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Entry
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- *607854 - BESTROPHIN 1; BEST1
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*607854</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607854">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000167995;t=ENST00000378043" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=7439" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607854" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000167995;t=ENST00000378043" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001139443,NM_001300786,NM_001300787,NM_001363591,NM_001363592,NM_001363593,NM_004183,NR_134580,XM_005274210,XM_005274221,XM_047427523" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_004183" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607854" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01094&isoform_id=01094_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/BEST1" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/3335159,3335161,3511242,3598876,4759310,6175195,22800661,27371320,41216873,62088482,119594388,119594389,119594390,119594391,119594392,119594393,119594394,158260385,212720889,221039622,221040108,221040790,221040820,221041042,221041114,221042376,221043590,402810657,530397218,530397241,663856447,663856513,957950372,957950375,957950378,957950381,957950384,1391723869,1391723925,1391723949,2217284449,2462527315,2462527317,2462527319" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/O76090" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=7439" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000167995;t=ENST00000378043" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=BEST1" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=BEST1" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+7439" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/BEST1" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:7439" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/7439" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr11&hgg_gene=ENST00000378043.9&hgg_start=61949821&hgg_end=61965515&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:12703" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607854[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607854[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000167995" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=BEST1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=BEST1" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=BEST1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://www-huge.uni-regensburg.de/BEST1_database/home.php" title="University of Regensburg BEST1 database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">University of Regensburg B…</a></div><div style="margin-left: 0.5em;"><a href="http://www.retina-international.org/files/sci-news/vmd2mut.htm" title="Mutations of the Bestrophin Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Mutations of the Bestrophi…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=BEST1&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA162377454" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:12703" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0035696.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1346332" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/BEST1#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1346332" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/7439/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/results?search_type=advanced&omia_id=001444,001553,001554" class="mim-tip-hint" title="OMIA" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OMIA', 'domain': 'omia.angis.org.au'})">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=7439" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00007988;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00007988 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00008186;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00008186 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00008821;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00008821 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00009323;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00009323 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00009340;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00009340 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00014989;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00014989 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00015288;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00015288 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00015628;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00015628 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00016613;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00016613 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00020046;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00020046 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00021368;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00021368 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00022797;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00022797 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00206487;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00206487 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00220250;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00220250 </a></div>
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<div><a href="https://zfin.org/ZDB-GENE-110411-214" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=BEST1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 711162004, 723828008, 763387005<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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607854
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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BESTROPHIN 1; BEST1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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VMD2 GENE<br />
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TU15B
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=BEST1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BEST1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/11/467?start=-3&limit=10&highlight=467">11q12.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:61949821-61965515&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">11:61,949,821-61,965,515</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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<a href="/clinicalSynopsis/table?mimNumber=193220,611809,153700,613194,613194,193220" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
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View Clinical Synopses
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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<a href="/geneMap/11/467?start=-3&limit=10&highlight=467">
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11q12.3
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?Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2
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<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
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<a href="/entry/193220"> 193220 </a>
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Bestrophinopathy, autosomal recessive
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<span class="mim-font">
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<a href="/entry/611809"> 611809 </a>
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Macular dystrophy, vitelliform, 2
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<a href="/entry/153700"> 153700 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Retinitis pigmentosa-50
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<a href="/entry/613194"> 613194 </a>
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<span class="mim-font">
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<span class="mim-font">
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Retinitis pigmentosa, concentric
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<span class="mim-font">
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<a href="/entry/613194"> 613194 </a>
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<span class="mim-font">
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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Vitreoretinochoroidopathy
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<span class="mim-font">
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<a href="/entry/193220"> 193220 </a>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/607854" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/607854" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</ul>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<a id="description" class="mim-anchor"></a>
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>Description</strong>
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<p>BEST1 belongs to the bestrophin family of anion channels, which includes BEST2 (<a href="/entry/607335">607335</a>), BEST3 (<a href="/entry/607337">607337</a>), and BEST4 (<a href="/entry/607336">607336</a>). Bestrophins are transmembrane (TM) proteins that share a homology region containing a high content of aromatic residues, including an invariant arg-phe-pro (RFP) motif. The bestrophin genes share a conserved gene structure, with almost identical sizes of the 8 RFP-TM domain-encoding exons and highly conserved exon-intron boundaries. Each of the 4 bestrophin genes has a unique 3-prime end of variable length (<a href="#28" class="mim-tip-reference" title="Stohr, H., Marquardt, A., Nanda, I., Schmid, M., Weber, B. H. F. <strong>Three novel human VMD2-like genes are members of the evolutionary highly conserved RFP-TM family.</strong> Europ. J. Hum. Genet. 10: 281-284, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12032738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12032738</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200796" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12032738">Stohr et al., 2002</a>; <a href="#31" class="mim-tip-reference" title="Tsunenari, T., Sun, H., Williams, J., Cahill, H., Smallwood, P., Yau, K.-W., Nathans, J. <strong>Structure-function analysis of the bestrophin family of anion channels.</strong> J. Biol. Chem. 278: 41114-41125, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12907679[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M306150200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12907679">Tsunenari et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12032738+12907679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>Cloning and Expression</strong>
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<p>To identify the gene that is mutant in an early-onset form of vitelliform macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), also known as Best macular dystrophy, <a href="#25" class="mim-tip-reference" title="Petrukhin, K., Koisti, M. J., Bakall, B., Li, W., Xie, G., Marknell, T., Sandgren, O., Forsman, K., Holmgren, G., Andreasson, S., Vujic, M., Bergen, A. A. B., McGarty-Dugan, V., Figueroa, D., Austin, C. P., Metzker, M. L., Caskey, C. T., Wadelius, C. <strong>Identification of the gene responsible for Best macular dystrophy.</strong> Nature Genet. 19: 241-247, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662395</a>] [<a href="https://doi.org/10.1038/915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662395">Petrukhin et al. (1998)</a> defined the minimum genetic region on chromosome 11 by recombination breakpoint analysis, and scanned PAC clones of the region. They identified a novel retina-specific gene, designated VMD2, that encodes a 585-amino acid protein with a molecular mass of 68 kD and an isoelectric point of 6.9. The hydropathy profile predicted the presence of at least 4 putative transmembrane domains. Alternatively, these stretches of hydrophobic amino acids may be involved in the formation of hydrophobic pockets or may interact tightly with the membrane without crossing it. The 3-prime untranslated region (UTR) of the gene contains a region of antisense complementarity to the 3-prime UTR of the ferritin heavy-chain gene (FTH1; <a href="/entry/134770">134770</a>), suggesting the possibility of antisense interaction between VMD2 and FTH1 transcripts. A mouse VMD2 probe representing a protein fragment with 89% identity to human VMD2 demonstrated exquisitely specific expression in the retinal pigment epithelium (RPE) of the adult mouse eye; similar results were seen in the human retina. The only other site of VMD2 gene expression identified by in situ hybridization was Sertoli cells in mouse testis. <a href="#25" class="mim-tip-reference" title="Petrukhin, K., Koisti, M. J., Bakall, B., Li, W., Xie, G., Marknell, T., Sandgren, O., Forsman, K., Holmgren, G., Andreasson, S., Vujic, M., Bergen, A. A. B., McGarty-Dugan, V., Figueroa, D., Austin, C. P., Metzker, M. L., Caskey, C. T., Wadelius, C. <strong>Identification of the gene responsible for Best macular dystrophy.</strong> Nature Genet. 19: 241-247, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662395</a>] [<a href="https://doi.org/10.1038/915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662395">Petrukhin et al. (1998)</a> proposed the name 'bestrophin' for the protein encoded by the VMD2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Marquardt, A., Stohr, H., Passmore, L. A., Kramer, F., Rivera, A., Weber, B. H. F. <strong>Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease).</strong> Hum. Molec. Genet. 7: 1517-1525, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700209</a>] [<a href="https://doi.org/10.1093/hmg/7.9.1517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700209">Marquardt et al. (1998)</a> pursued further the work of <a href="#29" class="mim-tip-reference" title="Stohr, H., Marquardt, A., Rivera, A., Cooper, P. R., Nowak, N. J., Shows, T. B., Gerhard, D. S., Weber, B. H. F. <strong>A gene map of the Best's vitelliform macular dystrophy region in chromosome 11q12-q13.1.</strong> Genome Res. 8: 48-56, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9445487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9445487</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9445487[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gr.8.1.48" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9445487">Stohr et al. (1998)</a> in identifying novel genes located within the critical region for Best disease on 11q13. They characterized 9 novel genes, determining their expression profiles as well as their genomic organizations, and analyzed their exonic sequences for the presence of mutations in patients from multigenerational Best disease pedigrees. By Northern blot analysis, one of the genes, termed TU15B, was found to be expressed exclusively in retinal pigment epithelium (RPE) as a single 2.4-kb transcript. Database analysis of the putative translation product of TU15B revealed a high degree of sequence conservation throughout evolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9700209+9445487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>Gene Function</strong>
