◽  
Loss Of Function ◽  
Vitelliform Macular Dystrophy ◽  
Light Peak ◽  
Voltage Dependent ◽  
Flash Electroretinogram

Mutations in VMD2, encoding bestrophin (best-1), cause Best vitelliform macular dystrophy (BMD), adult-onset vitelliform macular dystrophy (AVMD), and autosomal dominant vitreoretinochoroidopathy (ADVIRC). BMD is distinguished from AVMD by a diminished electrooculogram light peak (LP) in the absence of changes in the flash electroretinogram. Although the LP is thought to be generated by best-1, we find enhanced LP luminance responsiveness with normal amplitude in Vmd2−/− mice and no differences in cellular Cl− currents in comparison to Vmd2+/+ littermates. The putative Ca2+ sensitivity of best-1, and our recent observation that best-1 alters the kinetics of voltage-dependent Ca2+ channels (VDCC), led us to examine the role of VDCCs in the LP. Nimodipine diminished the LP, leading us to survey VDCC β-subunit mutant mice. Lethargic mice, which harbor a loss of function mutation in the β4 subunit of VDCCs, exhibited a significant shift in LP luminance response, establishing a role for Ca2+ in LP generation. When stimulated with ATP, which increases [Ca++]I, retinal pigment epithelial cells derived from Vmd2−/− mice exhibited a fivefold greater response than Vmd2+/+ littermates, indicating that best-1 can suppress the rise in [Ca2+]I associated with the LP. We conclude that VDCCs regulated by a β4 subunit are required to generate the LP and that best-1 antagonizes the LP luminance response potentially via its ability to modulate VDCC function. Furthermore, we suggest that the loss of vision associated with BMD is not caused by the same pathologic process as the diminished LP, but rather is caused by as yet unidentified effects of best-1 on other cellular processes.

scholarly journals Voltage-Dependent Calcium Channel CaV1.3 Subunits Regulate the Light Peak of the Electroretinogram

2007 ◽  
Vol 97 (5) ◽  
pp. 3731-3735 ◽  
Author(s):  
Jiang Wu ◽  
Alan D. Marmorstein ◽  
Jörg Striessnig ◽  
Neal S. Peachey
Keyword(s):  
Calcium Channel ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Rod Photoreceptor ◽  
Wild Type ◽  
Fast Oscillation ◽  
Light Peak ◽  
Voltage Dependent Calcium Channel ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

In response to light, the mouse retinal pigment epithelium (RPE) generates a series of slow changes in potential that are referred to as the c-wave, fast oscillation (FO), and light peak (LP) of the electroretinogram (ERG). The LP is generated by a depolarization of the basolateral RPE plasma membrane by the activation of a calcium-sensitive chloride conductance. We have previously shown that the LP is reduced in both mice and rats by nimodipine, which blocks voltage-dependent calcium channels (VDCCs) and is abnormal in lethargic mice, carrying a null mutation in the calcium channel β4 subunit. To define the α1 subunit involved in this process, we examined mice lacking CaV1.3. In comparison with wild-type (WT) control littermates, LPs were reduced in CaV1.3−/− mice. This pattern matched closely with that previously noted in lethargic mice, confirming a role for VDCCs in regulating the signaling pathway that culminates in LP generation. These abnormalities do not reflect a defect in rod photoreceptor activity, which provides the input to the RPE to generate the c-wave, FO, and LP, because ERG a-waves were comparable in WT and CaV1.3−/− littermates. Our results identify CaV1.3 as the principal pore-forming subunit of VDCCs involved in stimulating the ERG LP.

scholarly journals Nanomedicine-based Curcumin Approach Improved ROS Damage in Best Dystrophy-specific Induced Pluripotent Stem Cells

2019 ◽  
Vol 28 (11) ◽  
pp. 1345-1357 ◽  
Author(s):  
Tai-Chi Lin ◽  
Yi-Ying Lin ◽  
Chih-Chen Hsu ◽  
Yi-Ping Yang ◽  
Chang-Hao Yang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Drug Screening ◽  
Pluripotent Stem Cells ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Patient Specific ◽  
Macular Dystrophy ◽  
Junction Protein ◽  
Induced Pluripotent

