VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies

White, Karen L.; Marquardt, Andreas; Weber, Bernhard H. F.

doi:10.1002/(sici)1098-1004(200004)15:4<301::aid-humu1>3.0.co;2-n

Cited by 84 publications

(44 citation statements)

References 19 publications

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“…8,[11][12][13][14][15][16] In the present study, sequencing analysis of all BEST1 exons revealed heterozygous missense changes that are likely pathogenic in all eight analyzed families as well as one sporadic case (Fig. 2, Supplemental material at AJO.com or Supplemental Fig.…”

Section: Mutation Analysismentioning

confidence: 85%

Frequency, Genotype, and Clinical Spectrum of Best Vitelliform Macular Dystrophy: Data From a National Center in Denmark

Bitner

Schatz

Mizrahi-Meissonnier

et al. 2012

American Journal of Ophthalmology

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Section: Mutation Analysismentioning

confidence: 85%

Frequency, Genotype, and Clinical Spectrum of Best Vitelliform Macular Dystrophy: Data From a National Center in Denmark

Bitner

Schatz

Mizrahi-Meissonnier

et al. 2012

American Journal of Ophthalmology

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“…Bestrophin is predicted to be a transmembrane protein (14,20,21). To determine whether bestrophin is associated with cellular membranes, three independent assays were used.…”

Section: Localization Of Bestrophinmentioning

confidence: 99%

“…However, the function of the RFP genes is unknown. Computer-assisted structural analysis predicts that bestrophin is a transmembrane protein with four membrane-spanning ␣ helical domains, although a less likely five-transmembrane domain model recently has been proposed (21). There are no obvious targeting signals present in the amino acid sequence that would provide clues to its subcellular localization, and based on the four-transmembrane domain model, bestrophin has no obvious sites for posttranslational modifications such as N-glycosylation.…”

mentioning

confidence: 99%

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

Marmorstein

Rayborn

et al. 2000

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

395

329

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Best vitelliform macular dystrophy is a dominantly inherited, early onset, macular degenerative disease that exhibits some histopathologic similarities to age-related macular degeneration. Although the vitelliform lesion is common in the fundus of individuals with Best disease, diagnosis is based on a reduced ratio of the light peak to dark trough in the electrooculogram. Recently, the VMD2 gene on chromosome 11q13, encoding the protein bestrophin, was identified. The function of bestrophin is unknown. To facilitate studies of bestrophin, we produced both rabbit polyclonal and mouse monoclonal antibodies that proved useful for Western blotting, immunoprecipitation, and immunocytochemistry. To characterize bestrophin, we initially probed the retinal pigment epithelium (

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“…Several BMD-causing mutations have been mapped to the coiled-coil segment of hBest1, which has been called a mutational hot-spot (42). In light of the above results, this suggests that aberrant assembly can be a cause of pathology.…”

Section: Resultsmentioning

confidence: 99%

“…We found that the L 2 domain is both necessary and sufficient to determine specific self-assembly, and that it is the coiled-coil domain located at the C terminus of L 2 which is responsible. This coiled-coil domain has been identified as one of the four regions where mutations are associated with disease (42). Some of the mutations in the coiled-coil affect the surface expression of hBest1 in MDCKII cells (47), an expected outcome of disrupted assembly and a clear cause of pathology.…”

Section: Discussionmentioning

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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VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies

Cited by 84 publications

References 19 publications

Frequency, Genotype, and Clinical Spectrum of Best Vitelliform Macular Dystrophy: Data From a National Center in Denmark

Frequency, Genotype, and Clinical Spectrum of Best Vitelliform Macular Dystrophy: Data From a National Center in Denmark

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

Stoichiometry and specific assembly of Best ion channels

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