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<p>Using rabbit polyclonal and mouse monoclonal antibodies and immunocytochemical staining of macaque and porcine eyes, <a href="#19" class="mim-tip-reference" title="Marmorstein, A. D., Marmorstein, L. Y., Rayborn, M., Wang, X., Hollyfield, J. G., Petrukhin, K. <strong>Bestrophin, the product of the Best vitelliform macular dystrophy gene (VMD2), localizes to the basolateral plasma membrane of the retinal pigment epithelium.</strong> Proc. Nat. Acad. Sci. 97: 12758-12763, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11050159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11050159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11050159[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.220402097" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11050159">Marmorstein et al. (2000)</a> found that bestrophin is localized at the basolateral plasma membrane of RPE cells. This localization suggested that bestrophin may play a role in generating the altered electrooculogram of individuals with Best disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11050159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Goodstadt, L., Ponting, C. P. <strong>Sequence variation and disease in the wake of the draft human genome.</strong> Hum. Molec. Genet. 10: 2209-2214, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11673403/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11673403</a>] [<a href="https://doi.org/10.1093/hmg/10.20.2209" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11673403">Goodstadt and Ponting (2001)</a> used the prediction of enzymatic activity for bestrophin as an example of how genetic databases can expand understanding of genes of unknown function by identifying homologies and functional motifs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11673403" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using heterologous expression, <a href="#30" class="mim-tip-reference" title="Sun, H., Tsunenari, T., Yau, K.-W., Nathans, J. <strong>The vitelliform macular dystrophy protein defines a new family of chloride channels.</strong> Proc. Nat. Acad. Sci. 99: 4008-4013, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11904445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11904445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11904445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.052692999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11904445">Sun et al. (2002)</a> showed that the human, Drosophila, and C. elegans bestrophin homologs form oligomeric chloride channels, and that human bestrophin is sensitive to intracellular calcium. Each of 15 missense mutations associated with vitelliform macular dystrophy greatly reduced or abolished the membrane current. Four of these mutant bestrophins were coexpressed with wildtype and each dominantly inhibited the wildtype membrane current, consistent with the dominant nature of the disorder. These experiments established the existence of a new chloride channel family and VMD as a channelopathy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11904445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By whole-cell recordings of BEST1-transfected 293 cells, <a href="#30" class="mim-tip-reference" title="Sun, H., Tsunenari, T., Yau, K.-W., Nathans, J. <strong>The vitelliform macular dystrophy protein defines a new family of chloride channels.</strong> Proc. Nat. Acad. Sci. 99: 4008-4013, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11904445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11904445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11904445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.052692999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11904445">Sun et al. (2002)</a> and <a href="#31" class="mim-tip-reference" title="Tsunenari, T., Sun, H., Williams, J., Cahill, H., Smallwood, P., Yau, K.-W., Nathans, J. <strong>Structure-function analysis of the bestrophin family of anion channels.</strong> J. Biol. Chem. 278: 41114-41125, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12907679[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M306150200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12907679">Tsunenari et al. (2003)</a> detected a weakly outward-rectifying current in response to a negative voltage step. <a href="#31" class="mim-tip-reference" title="Tsunenari, T., Sun, H., Williams, J., Cahill, H., Smallwood, P., Yau, K.-W., Nathans, J. <strong>Structure-function analysis of the bestrophin family of anion channels.</strong> J. Biol. Chem. 278: 41114-41125, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12907679[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1074/jbc.M306150200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12907679">Tsunenari et al. (2003)</a> did not find new chloride currents in Xenopus oocytes following injection of BEST1 cRNA, suggesting that human cells contain a factor or subunit required for bestrophin function or plasma membrane localization. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11904445+12907679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using Western blot analysis and confocal microscopy, <a href="#10" class="mim-tip-reference" title="Duta, V., Szkotak, A. J., Nahirney, D., Duszyk, M. <strong>The role of bestrophin in airway epithelial ion transport.</strong> FEBS Lett. 577: 551-554, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15556645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15556645</a>] [<a href="https://doi.org/10.1016/j.febslet.2004.10.068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15556645">Duta et al. (2004)</a> showed that bestrophin was expressed in a human lung adenocarcinoma cell line. Bestrophin-directed small interfering RNA reduced the movement of radioactive chloride across cell monolayers. <a href="#10" class="mim-tip-reference" title="Duta, V., Szkotak, A. J., Nahirney, D., Duszyk, M. <strong>The role of bestrophin in airway epithelial ion transport.</strong> FEBS Lett. 577: 551-554, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15556645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15556645</a>] [<a href="https://doi.org/10.1016/j.febslet.2004.10.068" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15556645">Duta et al. (2004)</a> concluded that bestrophin contributes to the basolateral cell conductance in airway epithelial cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15556645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Although phasic GABA release arises from Ca(2+)-dependent exocytosis from neurons, the mechanism of tonic GABA release was unknown. <a href="#18" class="mim-tip-reference" title="Lee, S., Yoon, B.-E., Berglund, K., Oh, S.-J., Park, H., Shin, H.-S., Augustine, G. J., Lee, C. J. <strong>Channel-mediated tonic GABA release from glia.</strong> Science 330: 790-796, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20929730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20929730</a>] [<a href="https://doi.org/10.1126/science.1184334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20929730">Lee et al. (2010)</a> reported that tonic inhibition in the cerebellum is due to GABA being released from glial cells by permeation of the bestrophin-1 (Best1) anion channel. They demonstrated that GABA directly permeates Best1 to yield GABA release and that tonic inhibition is eliminated by silencing of Best1. Glial cells express both GABA and Best1, and selective expression of Best1 in glial cells, after preventing general expression of Best1, fully rescues tonic inhibition. <a href="#18" class="mim-tip-reference" title="Lee, S., Yoon, B.-E., Berglund, K., Oh, S.-J., Park, H., Shin, H.-S., Augustine, G. J., Lee, C. J. <strong>Channel-mediated tonic GABA release from glia.</strong> Science 330: 790-796, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20929730/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20929730</a>] [<a href="https://doi.org/10.1126/science.1184334" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20929730">Lee et al. (2010)</a> concluded that their results identified a molecular mechanism for tonic inhibition and established a role for interactions between glia and neurons in mediating tonic inhibition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20929730" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Moshfegh, Y., Velez, G., Li, Y., Bassuk, A. G., Mahajan, V. B., Tsang, S. H. <strong>BESTROPHIN1 mutations cause defective chloride conductance in patient stem cell-derived RPE.</strong> Hum. Molec. Genet. 25: 2672-2680, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27193166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27193166</a>] [<a href="https://doi.org/10.1093/hmg/ddw126" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27193166">Moshfegh et al. (2016)</a> found that mutations in BEST1 associated with VMD2 affected highly conserved residues. Structural modeling predicted that these BEST1 mutations would disrupt stability of pentamer formation and affect channel function. Studies of wildtype and patient stem cell-derived RPE cells suggested that BEST1 mediates chloride ion efflux in RPE cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27193166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#34" class="mim-tip-reference" title="Yang, T., Liu, Q., Kloss, B., Bruni, R., Kalathur, R. C., Guo, Y., Kloppmann, E., Rost, B., Colecraft, H. M., Hendrickson, W. A. <strong>Structure and selectivity in bestrophin ion channels.</strong> Science 346: 355-359, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25324390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25324390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25324390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1259723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25324390">Yang et al. (2014)</a> described the structure of a bacterial homolog (KpBest) of BEST1 as well as functional characterizations of both channels. KpBest is a pentamer that forms a 5-helix transmembrane pore, closed by 3 rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiologic analysis of structure-inspired mutations in KpBest and BEST1, <a href="#34" class="mim-tip-reference" title="Yang, T., Liu, Q., Kloss, B., Bruni, R., Kalathur, R. C., Guo, Y., Kloppmann, E., Rost, B., Colecraft, H. M., Hendrickson, W. A. <strong>Structure and selectivity in bestrophin ion channels.</strong> Science 346: 355-359, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25324390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25324390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25324390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1259723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25324390">Yang et al. (2014)</a> found a sensitive control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the cytoplasmic exit. <a href="#34" class="mim-tip-reference" title="Yang, T., Liu, Q., Kloss, B., Bruni, R., Kalathur, R. C., Guo, Y., Kloppmann, E., Rost, B., Colecraft, H. M., Hendrickson, W. A. <strong>Structure and selectivity in bestrophin ion channels.</strong> Science 346: 355-359, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25324390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25324390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25324390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1259723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25324390">Yang et al. (2014)</a> also created a homology model of BEST1 that shows the locations of disease-causing mutations and suggests possible roles in regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25324390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Dickson, V. K., Pedi, L., Long, S. B. <strong>Structure and insights into the function of a Ca(2+)-activated Cl- channel.</strong> Nature 516: 213-218, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25337878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25337878</a>] [<a href="https://doi.org/10.1038/nature13913" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25337878">Dickson et al. (2014)</a> presented the x-ray crystal structures of chicken BEST1-Fab complexes at 2.85-angstrom resolution with permeant anions and Ca(2+). Representing the first structure of a calcium-activated chloride channel, the eukaryotic BEST1 channel is formed from a pentameric assembly of subunits. Ca(2+) binds to the channels large cytosolic region. A single ion pore approximately 95 angstroms in length is located along the central axis and contains at least 15 binding sites for anions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25337878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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In several Swedish and Dutch families with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), including a large Swedish family reported by <a href="#24" class="mim-tip-reference" title="Nordstrom, S., Barkman, Y. <strong>Hereditary macular degeneration (HMD) in 246 cases traced to one gene-source in central Sweden.</strong> Hereditas 84: 163-176, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/838599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">838599</a>] [<a href="https://doi.org/10.1111/j.1601-5223.1977.tb01394.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="838599">Nordstrom and Barkman (1977)</a> and studied by <a href="#13" class="mim-tip-reference" title="Graff, C., Eriksson, A., Forsman, K., Sandgren, O., Holmgren, G., Wadelius, C. <strong>Refined genetic localization of the Best disease gene in 11q13 and physical mapping of linked markers on radiation hybrids.</strong> Hum. Genet. 