Best dystrophy (BD), also termed best vitelliform macular dystrophy (BVMD), is a juvenile-onset form of macular degeneration and can cause central visual loss. Unfortunately, there is no clear definite therapy for BD or improving the visual function on this progressive disease. The human induced pluripotent stem cell (iPSC) system has been recently applied as an effective tool for genetic consultation and chemical drug screening. In this study, we developed patient-specific induced pluripotent stem cells (BD-iPSCs) from BD patient-derived dental pulp stromal cells and then differentiated BD-iPSCs into retinal pigment epithelial cells (BD-RPEs). BD-RPEs were used as an expandable platform for in vitro candidate drug screening. Compared with unaffected sibling-derived iPSC-derived RPE cells (Ctrl-RPEs), BD-RPEs exhibited typical RPE-specific markers with a lower expression of the tight junction protein ZO-1 and Bestrophin-1 (BEST1), as well as reduced phagocytic capabilities. Notably, among all candidate drugs, curcumin was the most effective for upregulating both the BEST1 and ZO-1 genes in BD-RPEs. Using the iPSC-based drug-screening platform, we further found that curcumin can significantly improve the mRNA expression levels of Best gene in BD-iPSC-derived RPEs. Importantly, we demonstrated that curcumin-loaded PLGA nanoparticles (Cur-NPs) were efficiently internalized by BD-RPEs. The Cur-NPs-based controlled release formulation further increased the expression of ZO-1 and Bestrophin-1, and promoted the function of phagocytosis and voltage-dependent calcium channels in BD-iPSC-derived RPEs. We further demonstrated that Cur-NPs enhanced the expression of antioxidant enzymes with a decrease in intracellular ROS production and hydrogen peroxide-induced oxidative stress. Collectively, these data supported that Cur-NPs provide a potential cytoprotective effect by regulating the anti-oxidative abilities of degenerated RPEs. In addition, the application of patient-specific iPSCs provides an effective platform for drug screening and personalized medicine in incurable diseases.

Optical Coherence Tomography in Best Vitelliform Macular Dystrophy

2017 ◽  
Vol 27 (2) ◽  
pp. 201-204 ◽  
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.

scholarly journals Stage-dependent choriocapillaris impairment in Best vitelliform macular dystrophy characterized by optical coherence tomography angiography

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ruben Jauregui ◽  
Rait Parmann ◽  
Yan Nuzbrokh ◽  
Stephen H. Tsang ◽  
Janet R. Sparrow
Keyword(s):  
Optical Coherence Tomography ◽  
Optical Coherence Tomography Angiography ◽  
Retinal Pigment ◽  
Disease Process ◽  
Treatment Modalities ◽  
Macular Dystrophy ◽  
Optical Coherence ◽  
Genetic Sequencing ◽  
Vitelliform Macular Dystrophy ◽  
Best Vitelliform Macular Dystrophy

AbstractCharacterization of vascular impairment in Best vitelliform macular dystrophy (BVMD) is essential for the development of treatment modalities and therapy trials. As such, we seek to characterize the choriocapillaris (CC) at each stage of the disease process in 22 patients (44 eyes) with a diagnosis of BVMD confirmed by genetic sequencing. We utilize optical coherence tomography angiography (OCTA) images to characterize the CC and correlate our findings to the status of the retinal pigment epithelium (RPE) as observed on short-wavelength fundus autofluorescence (SW-AF) images. We observed that in the vitelliruptive stage, the CC appeared as bright and granular in the area where the vitelliform lesion was present. In the atrophic stage, varying degrees of CC atrophy were observed within the lesion area, with the regions of CC atrophy appearing as hypoautofluorescent on SW-AF images. Our results suggest that the CC impairment observed in the vitelliruptive stage of BVMD progressively culminates in the CC atrophy observed at the atrophic stage. As such, OCTA imaging can be used to characterize CC impairment in BVMD patients as part of diagnosis and tracking of disease progression. Our findings suggest that the best window of opportunity for therapeutic approaches is before the atrophic stage, as it is during this stage that CC atrophy is observed.

New Evidence on BEST1 Genetic Variant Identified in a Patient with Best Vitelliform Macular Dystrophy Phenotype

2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Falah R ◽  
◽  
Distefano LN ◽  
Abuli-Vidal A ◽  
Garcia Arumi J ◽  
...  
Keyword(s):  
Genetic Variant ◽  
Age Of Onset ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Subretinal Fluid ◽  
Genetic Mutation ◽  
Macular Dystrophy ◽  
Vitelliform Macular Dystrophy ◽  
Best Vitelliform Macular Dystrophy ◽  
Best Disease

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].

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

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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