A Model of Best Vitelliform Macular Dystrophy in Rats

Marmorstein, Alan D.; Stanton, J. Brett; Yocom, J.; Bakall, Benjamin; Schiavone, Marc; Wadelius, Claes; Marmorstein, Lihua Y.; Peachey, Neal S.

doi:10.1167/iovs.04-0307

Cited by 50 publications

(53 citation statements)

References 27 publications

(36 reference statements)

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“…11 Animal models of Best disease have been sought. Neither overexpression of mutant alleles in rats, 12 nor targeted deletion of the BEST1 gene in mice, 13 produces the complete Best disease phenotype. However, mice carrying a W93C mutation do mimic some aspects of Best disease, including abnormal direct current electroretinograms (dc-ERGs), lipofuscin accumulation in the RPE, and debris in the subretinal space.…”

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confidence: 99%

Human Photoreceptor Outer Segments Shorten During Light Adaptation

Abràmoff

Mullins

Lee

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Best disease is a macular dystrophy caused by mutations in the BEST1 gene. Affected individuals exhibit a reduced electro-oculographic (EOG) response to changes in light exposure and have significantly longer outer segments (OS) than age-matched controls. The purpose of this study was to investigate the anatomical changes in the outer retina during dark and light adaptation in unaffected and Best disease subjects, and to compare these changes to the EOG.METHODS. Unaffected (n ¼ 11) and Best disease patients (n ¼ 7) were imaged at approximately 4-minute intervals during an approximately 40-minute dark-light cycle using spectral domain optical coherence tomography (SD-OCT). EOGs of two subjects were obtained under the same conditions. Automated three-dimensional (3-D) segmentation allowed measurement of light-related changes in the distances between five retinal surfaces.RESULTS. In normal subjects, there was a significant decrease in outer segment equivalent length (OSEL) of À2.14 lm (95% confidence interval [CI], À1.77 to À2.51 lm) 10 to 20 minutes after the start of light adaptation, while Best disease subjects exhibited a significant increase in OSEL of 2.07 lm (95% CI, 1.79-2.36 lm). The time course of the change in OS length corresponded to that of the EOG waveform. CONCLUSIONS.Our results strongly suggest that the light peak phase of the EOG is temporally related to a decreased OSEL in normal subjects, and the lack of a light peak phase in Best disease subjects is associated with an increase in OSEL. One potential role of Bestrophin-1 is to trigger an increase in the standing potential that approximates the OS to the apical surface of the RPE to facilitate phagocytosis.

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confidence: 99%

Human Photoreceptor Outer Segments Shorten During Light Adaptation

Abràmoff

Mullins

Lee

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…10 -12 and reviewed in Ref. 13) or indirectly as an accessory protein modulating neighboring channel function (14). On this note, studies on Vmd2-deficient mice suggested that the light peak of the EOG may be dependent on voltage-gated calcium channels that in turn may be regulated by bestrophin-1 (15).…”

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confidence: 99%

Insertion and Topology of Normal and Mutant Bestrophin-1 in the Endoplasmic Reticulum Membrane