101: 263-270, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9439653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9439653</a>] [<a href="https://doi.org/10.1007/s004390050627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9439653">Graff et al. (1997)</a>, <a href="#25" class="mim-tip-reference" title="Petrukhin, K., Koisti, M. J., Bakall, B., Li, W., Xie, G., Marknell, T., Sandgren, O., Forsman, K., Holmgren, G., Andreasson, S., Vujic, M., Bergen, A. A. B., McGarty-Dugan, V., Figueroa, D., Austin, C. P., Metzker, M. L., Caskey, C. T., Wadelius, C. <strong>Identification of the gene responsible for Best macular dystrophy.</strong> Nature Genet. 19: 241-247, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662395</a>] [<a href="https://doi.org/10.1038/915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662395">Petrukhin et al. (1998)</a> identified 5 different heterozygous mutations in the VMD2 gene (<a href="#0001">607854.0001</a>-<a href="#0005">607854.0005</a>) that segregated with the disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9439653+9662395+838599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 12 patients with Best macular dystrophy, <a href="#20" class="mim-tip-reference" title="Marquardt, A., Stohr, H., Passmore, L. A., Kramer, F., Rivera, A., Weber, B. H. F. <strong>Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease).</strong> Hum. Molec. Genet. 7: 1517-1525, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700209</a>] [<a href="https://doi.org/10.1093/hmg/7.9.1517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700209">Marquardt et al. (1998)</a> identified heterozygous sequence changes in the TU15B gene (see, e.g., <a href="#0006">607854.0006</a>). For 10 sequence changes, segregation with the disease was shown in multigenerational families. These data provided strong evidence that TU15B is the VMD2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9700209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Bakall, B., Marknell, T., Ingvast, S., Koisti, M. J., Sandgren, O., Li, W., Bergen, A. A. B., Andreasson, S., Rosenberg, T., Petrukhin, K., Wadelius, C. <strong>The mutation spectrum of the bestrophin protein--functional implications.</strong> Hum. Genet. 104: 383-389, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10394929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10394929</a>] [<a href="https://doi.org/10.1007/s004390050972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10394929">Bakall et al. (1999)</a> analyzed the bestrophin gene in 14 unrelated Swedish, Dutch, Danish, and Moroccan families with Best macular dystrophy and identified 8 previously unreported mutations. No mutations were detected in 3 families. The authors noted that the 19 mutations identified to date were missense mutations aggregating in 4 regions of the gene, and suggested that null alleles might result in other ocular diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10394929" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated women who had vitelliform macular dystrophy diagnosed in the sixth decade of life, <a href="#1" class="mim-tip-reference" title="Allikmets, R., Seddon, J. M., Bernstein, P. S., Hutchinson, A., Atkinson, A., Sharma, S., Gerrard, B., Li, W., Metzker, M. L., Wadelius, C., Caskey, C. T., Dean, M., Petrukhin, K. <strong>Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies.</strong> Hum. Genet. 104: 449-453, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10453731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10453731</a>] [<a href="https://doi.org/10.1007/s004390050986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10453731">Allikmets et al. (1999)</a> identified heterozygous missense mutations in the BEST1 gene (E119Q, <a href="#0008">607854.0008</a>; A146K, <a href="#0009">607854.0009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10453731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Caldwell, G. M., Kakuk, L. E., Griesinger, I. B., Simpson, S. A., Nowak, N. J., Small, K. W., Maumenee, I. H., Rosenfeld, P. J., Sieving, P. A., Shows, T. B., Ayyagari, R. <strong>Bestrophin gene mutations in patients with Best vitelliform macular dystrophy.</strong> Genomics 58: 98-101, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10331951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10331951</a>] [<a href="https://doi.org/10.1006/geno.1999.5808" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10331951">Caldwell et al. (1999)</a> analyzed the bestrophin gene in 13 families with Best macular dystrophy and identified mutations in 9 families, including 6 missense mutations and a 2-bp deletion (<a href="#0012">607854.0012</a>). The deletion occurred in exon 10; the authors stated that this was the first mutation reported in the 3-prime half of the bestrophin gene, beyond exon 8. In 3 of the families, there was a parent carrying the mutation who lacked the clinical phenotype, suggesting variable expression of the disease gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10331951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Kramer, F., White, K., Pauleikhoff, D., Gehrig, A., Passmore, L., Rivera, A., Rudolph, G., Kellner, U., Andrassi, M., Lorenz, B., Rohrschneider, K., Blankenagel, A., Jurklies, B., Schilling, H., Schutt, F., Holz, F. G., Weber, B. H. F. <strong>Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration.</strong> Europ. J. Hum. Genet. 8: 286-292, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854112</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854112">Kramer et al. (2000)</a> identified several mutations in the VMD2 gene in German patients with macular dystrophy of juvenile onset as well as in 8 of 32 patients with adult-onset disease who were negative for mutation in the PRPH2 gene (see, e.g., <a href="#0005">607854.0005</a> and <a href="#0010">607854.0010</a>-<a href="#0011">607854.0011</a>). The authors suggested that the adult-onset patients represented a mild form of Best disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10854112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="White, K., Marquardt, A., Weber, B. H. F. <strong>VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies.</strong> Hum. Mutat. 15: 301-308, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10737974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10737974</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(200004)15:4<301::AID-HUMU1>3.0.CO;2-N" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10737974">White et al. (2000)</a> stated that 48 different mutations, predominantly missense mutations, had been described in the VMD2 gene in Best disease families. For the most part, these mutations affected amino acids in the first 50% of the protein and occurred in 4 distinct clusters possibly representing regions of functional importance. Results of analysis in 2 large series of patients with age-related macular degeneration (see <a href="/entry/603785">603785</a>) suggested that the VMD2 gene does not play a major role in this disorder (<a href="#16" class="mim-tip-reference" title="Kramer, F., White, K., Pauleikhoff, D., Gehrig, A., Passmore, L., Rivera, A., Rudolph, G., Kellner, U., Andrassi, M., Lorenz, B., Rohrschneider, K., Blankenagel, A., Jurklies, B., Schilling, H., Schutt, F., Holz, F. G., Weber, B. H. F. <strong>Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration.</strong> Europ. J. Hum. Genet. 8: 286-292, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854112</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854112">Kramer et al., 2000</a>; <a href="#1" class="mim-tip-reference" title="Allikmets, R., Seddon, J. M., Bernstein, P. S., Hutchinson, A., Atkinson, A., Sharma, S., Gerrard, B., Li, W., Metzker, M. L., Wadelius, C., Caskey, C. T., Dean, M., Petrukhin, K. <strong>Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies.</strong> Hum. Genet. 104: 449-453, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10453731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10453731</a>] [<a href="https://doi.org/10.1007/s004390050986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10453731">Allikmets et al., 1999</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10737974+10854112+10453731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Schatz, P., Klar, J., Andreasson, S., Ponjavic, V., Dahl, N. <strong>Variant phenotype of Best vitelliform macular dystrophy associated with compound heterozygous mutation in VMD2.</strong> Ophthal. Genet. 27: 51-56, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16754206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16754206</a>] [<a href="https://doi.org/10.1080/13816810600677990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16754206">Schatz et al. (2006)</a> reported 6 affected members of a Swedish family with Best macular dystrophy who had mutations in the BEST1 gene. Four were heterozygous for either an R141H (<a href="#0013">607854.0013</a>) or a Y29X (<a href="#0014">607854.0014</a>) mutation and 2 were compound heterozygous for these mutations. The latter 2 patients presented with a variant form of the disorder. Both had onset of visual symptoms in early childhood and markedly reduced visual acuities. Fundus examination and OCT scan showed degenerative yellowish changes in the macula, thickening and elevation of the outer retina-RPE-choroid complex, and cystic edema of the macula. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16754206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Katagiri, S., Hayashi, T., Ohkuma, Y., Sekiryu, T., Takeuchi, T., Gekka, T., Kondo, M., Iwata, T., Tsuneoka, H. <strong>Mutation analysis of BEST1 in Japanese patients with Best's vitelliform macular dystrophy.</strong> Brit. J. Ophthal. 99: 1577-1582, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26201355/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26201355</a>] [<a href="https://doi.org/10.1136/bjophthalmol-2015-306830" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26201355">Katagiri et al. (2015)</a> performed a mutation analysis of the BEST1 and PRPH2 genes in 16 Japanese families with typical features of VMD and identified 12 different BEST1 variants in 13 probands (81%). Two of the variants were novel and 10 had previously been reported. Twelve probands had heterozygous mutations and 1 proband had compound heterozygous mutations. No mutations were identified in the PRPH2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26201355" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Bestrophinopathy, Autosomal Recessive</em></strong></p><p>
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<a href="#6" class="mim-tip-reference" title="Burgess, R., Millar, I. D., Leroy, B. P., Urquhart, J. E., Fearon, I. M., De Baere, E., Brown, P. D., Robson, A. G., Wright, G. A., Kestelyn, P., Holder, G. E., Webster, A. R., Manson, F. D. C., Black, G. C. M. <strong>Biallelic mutation of BEST1 causes a distinct retinopathy in humans.</strong> Am. J. Hum. Genet. 82: 19-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179881[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.08.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179881">Burgess et al. (2008)</a> described a retinal disorder, which they designated autosomal recessive bestrophinopathy (ARB; <a href="/entry/611809">611809</a>), caused by biallelic mutation in BEST1 (e.g., <a href="#0013">607854.0013</a> and <a href="#0017">607854.0017</a>) and associated with central visual loss, a characteristic retinopathy, an absent electrooculogram light rise, and a reduced electroretinogram. In 5 families, DNA variants were identified in each of 10 alleles. These encoded 6 different missense variants and 1 nonsense variant. No clinical or electrophysiologic abnormalities were found in heterozygotes. Two ARB missense isoforms severely reduced chloride channel activity. However, unlike 2 other alleles previously associated with Best disease, cotransfection with wildtype bestrophin-1 did not impair the formation of active wildtype bestrophin-1 channels, consistent with the recessive nature of the condition. <a href="#6" class="mim-tip-reference" title="Burgess, R., Millar, I. D., Leroy, B. P., Urquhart, J. E., Fearon, I. M., De Baere, E., Brown, P. D., Robson, A. G., Wright, G. A., Kestelyn, P., Holder, G. E., Webster, A. R., Manson, F. D. C., Black, G. C. M. <strong>Biallelic mutation of BEST1 causes a distinct retinopathy in humans.</strong> Am. J. Hum. Genet. 82: 19-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179881[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.08.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179881">Burgess et al. (2008)</a> proposed that ARB is a null phenotype of bestrophin-1 in humans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Vitreoretinochoroidopathy</em></strong></p><p>
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<a href="#35" class="mim-tip-reference" title="Yardley, J., Leroy, B. P., Hart-Holden, N., Lafaut, B. A., Loeys, B., Messiaen, L. M., Perveen, R., Reddy, M. A., Bhattacharya, S. S., Traboulsi, E., Baralle, D., De Laey, J.-J., Puech, B., Kestelyn, P., Moore, A. T., Manson, F. D. C., Black, G. C. M. <strong>Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC).</strong> Invest. Ophthal. Vis. Sci. 45: 3683-3689, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452077</a>] [<a href="https://doi.org/10.1167/iovs.04-0550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15452077">Yardley et al. (2004)</a> sequenced the BEST1 gene in 5 families with autosomal dominant developmental eye abnormalities associated with retinal dystrophy (see vitreoretinochoroidopathy, or ADVIRC, <a href="/entry/193220">193220</a>), and identified 3 different heterozygous missense mutations (V86M, <a href="#0019">607854.0019</a>; V239M, <a href="#0020">607854.0020</a>; and Y236C, <a href="#0021">607854.0021</a>). In vitro functional assays demonstrated that all 3 of these mutations disrupted splicing and caused exon skipping, whereas 2 mutations in close proximity that are known to cause Best disease, Y85H (<a href="#0002">607854.0002</a>) and A243T, did not. Screening of the BEST1 gene in 18 unrelated individuals with microphthalmia/coloboma (see MCOPCB1, <a href="/entry/300345">300345</a>) and 50 individuals with various forms of anterior segment dysgenesis revealed no pathogenic alterations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15452077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Retinitis Pigmentosa 50</em></strong></p><p>
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In the proband of a nonconsanguineous family of European descent segregating autosomal dominant retinitis pigmentosa (adRP) mapping to chromosome 11 (RP50; <a href="/entry/613194">613194</a>), <a href="#8" class="mim-tip-reference" title="Davidson, A. E., Millar, I. D., Urquhart, J. E., Burgess-Mullan, R., Shweikh, Y., Parry, N., O'Sullivan, J., Maher, G. J., McKibbin, M., Downes, S. M., Lotery, A. J., Jacobson, S. G., Brown, P. D., Black, G. C. M., Manson, F. D. C. <strong>Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa.</strong> Am. J. Hum. Genet. 85: 581-592, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853238[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853238">Davidson et al. (2009)</a> sequenced the BEST1 gene and identified heterozygosity for a missense mutation (I205T; <a href="#0022">607854.0022</a>) that segregated with disease in the family. Analysis of BEST1 in a panel of 95 adRP patients who were negative for mutation in 10 known RP genes and in 12 patients with concentric RP revealed heterozygosity for a D228N missense mutation (<a href="#0023">607854.0023</a>) in affected members of 1 adRP family and 1 concentric RP family, and heterozygosity for a Y227C mutation (<a href="#0024">607854.0024</a>) in another concentric RP family. Homozygosity for a missense mutation in BEST1 (L140V; <a href="#0025">607854.0025</a>) was found in affected members of a Pakistani family that appeared to be segregating adRP, but in which the parents were from the same village. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19853238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an affected sister and brother from a family segregating autosomal dominant vitreoretinochoroidopathy (ADVIRC), <a href="#5" class="mim-tip-reference" title="Burgess, R., MacLaren, R. E., Davidson, A. E., Urquhart, J. E., Holder, G. E., Robson, A. G., Moore, A. T., O'Keefe, R., Black, G. C. M., Manson, F. D. C. <strong>ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. (Letter)</strong> J. Med. Genet. 46: 620-625, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18611979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18611979</a>] [<a href="https://doi.org/10.1136/jmg.2008.059881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18611979">Burgess et al. (2009)</a> identified heterozygosity for a 704T-C transition in the BEST1 gene (V235A; <a href="#0026">607854.0026</a>). Analysis of exonic splice enhancer (ESE) activity in exon 6 of the BEST1 gene demonstrated that 2 ADVIRC-associated mutations, V235A and Y236C (<a href="#0021">607854.0021</a>; 707A-G), weakened or abolished ESE site-dependent splicing, respectively, whereas a Best disease-associated mutation (V235L; 703G-C; see <a href="#35" class="mim-tip-reference" title="Yardley, J., Leroy, B. P., Hart-Holden, N., Lafaut, B. A., Loeys, B., Messiaen, L. M., Perveen, R., Reddy, M. A., Bhattacharya, S. S., Traboulsi, E., Baralle, D., De Laey, J.-J., Puech, B., Kestelyn, P., Moore, A. T., Manson, F. D. C., Black, G. C. M. <strong>Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC).</strong> Invest. Ophthal. Vis. Sci. 45: 3683-3689, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452077</a>] [<a href="https://doi.org/10.1167/iovs.04-0550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15452077">Yardley et al., 2004</a>) strengthened ESE activity compared to wildtype. In addition, gel-shift assays involving serine/arginine (SR)-rich proteins, such as SFRS1 (<a href="/entry/600812">600812</a>), showed that SFRS1 had increased binding to the V235A- or V236C-mutant sequences compared to wildtype or V235L-mutant sequence. Given the exon skipping observed with the ADVIRC-associated mutations and their affinity for SFRS1, <a href="#5" class="mim-tip-reference" title="Burgess, R., MacLaren, R. E., Davidson, A. E., Urquhart, J. E., Holder, G. E., Robson, A. G., Moore, A. T., O'Keefe, R., Black, G. C. M., Manson, F. D. C. <strong>ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. (Letter)</strong> J. Med. Genet. 46: 620-625, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18611979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18611979</a>] [<a href="https://doi.org/10.1136/jmg.2008.059881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18611979">Burgess et al. (2009)</a> suggested that the region encompassing V235A and Y236C mutations (nucleotides 704 to 709) may form part of a composite exonic regulatory elements of splicing (CERES) site. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18611979+15452077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Milenkovic, A., Milenkovic, V. M., Wetzel, C. H., Weber, B. H. F. <strong>BEST1 protein stability and degradation pathways differ between autosomal dominant Best disease and autosomal recessive bestrophinopathy accounting for the distinct retinal phenotypes.</strong> Hum. Molec. Genet. 27: 1630-1641, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29668979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29668979</a>] [<a href="https://doi.org/10.1093/hmg/ddy070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29668979">Milenkovic et al. (2018)</a> found that pathologic mutations affecting highly conserved residues in the N-terminal half of BEST1 likely affect protein stability. Analysis of BEST1 half-life in transfected canine MDCKII cells confirmed that BEST1 mutations enhanced protein instability. BEST1 proteins with autosomal recessive mutations were degraded more quickly than wildtype BEST1 or BEST1 proteins with autosomal dominant mutations due to the use of different degradation mechanisms. BEST1 proteins with autosomal recessive mutations were recognized by the endoplasmic reticulum (ER) and subsequently degraded, whereas BEST1 proteins with autosomal dominant mutations escaped the ER quality check and were degraded by a post-ER quality control mechanism at the Golgi complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29668979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Esumi, N., Kachi, S., Hackler, L., Jr., Masuda, T., Yang, Z., Campochiaro, P. A., Zack, D. J. <strong>BEST1 expression in the retinal pigment epithelium is modulated by OTX family members.</strong> Hum. Molec. Genet. 18: 128-141, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18849347/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18849347</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18849347[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn323" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18849347">Esumi et al. (2009)</a> showed that the -154 to -104 bp region of the Best1 gene is necessary for retinal pigment epithelium (RPE) expression in transgenic mice. The Best1 promoter region contains a predicted canonical OTX-binding site (-127 to -122 bp) and a neighboring noncanonical OTX-binding site (-81 to -76 bp), and mutation of either OTX-binding site results in reduced promoter activity. The 3 OTX family proteins, OTX1 (<a href="/entry/600036">600036</a>), OTX2 (<a href="/entry/600037">600037</a>), and CRX (<a href="/entry/602225">602225</a>) bound to both OTX-binding sites in vitro, and all of them increased BEST1 promoter activity. Human and bovine RPE expressed not only OTX2 but also CRX, and both OTX2 and CRX bound to the BEST1 proximal promoter region in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18849347" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Zhang, Y., Stanton, J. B., Wu, J., Yu, K., Hartzell, H. C., Peachey, N. S., Marmorstein, L. Y., Marmorstein, A. D. <strong>Suppression of Ca(2+) signaling in a mouse model of Best disease.</strong> Hum. Molec. Genet. 19: 1108-1118, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20053664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20053664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20053664[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddp583" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20053664">Zhang et al. (2010)</a> generated knockin mice carrying the Best vitelliform macular dystrophy-causing mutation W93C (607854.0001) in Best1. Both Best1(+/W93C) and Best1(W93C/W93C) mice had normal ERG a- and b-waves, but exhibited an altered light peak luminance response reminiscent of that observed in BVMD patients. Morphologic analysis identified fluid- and debris-filled retinal detachments in mice as young as 6 months of age. By 18 to 24 months of age, Best1(+/W93C) and Best1(W93C/W93C) mice exhibited enhanced accumulation of lipofuscin in the RPE, and a significant deposition of debris composed of unphagocytosed photoreceptor outer segments and lipofuscin granules in the subretinal space. The RPE cells from Best1(W93C) mice exhibited normal chloride conductances, and ATP-stimulated changes in calcium concentration in RPE cells from Best1(+/W93C) and Best1(W93C/W93C) mice were suppressed relative to Best1 +/+ littermates. The authors hypothesized that BVMD does not occur because of Best1 deficiency, as the phenotypes of Best1(+/W93C0) and Best1(W93C/W93C) mice are distinct from that of Best1 -/- mice with regard to lipofuscin accumulation and changes in the light peak and ATP calcium responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20053664" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a large Swedish family with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>) first reported by <a href="#24" class="mim-tip-reference" title="Nordstrom, S., Barkman, Y. <strong>Hereditary macular degeneration (HMD) in 246 cases traced to one gene-source in central Sweden.</strong> Hereditas 84: 163-176, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/838599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">838599</a>] [<a href="https://doi.org/10.1111/j.1601-5223.1977.tb01394.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="838599">Nordstrom and Barkman (1977)</a>, <a href="#25" class="mim-tip-reference" title="Petrukhin, K., Koisti, M. J., Bakall, B., Li, W., Xie, G., Marknell, T., Sandgren, O., Forsman, K., Holmgren, G., Andreasson, S., Vujic, M., Bergen, A. A. B., McGarty-Dugan, V., Figueroa, D., Austin, C. P., Metzker, M. L., Caskey, C. T., Wadelius, C. <strong>Identification of the gene responsible for Best macular dystrophy.</strong> Nature Genet. 19: 241-247, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662395</a>] [<a href="https://doi.org/10.1038/915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662395">Petrukhin et al. (1998)</a> identified heterozygosity for a 383G-C transversion in exon 4 of the VMD2 gene, resulting in a trp93-to-cys (W93C) amino acid substitution. The W93C mutation in this Swedish family was not found in 50 unrelated individuals of predominantly European descent or in 50 healthy Swedish blood donors. One of the affected family members was homozygous for W93C; <a href="#24" class="mim-tip-reference" title="Nordstrom, S., Barkman, Y. <strong>Hereditary macular degeneration (HMD) in 246 cases traced to one gene-source in central Sweden.</strong> Hereditas 84: 163-176, 1977.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/838599/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">838599</a>] [<a href="https://doi.org/10.1111/j.1601-5223.1977.tb01394.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="838599">Nordstrom and Barkman (1977)</a> had noted that there was no difference in phenotype between heterozygotes and apparent homozygotes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9662395+838599" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a Swedish family with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), <a href="#25" class="mim-tip-reference" title="Petrukhin, K., Koisti, M. J., Bakall, B., Li, W., Xie, G., Marknell, T., Sandgren, O., Forsman, K., Holmgren, G., Andreasson, S., Vujic, M., Bergen, A. A. B., McGarty-Dugan, V., Figueroa, D., Austin, C. P., Metzker, M. L., Caskey, C. T., Wadelius, C. <strong>Identification of the gene responsible for Best macular dystrophy.</strong> Nature Genet. 19: 241-247, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662395</a>] [<a href="https://doi.org/10.1038/915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662395">Petrukhin et al. (1998)</a> identified heterozygosity for a 357T-C transition in the VMD2 gene, resulting in a tyr85-to-his (Y85H) substitution. All related proteins from C. elegans contained tyrosine or isofunctional phenylalanine in this position; tyrosine is highly similar to phenylalanine in that it also is an aromatic hydrophobic amino acid. The Y85H mutation was found to cosegregate with the disease in all affected members of the pedigree and was not detected in 200 chromosomes from normal individuals of North American and Swedish descent. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a Swedish family with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), <a href="#25" class="mim-tip-reference" title="Petrukhin, K., Koisti, M. J., Bakall, B., Li, W., Xie, G., Marknell, T., Sandgren, O., Forsman, K., Holmgren, G., Andreasson, S., Vujic, M., Bergen, A. A. B., McGarty-Dugan, V., Figueroa, D., Austin, C. P., Metzker, M. L., Caskey, C. T., Wadelius, C. <strong>Identification of the gene responsible for Best macular dystrophy.</strong> Nature Genet. 19: 241-247, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662395</a>] [<a href="https://doi.org/10.1038/915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662395">Petrukhin et al. (1998)</a> identified heterozygosity for a 1000G-A transition in the VMD2 gene, resulting in a gly299-to-glu (G299E) substitution. The G299E mutation was found in all affected members of this Swedish pedigree and was not found in 94 normal chromosomes from the Swedish sample. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28941469 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28941469;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28941469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28941469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002850 OR RCV000086157 OR RCV001073354" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002850, RCV000086157, RCV001073354" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002850...</a>