Milenkovic

Rivera

Horling

et al. 2007

Journal of Biological Chemistry

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The vitelliform macular dystrophy type 2 (VMD2) gene mutated in Best macular dystrophy encodes a 585-amino acid putative transmembrane protein termed bestrophin-1. The vast majority of known disease-associated alterations are of the missense type, which cluster near predicted transmembrane domains (TMDs). To investigate bestrophin-1 membrane topology and to assess consequences of point mutations on membrane integration, we have analyzed the insertion of putative TMDs into the endoplasmic reticulum (ER) membrane. Out of six potential TMDs, our data suggest a topological model of bestrophin-1 with four transmembrane-spanning segments and one large cytoplasmatic loop between putative TMD2 and TMD5. Consequently, a relatively hydrophobic segment containing putative TMD3 (aa 130 -149) and TMD4 (aa 179 -201) is located within the cytoplasm. Furthermore, we show that three out of 18 disease-associated alterations investigated (I73N, Y85H, F281del) reveal measurable effects on membrane insertion suggesting that defective membrane integration of bestrophin-1 may represent a potential disease mechanism for a small subset of Best macular dystrophy-related mutations.Bestrophin-1 is encoded by the vitelliform macular dystrophy type 2 (VMD2) 2 gene as a 585-amino acid putative integral transmembrane protein localized to the basolateral aspect of the retinal pigment epithelium (RPE) (1). Disease-related mutations in the gene are responsible for the autosomal dominant Best macular dystrophy (BMD) (2, 3) but have also been associated with a minor proportion of cases presenting with adult vitelliforme macular dystrophy (4), bulls eye maculopathy (5), and autosomal dominant vitreoretinochoroidopathy (6). Thus far, a total of 100 distinct mutations have been identified including 92 in BMD, four in adult vitelliforme macular dystrophy, one in bulls eye maculopathy, and three in autosomal dominant vitreoretinochoroidopathy patients (for further information see BMD mutation data base). Of these, more than 93% are missense mutations, distributed in a non-random fashion across the highly conserved N-terminal half of the protein.Clinically, BMD is characterized by striking yellowish lesions in the macular area eventually leading to a decline in central vision at later stages in disease pathology. The disease manifests in teenage years although with reduced penetrance and considerable variability in phenotypic expression. Histopathologically, aberrant remnants of heterogeneous material including proteins, lipids, and lipofuscin-containing particles are found in the central retina at the level of the RPE. Typically, BMD patients display a characteristic electrooculogram (EOG) abnormality with a greatly reduced light peak/dark trough ratio reflecting RPE dysfunction (7).Accumulating experimental evidence suggests bestrophin-1, but also its highly conserved family members bestrophin-2, bestrophin-3 and bestrophin-4 (8, 9), to be involved in Ca 2ϩ -dependent transport of chloride ions across cellular membranes. It is still unclear whether bes...

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“…Because bestrophin 1 mutants have been shown to exert a dominant negative effect on wild-type bestrophin 1 (22,(36)(37)(38), and because hBest1 mutations cause BMD (39), but a knockout does not (40), we wondered if hBest1 mutants also exert a dominant negative effect through interaction with other CACCs, such as hBest2, 3, or 4, or TMEM16A, a member of another CACC family. To address this, we turned to the single-molecule colocalization method.…”

Section: Resultsmentioning

confidence: 99%

Stoichiometry and specific assembly of Best ion channels

Bharill

Palty

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Human Bestrophin 1 (hBest1) is a calcium-activated chloride channel that regulates neuronal excitability, synaptic activity, and retinal homeostasis. Mutations in hBest1 cause the autosomal-dominant Best macular dystrophy (BMD). Because hBest1 mutations cause BMD, but a knockout does not, we wondered if hBest1 mutants exert a dominant negative effect through interaction with other calciumactivated chloride channels, such as hBest2, 3, or 4, or transmembrane member 16A (TMEM16A), a member of another channel family. The subunit architecture of Best channels is debated, and their ability to form heteromeric channel assemblies is unclear. Using single-molecule subunit analysis, we find that each of hBest1, 2, 3, and 4 forms a homotetrameric channel. Despite considerable conservation among hBests, hBest1 has little or no interaction with other hBests or mTMEM16A. We identify the domain responsible for assembly specificity. This domain also plays a role in channel function. Our results indicate that Best channels preferentially self-assemble into homotetramers.

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A Model of Best Vitelliform Macular Dystrophy in Rats

Cited by 50 publications

References 27 publications

Human Photoreceptor Outer Segments Shorten During Light Adaptation

Human Photoreceptor Outer Segments Shorten During Light Adaptation

Insertion and Topology of Normal and Mutant Bestrophin-1 in the Endoplasmic Reticulum Membrane

Stoichiometry and specific assembly of Best ion channels

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