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<p>In all affected members of an Iowa family of Dutch ancestry with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), originally reported by <a href="#4" class="mim-tip-reference" title="Braley, A. E., Spivey, B. E. <strong>Hereditary vitelline macular degeneration: a clinical and functional evaluation of a new pedigree with variable expressivity and dominant inheritance.</strong> Arch. Ophthal. 72: 743-762, 1964.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14205432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14205432</a>] [<a href="https://doi.org/10.1001/archopht.1964.00970020743003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14205432">Braley and Spivey (1964)</a>, <a href="#25" class="mim-tip-reference" title="Petrukhin, K., Koisti, M. J., Bakall, B., Li, W., Xie, G., Marknell, T., Sandgren, O., Forsman, K., Holmgren, G., Andreasson, S., Vujic, M., Bergen, A. A. B., McGarty-Dugan, V., Figueroa, D., Austin, C. P., Metzker, M. L., Caskey, C. T., Wadelius, C. <strong>Identification of the gene responsible for Best macular dystrophy.</strong> Nature Genet. 19: 241-247, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662395</a>] [<a href="https://doi.org/10.1038/915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662395">Petrukhin et al. (1998)</a> identified a heterozygous 783T-A transversion in the VMD2 gene, resulting in a tyr227-to-asn (Y227N) substitution. All related proteins from C. elegans contained tyrosine or isofunctional phenylalanine in this position. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14205432+9662395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Mullins, R. F., Oh, K. T., Heffron, E., Hageman, G. S., Stone, E. M. <strong>Late development of vitelliform lesions and flecks in a patient with Best disease: clinicopathologic correlation.</strong> Arch. Ophthal. 123: 1588-1594, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16286623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16286623</a>] [<a href="https://doi.org/10.1001/archopht.123.11.1588" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16286623">Mullins et al. (2005)</a> restudied a male mutation carrier from this pedigree who had photographically documented normal maculae at age 51 years, but subsequently developed small vitelliform lesions at age 75 years, followed by widespread flecks in the midperiphery; 2 additional family members exhibited similar multifocal lesions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16286623" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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BEST1, THR6PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28940275 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940275;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28940275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28940275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002851 OR RCV000086095" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002851, RCV000086095" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002851...</a>
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<p>In affected members from 2 unrelated Dutch families with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), <a href="#25" class="mim-tip-reference" title="Petrukhin, K., Koisti, M. J., Bakall, B., Li, W., Xie, G., Marknell, T., Sandgren, O., Forsman, K., Holmgren, G., Andreasson, S., Vujic, M., Bergen, A. A. B., McGarty-Dugan, V., Figueroa, D., Austin, C. P., Metzker, M. L., Caskey, C. T., Wadelius, C. <strong>Identification of the gene responsible for Best macular dystrophy.</strong> Nature Genet. 19: 241-247, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9662395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9662395</a>] [<a href="https://doi.org/10.1038/915" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9662395">Petrukhin et al. (1998)</a> identified heterozygosity for a 120A-C transversion in the VMD2 gene, resulting in a thr6-to-pro (T6P) substitution. Analysis of this residue among 14 C. elegans proteins had not shown this threonine to be conserved. However, the authors classified the 120A-C change as a disease mutation because thr6 is located next to the evolutionarily conserved tyrosine at amino acid position 5, and a Chou-Fasman algorithm predicted a dramatic change in the secondary structure as a result of the threonine to proline substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9662395" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a German patient with adult-onset vitelliform macular dystrophy, <a href="#16" class="mim-tip-reference" title="Kramer, F., White, K., Pauleikhoff, D., Gehrig, A., Passmore, L., Rivera, A., Rudolph, G., Kellner, U., Andrassi, M., Lorenz, B., Rohrschneider, K., Blankenagel, A., Jurklies, B., Schilling, H., Schutt, F., Holz, F. G., Weber, B. H. F. <strong>Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration.</strong> Europ. J. Hum. Genet. 8: 286-292, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854112</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854112">Kramer et al. (2000)</a> identified heterozygosity for the T6P mutation in exon 2 of the VMD2 gene. There was no family history of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10854112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with Best dystrophy who exhibited multifocal lesions, <a href="#3" class="mim-tip-reference" title="Boon, C. J. F., Klevering, B. J., den Hollander, A. I., Zonneveld, M. N., Theelen, T., Cremers, F. P. M., Hoyng, C. B. <strong>Clinical and genetic heterogeneity in multifocal vitelliform dystrophy.</strong> Arch. Ophthal. 125: 1100-1106, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17698758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17698758</a>] [<a href="https://doi.org/10.1001/archopht.125.8.1100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17698758">Boon et al. (2007)</a> identified heterozygosity for the T6P mutation in the VMD2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17698758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918283 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918283;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918283" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002854 OR RCV000086179 OR RCV004814807" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002854, RCV000086179, RCV004814807" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002854...</a>
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<p>In affected members of 2 unrelated families with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), 1 from Germany and 1 from Canada, <a href="#20" class="mim-tip-reference" title="Marquardt, A., Stohr, H., Passmore, L. A., Kramer, F., Rivera, A., Weber, B. H. F. <strong>Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease).</strong> Hum. Molec. Genet. 7: 1517-1525, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700209</a>] [<a href="https://doi.org/10.1093/hmg/7.9.1517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700209">Marquardt et al. (1998)</a> found a heterozygous deletion of codon 295, an isoleucine, in the VMD2 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9700209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28940276 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940276;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28940276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28940276" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Among 10 missense mutations identified in the VMD2 gene in association with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), <a href="#20" class="mim-tip-reference" title="Marquardt, A., Stohr, H., Passmore, L. A., Kramer, F., Rivera, A., Weber, B. H. F. <strong>Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease).</strong> Hum. Molec. Genet. 7: 1517-1525, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700209</a>] [<a href="https://doi.org/10.1093/hmg/7.9.1517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700209">Marquardt et al. (1998)</a> identified a val9-to-met (V9M) amino acid substitution in exon 2 of the VMD2 gene resulting from a GTG-to-ATG transition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9700209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs1805142 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1805142;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs1805142?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1805142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1805142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002856 OR RCV000086129 OR RCV004814809" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002856, RCV000086129, RCV004814809" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002856...</a>
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<p>In a 61-year-old woman with vitelliform macular dystrophy (VMD2; <a href="/entry/153700">153700</a>) diagnosed at age 57 years, who had mottling of the retinal pigment epithelium in the right eye and exhibited a bull's-eye configuration in her left eye, <a href="#1" class="mim-tip-reference" title="Allikmets, R., Seddon, J. M., Bernstein, P. S., Hutchinson, A., Atkinson, A., Sharma, S., Gerrard, B., Li, W., Metzker, M. L., Wadelius, C., Caskey, C. T., Dean, M., Petrukhin, K. <strong>Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies.</strong> Hum. Genet. 104: 449-453, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10453731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10453731</a>] [<a href="https://doi.org/10.1007/s004390050986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10453731">Allikmets et al. (1999)</a> identified heterozygosity for a 355G-C transversion in the VMD2 gene, resulting in a glu119-to-gln (E119Q) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10453731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0009 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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BEST1, ALA146LYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1800995 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1800995;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1800995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1800995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002857 OR RCV000086136" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002857, RCV000086136" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002857...</a>
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<p>In a 60-year-old woman with vitelliform macular dystrophy (VMD2; <a href="/entry/153700">153700</a>) diagnosed at age 54 years, <a href="#1" class="mim-tip-reference" title="Allikmets, R., Seddon, J. M., Bernstein, P. S., Hutchinson, A., Atkinson, A., Sharma, S., Gerrard, B., Li, W., Metzker, M. L., Wadelius, C., Caskey, C. T., Dean, M., Petrukhin, K. <strong>Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies.</strong> Hum. Genet. 104: 449-453, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10453731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10453731</a>] [<a href="https://doi.org/10.1007/s004390050986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10453731">Allikmets et al. (1999)</a> identified a heterozygous 540GC-AA change in the VMD2 gene, resulting in an ala146-to-lys (A146K) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10453731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0010 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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BEST1, ALA243VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940570 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940570;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28940570?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28940570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28940570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002858 OR RCV000086167 OR RCV001075633 OR RCV003326112 OR RCV003448243" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002858, RCV000086167, RCV001075633, RCV003326112, RCV003448243" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002858...</a>
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<p>In 8 unrelated patients with vitelliform macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), 3 with onset of disease in childhood and 5 with onset in adulthood, <a href="#16" class="mim-tip-reference" title="Kramer, F., White, K., Pauleikhoff, D., Gehrig, A., Passmore, L., Rivera, A., Rudolph, G., Kellner, U., Andrassi, M., Lorenz, B., Rohrschneider, K., Blankenagel, A., Jurklies, B., Schilling, H., Schutt, F., Holz, F. G., Weber, B. H. F. <strong>Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration.</strong> Europ. J. Hum. Genet. 8: 286-292, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854112</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854112">Kramer et al. (2000)</a> identified heterozygosity for a 728C-T transition in exon 7 of the BEST1 gene, resulting in an ala243-to-val (A243V) substitution. Four of the patients, 3 with childhood-onset disease and 1 with adult-onset, had a first-degree affected relative who also carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10854112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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BEST1, ARG47HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940278 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940278;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs28940278?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28940278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs28940278" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002860 OR RCV000086086 OR RCV004795367 OR RCV004814810" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002860, RCV000086086, RCV004795367, RCV004814810" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002860...</a>
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<p>In a sporadic patient with adult-onset vitelliform macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), <a href="#16" class="mim-tip-reference" title="Kramer, F., White, K., Pauleikhoff, D., Gehrig, A., Passmore, L., Rivera, A., Rudolph, G., Kellner, U., Andrassi, M., Lorenz, B., Rohrschneider, K., Blankenagel, A., Jurklies, B., Schilling, H., Schutt, F., Holz, F. G., Weber, B. H. F. <strong>Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration.</strong> Europ. J. Hum. Genet. 8: 286-292, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10854112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10854112</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5200447" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10854112">Kramer et al. (2000)</a> identified a heterozygous 140G-A transition in exon 2 of the VMD2 gene, resulting in an arg47-to-his (R47H) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10854112" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0012 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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BEST1, 2-BP DEL, 1574CA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs281865528 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs281865528;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs281865528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs281865528" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002861 OR RCV000086087 OR RCV001074224 OR RCV003152665 OR RCV004732527" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002861, RCV000086087, RCV001074224, RCV003152665, RCV004732527" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002861...</a>
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<span class="mim-text-font">
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<p>In a patient with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), <a href="#7" class="mim-tip-reference" title="Caldwell, G. M., Kakuk, L. E., Griesinger, I. B., Simpson, S. A., Nowak, N. J., Small, K. W., Maumenee, I. H., Rosenfeld, P. J., Sieving, P. A., Shows, T. B., Ayyagari, R. <strong>Bestrophin gene mutations in patients with Best vitelliform macular dystrophy.</strong> Genomics 58: 98-101, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10331951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10331951</a>] [<a href="https://doi.org/10.1006/geno.1999.5808" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10331951">Caldwell et al. (1999)</a> identified heterozygosity for a 2-bp deletion (1574delCA) in exon 10 of the VMD2 gene, causing a frameshift resulting in a premature termination codon 24 amino acids downstream that truncates the protein by 71 amino acids. The authors stated that this was the first mutation reported in the 3-prime half of the bestrophin gene, beyond exon 8. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10331951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918284 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918284;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918284?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002862 OR RCV000002863 OR RCV000086135 OR RCV000787541 OR RCV001075875 OR RCV004532276" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002862, RCV000002863, RCV000086135, RCV000787541, RCV001075875, RCV004532276" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002862...</a>
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<p>In 6 affected members of Swedish family with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), <a href="#27" class="mim-tip-reference" title="Schatz, P., Klar, J., Andreasson, S., Ponjavic, V., Dahl, N. <strong>Variant phenotype of Best vitelliform macular dystrophy associated with compound heterozygous mutation in VMD2.</strong> Ophthal. Genet. 27: 51-56, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16754206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16754206</a>] [<a href="https://doi.org/10.1080/13816810600677990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16754206">Schatz et al. (2006)</a> identified mutations in the BEST1 gene. One was heterozygous for an arg141-to-his (R141H) mutation, 3 were heterozygous for a tyr29-to-ter (Y29X; <a href="#0014">607854.0014</a>) mutation, and 2 were compound heterozygous for these mutations. The 2 members who were compound heterozygous had a more severe phenotype. Neither mutation was found in 100 Swedish control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16754206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 15-year-old proband with multifocal Best vitelliform macular dystrophy, <a href="#33" class="mim-tip-reference" title="Wittstrom, E., Ekvall, S., Schatz, P., Bondeson, M.-L., Ponjavic, V., Andreasson, S. <strong>Morphological and functional changes in multifocal vitelliform retinopathy and biallelic mutations in BEST1.</strong> Ophthalmic Genet. 32: 83-96, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21192766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21192766</a>] [<a href="https://doi.org/10.3109/13816810.2010.535890" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21192766">Wittstrom et al. (2011)</a> identified compound heterozygosity for 2 mutations in the BEST1 gene: the R141H mutation and a de novo pro233-to-ala (P233A) substitution. The R141H mutation was present in heterozygous state in her mother and brother, neither of whom had any visual symptoms. However, both heterozygous carriers showed delayed implicit times in a- and b-waves of combined total rod and cone full-field ERG responses. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21192766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 patients with a distinctive retinopathy, called bestrophinopathy (ARB; <a href="/entry/611809">611809</a>), <a href="#6" class="mim-tip-reference" title="Burgess, R., Millar, I. D., Leroy, B. P., Urquhart, J. E., Fearon, I. M., De Baere, E., Brown, P. D., Robson, A. G., Wright, G. A., Kestelyn, P., Holder, G. E., Webster, A. R., Manson, F. D. C., Black, G. C. M. <strong>Biallelic mutation of BEST1 causes a distinct retinopathy in humans.</strong> Am. J. Hum. Genet. 82: 19-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179881[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.08.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179881">Burgess et al. (2008)</a> identified compound heterozygosity for missense mutations in the BEST1 gene. Both patients carried a 442G-A transition that caused the R141H substitution; 1 patient also had a 949G-A transition resulting in a val317-to-met substitution (V317M; <a href="#0017">607854.0017</a>), and the other patient had a 122T-C transition causing a leu41-to-pro substitution (L41P; <a href="#0018">607854.0018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918285 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918285;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918285?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918285" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002849 OR RCV001851591" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002849, RCV001851591" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002849...</a>
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<p>For discussion of the tyr29-to-ter (Y29X) mutation in the BEST1 gene that was found in compound heterozygous state in patients with Best macular dystrophy (VMD2; <a href="/entry/153700">153700</a>) by <a href="#27" class="mim-tip-reference" title="Schatz, P., Klar, J., Andreasson, S., Ponjavic, V., Dahl, N. <strong>Variant phenotype of Best vitelliform macular dystrophy associated with compound heterozygous mutation in VMD2.</strong> Ophthal. Genet. 27: 51-56, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16754206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16754206</a>] [<a href="https://doi.org/10.1080/13816810600677990" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16754206">Schatz et al. (2006)</a>, see <a href="#0013">607854.0013</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16754206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0015 BESTROPHINOPATHY, AUTOSOMAL RECESSIVE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918286 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918286;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918286?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918286" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918286" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002864 OR RCV001202565 OR RCV002490299 OR RCV004814811" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002864, RCV001202565, RCV002490299, RCV004814811" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002864...</a>
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<p>In a brother and sister with a distinctive retinopathy, designated bestrophinopathy (ARB; <a href="/entry/611809">611809</a>), <a href="#6" class="mim-tip-reference" title="Burgess, R., Millar, I. D., Leroy, B. P., Urquhart, J. E., Fearon, I. M., De Baere, E., Brown, P. D., Robson, A. G., Wright, G. A., Kestelyn, P., Holder, G. E., Webster, A. R., Manson, F. D. C., Black, G. C. M. <strong>Biallelic mutation of BEST1 causes a distinct retinopathy in humans.</strong> Am. J. Hum. Genet. 82: 19-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179881[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.08.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179881">Burgess et al. (2008)</a> identified homozygosity for a 598C-T transition in the BEST1 gene that caused truncation of the protein (arg200 to ter; R200X). The age at visual deterioration was 30 years in the brother and 18 years in the sister. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0016 MOVED TO <a href="/entry/607854#0013">607854.0013</a></strong>
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<p>In a patient reported by <a href="#6" class="mim-tip-reference" title="Burgess, R., Millar, I. D., Leroy, B. P., Urquhart, J. E., Fearon, I. M., De Baere, E., Brown, P. D., Robson, A. G., Wright, G. A., Kestelyn, P., Holder, G. E., Webster, A. R., Manson, F. D. C., Black, G. C. M. <strong>Biallelic mutation of BEST1 causes a distinct retinopathy in humans.</strong> Am. J. Hum. Genet. 82: 19-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179881[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.08.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179881">Burgess et al. (2008)</a> with autosomal recessive bestrophinopathy (ARB; <a href="/entry/611809">611809</a>), a val317-to-met (V317M) mutation occurred in compound heterozygosity with R141H (<a href="#0013">607854.0013</a>). Visual deterioration began at age 40 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918288 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918288;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918288?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002866 OR RCV000086085 OR RCV004814812" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002866, RCV000086085, RCV004814812" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002866...</a>
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<p>In a patient reported by <a href="#6" class="mim-tip-reference" title="Burgess, R., Millar, I. D., Leroy, B. P., Urquhart, J. E., Fearon, I. M., De Baere, E., Brown, P. D., Robson, A. G., Wright, G. A., Kestelyn, P., Holder, G. E., Webster, A. R., Manson, F. D. C., Black, G. C. M. <strong>Biallelic mutation of BEST1 causes a distinct retinopathy in humans.</strong> Am. J. Hum. Genet. 82: 19-31, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179881[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2007.08.004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18179881">Burgess et al. (2008)</a> with autosomal recessive bestrophinopathy (ARB; <a href="/entry/611809">611809</a>), a leu41-to-pro (L41P) mutation in the BEST1 gene occurred in compound heterozygosity with R141H (<a href="#0013">607854.0013</a>). Visual deterioration began at age 4 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0019 VITREORETINOCHOROIDOPATHY</strong>
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BEST1, VAL86MET
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121918289 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918289;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121918289?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918289" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002867 OR RCV001074078 OR RCV001851592" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002867, RCV001074078, RCV001851592" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002867...</a>
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<p>In affected members of 3 families segregating autosomal dominant vitreoretinochoroidopathy, microcornea, glaucoma, and cataract (VRCP; <a href="/entry/193220">193220</a>), including the 4-generation Belgian family previously reported by <a href="#17" class="mim-tip-reference" title="Lafaut, B. A., Loeys, B., Leroy, B. P., Spileers, W., De Laey, J. J., Kestelyn, P. <strong>Clinical and electrophysiological findings in autosomal dominant vitreoretinochoroidopathy: report of a new pedigree.</strong> Graefes Arch. Clin. Exp. Ophthal. 239: 575-582, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11585313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11585313</a>] [<a href="https://doi.org/10.1007/s004170100318" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11585313">Lafaut et al. (2001)</a>, a 6-generation French family originally reported by <a href="#14" class="mim-tip-reference" title="Hermann, P. <strong>Le syndrome: microphtalmie-retinite pigmentaire-glaucome.</strong> Arch. Ophtal. Rev. Gen. Ophtal. 18: 17-24, 1958.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13534955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13534955</a>]" pmid="13534955">Hermann (1958)</a>, and another Belgian family, <a href="#35" class="mim-tip-reference" title="Yardley, J., Leroy, B. P., Hart-Holden, N., Lafaut, B. A., Loeys, B., Messiaen, L. M., Perveen, R., Reddy, M. A., Bhattacharya, S. S., Traboulsi, E., Baralle, D., De Laey, J.-J., Puech, B., Kestelyn, P., Moore, A. T., Manson, F. D. C., Black, G. C. M. <strong>Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC).</strong> Invest. Ophthal. Vis. Sci. 45: 3683-3689, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452077</a>] [<a href="https://doi.org/10.1167/iovs.04-0550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15452077">Yardley et al. (2004)</a> identified heterozygosity for a 256G-A transition in exon 4 of the BEST1 gene, resulting in a val86-to-met (V86M) substitution at a conserved residue. In vitro functional assays demonstrated that V86M disrupts splicing and causes exon skipping. The mutation was not found in 400 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13534955+15452077+11585313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0020 MICROCORNEA, ROD-CONE DYSTROPHY, CATARACT, AND POSTERIOR STAPHYLOMA 2 (1 family)</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918290 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918290;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918290" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002868 OR RCV002054410" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002868, RCV002054410" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002868...</a>
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<p>In affected members of a 3-generation English family with microcornea, rod-cone dystrophy, cataract, and posterior staphyloma (MRCS2; <a href="/entry/193220">193220</a>), originally reported by <a href="#26" class="mim-tip-reference" title="Reddy, M. A., Francis, P. J., Berry, V., Bradshaw, K., Patel, R. J., Maher, E. R., Kumar, R., Bhattacharya, S. S., Moore, A. T. <strong>A clinical and molecular genetic study of a rare dominantly inherited syndrome (MRCS) comprising of microcornea, rod-cone dystrophy, cataract, and posterior staphyloma.</strong> Brit. J. Ophthal. 87: 197-202, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12543751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12543751</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12543751[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1136/bjo.87.2.197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12543751">Reddy et al. (2003)</a>, <a href="#35" class="mim-tip-reference" title="Yardley, J., Leroy, B. P., Hart-Holden, N., Lafaut, B. A., Loeys, B., Messiaen, L. M., Perveen, R., Reddy, M. A., Bhattacharya, S. S., Traboulsi, E., Baralle, D., De Laey, J.-J., Puech, B., Kestelyn, P., Moore, A. T., Manson, F. D. C., Black, G. C. M. <strong>Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC).</strong> Invest. Ophthal. Vis. Sci. 45: 3683-3689, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452077</a>] [<a href="https://doi.org/10.1167/iovs.04-0550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15452077">Yardley et al. (2004)</a> identified heterozygosity for a 715G-A transition in exon 7 of the BEST1 gene, resulting in a val239-to-met (V239M) substitution at a conserved residue. In vitro functional assays demonstrated that V239M disrupts splicing and causes exon skipping. The mutation was not found in 400 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12543751+15452077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121918291 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121918291;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121918291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121918291" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002869 OR RCV003555902" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002869, RCV003555902" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002869...</a>
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<p>In affected members of a family segregating autosomal dominant vitreoretinochoroidopathy and nanophthalmos (VRCP; <a href="/entry/193220">193220</a>), <a href="#35" class="mim-tip-reference" title="Yardley, J., Leroy, B. P., Hart-Holden, N., Lafaut, B. A., Loeys, B., Messiaen, L. M., Perveen, R., Reddy, M. A., Bhattacharya, S. S., Traboulsi, E., Baralle, D., De Laey, J.-J., Puech, B., Kestelyn, P., Moore, A. T., Manson, F. D. C., Black, G. C. M. <strong>Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC).</strong> Invest. Ophthal. Vis. Sci. 45: 3683-3689, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452077</a>] [<a href="https://doi.org/10.1167/iovs.04-0550" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15452077">Yardley et al. (2004)</a> identified heterozygosity for a 707A-G transition in exon 6 of the BEST1 gene, resulting in a tyr236-to-cys (Y236C) substitution at a conserved residue. In vitro functional assays demonstrated that Y236C disrupts splicing and causes exon skipping. The mutation was not found in 400 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15452077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Burgess, R., MacLaren, R. E., Davidson, A. E., Urquhart, J. E., Holder, G. E., Robson, A. G., Moore, A. T., O'Keefe, R., Black, G. C. M., Manson, F. D. C. <strong>ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. (Letter)</strong> J. Med. Genet. 46: 620-625, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18611979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18611979</a>] [<a href="https://doi.org/10.1136/jmg.2008.059881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18611979">Burgess et al. (2009)</a> analyzed exonic splice enhancer (ESE) activity in exon 6 of the BEST1 gene and found that the 707A-G variant abolished ESE site-dependent splicing. Gel-shift assays involving serine/arginine (SR)-rich proteins showed that SFRS1 (<a href="/entry/600812">600812</a>) had increased binding to 707A-G compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18611979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606680 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606680;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606680" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606680" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002870 OR RCV001382239" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002870, RCV001382239" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002870...</a>
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<p>In 10 affected members of a family with retinitis pigmentosa-50 (RP50; <a href="/entry/613194">613194</a>), <a href="#8" class="mim-tip-reference" title="Davidson, A. E., Millar, I. D., Urquhart, J. E., Burgess-Mullan, R., Shweikh, Y., Parry, N., O'Sullivan, J., Maher, G. J., McKibbin, M., Downes, S. M., Lotery, A. J., Jacobson, S. G., Brown, P. D., Black, G. C. M., Manson, F. D. C. <strong>Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa.</strong> Am. J. Hum. Genet. 85: 581-592, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853238[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853238">Davidson et al. (2009)</a> identified heterozygosity for a 614T-C transition in exon 5 of the BEST1 gene, resulting in an ile205-to-thr (I205T) substitution. The mutation was not found in 5 unaffected family members or in 210 ethnically matched control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19853238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267606676 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606676;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267606676?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606676" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002871 OR RCV000417725 OR RCV000787545 OR RCV001073474" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002871, RCV000417725, RCV000787545, RCV001073474" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002871...</a>
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<p>In a mother and son with retinitis pigmentosa-50 (RP50; <a href="/entry/613194">613194</a>) and a brother and sister with concentric RP (see <a href="/entry/613194">613194</a>), <a href="#8" class="mim-tip-reference" title="Davidson, A. E., Millar, I. D., Urquhart, J. E., Burgess-Mullan, R., Shweikh, Y., Parry, N., O'Sullivan, J., Maher, G. J., McKibbin, M., Downes, S. M., Lotery, A. J., Jacobson, S. G., Brown, P. D., Black, G. C. M., Manson, F. D. C. <strong>Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa.</strong> Am. J. Hum. Genet. 85: 581-592, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853238[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853238">Davidson et al. (2009)</a> identified heterozygosity for a 682G-A transition in exon 6 of the BEST1 gene, resulting in an asp228-to-asn (D228N) substitution. The mutation was not found in 210 ethnically matched control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19853238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0024 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606677 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606677;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606677" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002873 OR RCV000002874 OR RCV000086158" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002873, RCV000002874, RCV000086158" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002873...</a>
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<p>In affected members of a German family with vitelliform macular dystrophy (VMD2; <a href="/entry/153700">153700</a>), <a href="#20" class="mim-tip-reference" title="Marquardt, A., Stohr, H., Passmore, L. A., Kramer, F., Rivera, A., Weber, B. H. F. <strong>Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease).</strong> Hum. Molec. Genet. 7: 1517-1525, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9700209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9700209</a>] [<a href="https://doi.org/10.1093/hmg/7.9.1517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9700209">Marquardt et al. (1998)</a> identified heterozygosity for a 680A-G transition in exon 6 of the BEST1 gene, resulting in a tyr227-to-cys (Y227C) substitution at a highly conserved residue. The mutation, which segregated with disease, was not found in 84 control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9700209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 45-year-old woman with concentric retinitis pigmentosa (see <a href="/entry/613194">613194</a>), <a href="#8" class="mim-tip-reference" title="Davidson, A. E., Millar, I. D., Urquhart, J. E., Burgess-Mullan, R., Shweikh, Y., Parry, N., O'Sullivan, J., Maher, G. J., McKibbin, M., Downes, S. M., Lotery, A. J., Jacobson, S. G., Brown, P. D., Black, G. C. M., Manson, F. D. C. <strong>Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa.</strong> Am. J. Hum. Genet. 85: 581-592, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853238[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853238">Davidson et al. (2009)</a> identified heterozygosity for the BEST1 Y227C mutation. Funduscopic examination revealed an abrupt change from normal to abnormal retina in the periphery, suggestive of a bestrophinopathy (<a href="/entry/611809">611809</a>), but after detection of the Y227C mutation, adjacent to the D228N (<a href="#0023">607854.0023</a>) mutation that had been found in a family with concentric RP, the fundus images were considered to be consistent with concentric RP. The patient had 2 affected daughters with a similar phenotype who were unavailable for molecular testing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19853238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0025 RETINITIS PIGMENTOSA 50</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs267606678 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606678;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs267606678?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606678" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002875 OR RCV000726591 OR RCV000787540" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002875, RCV000726591, RCV000787540" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002875...</a>
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<p>In a father and 2 daughters from a Pakistani family with retinitis pigmentosa-50 (RP50; <a href="/entry/613194">613194</a>), <a href="#8" class="mim-tip-reference" title="Davidson, A. E., Millar, I. D., Urquhart, J. E., Burgess-Mullan, R., Shweikh, Y., Parry, N., O'Sullivan, J., Maher, G. J., McKibbin, M., Downes, S. M., Lotery, A. J., Jacobson, S. G., Brown, P. D., Black, G. C. M., Manson, F. D. C. <strong>Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa.</strong> Am. J. Hum. Genet. 85: 581-592, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853238[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853238">Davidson et al. (2009)</a> identified homozygosity for a 418C-G transversion in exon 4 of the BEST1 gene, resulting in a leu140-to-val (L140V) substitution. <a href="#8" class="mim-tip-reference" title="Davidson, A. E., Millar, I. D., Urquhart, J. E., Burgess-Mullan, R., Shweikh, Y., Parry, N., O'Sullivan, J., Maher, G. J., McKibbin, M., Downes, S. M., Lotery, A. J., Jacobson, S. G., Brown, P. D., Black, G. C. M., Manson, F. D. C. <strong>Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa.</strong> Am. J. Hum. Genet. 85: 581-592, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853238[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2009.09.015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19853238">Davidson et al. (2009)</a> stated that in unpublished results, they had previously found the L140V mutation in patients diagnosed with autosomal recessive bestrophinopathy (ARB; <a href="/entry/611809">611809</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19853238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0026 VITREORETINOCHOROIDOPATHY</strong>
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BEST1, VAL235ALA
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267606679 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267606679;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs267606679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs267606679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000002876" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002876" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002876</a>
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<p>In an affected sister and brother from a family segregating autosomal dominant vitreoretinochoroidopathy (VRCP; <a href="/entry/193220">193220</a>), <a href="#5" class="mim-tip-reference" title="Burgess, R., MacLaren, R. E., Davidson, A. E., Urquhart, J. E., Holder, G. E., Robson, A. G., Moore, A. T., O'Keefe, R., Black, G. C. M., Manson, F. D. C. <strong>ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. (Letter)</strong> J. Med. Genet. 46: 620-625, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18611979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18611979</a>] [<a href="https://doi.org/10.1136/jmg.2008.059881" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18611979">Burgess et al. (2009)</a> identified heterozygosity for a 704T-C transition in exon 6 of the BEST1 gene, predicted to result in a val235-to-ala (V235A) substitution. The mutation was not found in 210 control chromosomes. Splicing assay in HEK293 cells demonstrated the generation of both wildtype product and a larger splice product including an extra copy of exon 6, spliced between exons 6 and 7. Analysis of exonic splice enhancer (ESE) activity in exon 6 of the BEST1 gene demonstrated that the 704T-C variant weakened ESE site-dependent splicing compared to wildtype, and gel-shift assays involving serine/arginine (SR)-rich proteins showed that SFRS1 (<a href="/entry/600812">600812</a>) had increased binding to 704T-C compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18611979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Allikmets1999" class="mim-anchor"></a>
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Allikmets, R., Seddon, J. M., Bernstein, P. S., Hutchinson, A., Atkinson, A., Sharma, S., Gerrard, B., Li, W., Metzker, M. L., Wadelius, C., Caskey, C. T., Dean, M., Petrukhin, K.
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<strong>Evaluation of the Best disease gene in patients with age-related macular degeneration and other maculopathies.</strong>
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Hum. Genet. 104: 449-453, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10453731/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10453731</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10453731" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390050986" target="_blank">Full Text</a>]
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Bakall, B., Marknell, T., Ingvast, S., Koisti, M. J., Sandgren, O., Li, W., Bergen, A. A. B., Andreasson, S., Rosenberg, T., Petrukhin, K., Wadelius, C.
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<strong>The mutation spectrum of the bestrophin protein--functional implications.</strong>
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Hum. Genet. 104: 383-389, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10394929/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10394929</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10394929" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s004390050972" target="_blank">Full Text</a>]
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Boon, C. J. F., Klevering, B. J., den Hollander, A. I., Zonneveld, M. N., Theelen, T., Cremers, F. P. M., Hoyng, C. B.
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<strong>Clinical and genetic heterogeneity in multifocal vitelliform dystrophy.</strong>
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Arch. Ophthal. 125: 1100-1106, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17698758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17698758</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17698758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archopht.125.8.1100" target="_blank">Full Text</a>]
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<a id="Braley1964" class="mim-anchor"></a>
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<p class="mim-text-font">
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Braley, A. E., Spivey, B. E.
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<strong>Hereditary vitelline macular degeneration: a clinical and functional evaluation of a new pedigree with variable expressivity and dominant inheritance.</strong>
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Arch. Ophthal. 72: 743-762, 1964.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14205432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14205432</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14205432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archopht.1964.00970020743003" target="_blank">Full Text</a>]
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Burgess, R., MacLaren, R. E., Davidson, A. E., Urquhart, J. E., Holder, G. E., Robson, A. G., Moore, A. T., O'Keefe, R., Black, G. C. M., Manson, F. D. C.
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<strong>ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. (Letter)</strong>
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J. Med. Genet. 46: 620-625, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18611979/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18611979</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18611979" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1136/jmg.2008.059881" target="_blank">Full Text</a>]
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<a id="Burgess2008" class="mim-anchor"></a>
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Burgess, R., Millar, I. D., Leroy, B. P., Urquhart, J. E., Fearon, I. M., De Baere, E., Brown, P. D., Robson, A. G., Wright, G. A., Kestelyn, P., Holder, G. E., Webster, A. R., Manson, F. D. C., Black, G. C. M.
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<strong>Biallelic mutation of BEST1 causes a distinct retinopathy in humans.</strong>
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Am. J. Hum. Genet. 82: 19-31, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18179881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18179881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18179881[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18179881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2007.08.004" target="_blank">Full Text</a>]
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<a id="Caldwell1999" class="mim-anchor"></a>
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Caldwell, G. M., Kakuk, L. E., Griesinger, I. B., Simpson, S. A., Nowak, N. J., Small, K. W., Maumenee, I. H., Rosenfeld, P. J., Sieving, P. A., Shows, T. B., Ayyagari, R.
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<strong>Bestrophin gene mutations in patients with Best vitelliform macular dystrophy.</strong>
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Genomics 58: 98-101, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10331951/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10331951</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10331951" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1999.5808" target="_blank">Full Text</a>]
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<a id="Davidson2009" class="mim-anchor"></a>
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Davidson, A. E., Millar, I. D., Urquhart, J. E., Burgess-Mullan, R., Shweikh, Y., Parry, N., O'Sullivan, J., Maher, G. J., McKibbin, M., Downes, S. M., Lotery, A. J., Jacobson, S. G., Brown, P. D., Black, G. C. M., Manson, F. D. C.
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<strong>Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa.</strong>
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Am. J. Hum. Genet. 85: 581-592, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19853238/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19853238</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19853238[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19853238" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2009.09.015" target="_blank">Full Text</a>]
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<a id="Dickson2014" class="mim-anchor"></a>
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Dickson, V. K., Pedi, L., Long, S. B.
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<strong>Structure and insights into the function of a Ca(2+)-activated Cl- channel.</strong>
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Nature 516: 213-218, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25337878/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25337878</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25337878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature13913" target="_blank">Full Text</a>]
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Duta, V., Szkotak, A. J., Nahirney, D., Duszyk, M.
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<strong>The role of bestrophin in airway epithelial ion transport.</strong>
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FEBS Lett. 577: 551-554, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15556645/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15556645</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15556645" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.febslet.2004.10.068" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16754206/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16754206</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16754206" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1080/13816810600677990" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
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<a id="Stohr2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stohr, H., Marquardt, A., Nanda, I., Schmid, M., Weber, B. H. F.
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<strong>Three novel human VMD2-like genes are members of the evolutionary highly conserved RFP-TM family.</strong>
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Europ. J. Hum. Genet. 10: 281-284, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12032738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12032738</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12032738" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5200796" target="_blank">Full Text</a>]
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<a id="29" class="mim-anchor"></a>
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<a id="Stohr1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stohr, H., Marquardt, A., Rivera, A., Cooper, P. R., Nowak, N. J., Shows, T. B., Gerhard, D. S., Weber, B. H. F.
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<strong>A gene map of the Best's vitelliform macular dystrophy region in chromosome 11q12-q13.1.</strong>
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Genome Res. 8: 48-56, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9445487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9445487</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9445487[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9445487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1101/gr.8.1.48" target="_blank">Full Text</a>]
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</p>
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<a id="30" class="mim-anchor"></a>
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<a id="Sun2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sun, H., Tsunenari, T., Yau, K.-W., Nathans, J.
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<strong>The vitelliform macular dystrophy protein defines a new family of chloride channels.</strong>
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Proc. Nat. Acad. Sci. 99: 4008-4013, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11904445/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11904445</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11904445[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11904445" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.052692999" target="_blank">Full Text</a>]
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<a id="31" class="mim-anchor"></a>
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<a id="Tsunenari2003" class="mim-anchor"></a>
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<div class="">
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Tsunenari, T., Sun, H., Williams, J., Cahill, H., Smallwood, P., Yau, K.-W., Nathans, J.
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<strong>Structure-function analysis of the bestrophin family of anion channels.</strong>
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J. Biol. Chem. 278: 41114-41125, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12907679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12907679</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12907679[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12907679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M306150200" target="_blank">Full Text</a>]
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<a id="32" class="mim-anchor"></a>
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<a id="White2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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White, K., Marquardt, A., Weber, B. H. F.
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<strong>VMD2 mutations in vitelliform macular dystrophy (Best disease) and other maculopathies.</strong>
|
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Hum. Mutat. 15: 301-308, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10737974/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10737974</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10737974" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(200004)15:4<301::AID-HUMU1>3.0.CO;2-N" target="_blank">Full Text</a>]
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<a id="33" class="mim-anchor"></a>
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<a id="Wittstrom2011" class="mim-anchor"></a>
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<div class="">
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Wittstrom, E., Ekvall, S., Schatz, P., Bondeson, M.-L., Ponjavic, V., Andreasson, S.
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<strong>Morphological and functional changes in multifocal vitelliform retinopathy and biallelic mutations in BEST1.</strong>
|
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Ophthalmic Genet. 32: 83-96, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21192766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21192766</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21192766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.3109/13816810.2010.535890" target="_blank">Full Text</a>]
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<a id="34" class="mim-anchor"></a>
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<a id="Yang2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang, T., Liu, Q., Kloss, B., Bruni, R., Kalathur, R. C., Guo, Y., Kloppmann, E., Rost, B., Colecraft, H. M., Hendrickson, W. A.
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<strong>Structure and selectivity in bestrophin ion channels.</strong>
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Science 346: 355-359, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25324390/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25324390</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25324390[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25324390" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1259723" target="_blank">Full Text</a>]
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<a id="35" class="mim-anchor"></a>
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<a id="Yardley2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yardley, J., Leroy, B. P., Hart-Holden, N., Lafaut, B. A., Loeys, B., Messiaen, L. M., Perveen, R., Reddy, M. A., Bhattacharya, S. S., Traboulsi, E., Baralle, D., De Laey, J.-J., Puech, B., Kestelyn, P., Moore, A. T., Manson, F. D. C., Black, G. C. M.
|
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<strong>Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC).</strong>
|
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Invest. Ophthal. Vis. Sci. 45: 3683-3689, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15452077/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15452077</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15452077" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1167/iovs.04-0550" target="_blank">Full Text</a>]
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<li>
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<a id="36" class="mim-anchor"></a>
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<a id="Zhang2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, Y., Stanton, J. B., Wu, J., Yu, K., Hartzell, H. C., Peachey, N. S., Marmorstein, L. Y., Marmorstein, A. D.
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<strong>Suppression of Ca(2+) signaling in a mouse model of Best disease.</strong>
|
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Hum. Molec. Genet. 19: 1108-1118, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20053664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20053664</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20053664[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20053664" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddp583" target="_blank">Full Text</a>]
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<br />
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<a id="contributors" class="mim-anchor"></a>
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 05/11/2018
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 6/3/2016<br>Jane Kelly - updated : 3/8/2016<br>Marla J. F. O'Neill - updated : 12/30/2014<br>Ada Hamosh - updated : 11/10/2014<br>George E. Tiller - updated : 11/10/2011<br>Jane Kelly - updated : 8/16/2011<br>Ada Hamosh - updated : 12/28/2010<br>Marla J. F. O'Neill - updated : 1/28/2010<br>Marla J. F. O'Neill - updated : 12/24/2009<br>George E. Tiller - updated : 10/23/2009<br>Marla J. F. O'Neill - updated : 1/6/2009<br>Marla J. F. O'Neill - updated : 11/12/2008<br>Jane Kelly - updated : 11/12/2008<br>Jane Kelly - updated : 5/1/2008<br>Victor A. McKusick - updated : 2/19/2008<br>Jane Kelly - updated : 12/17/2007<br>Patricia A. Hartz - updated : 10/6/2006<br>Marla J. F. O'Neill - updated : 9/29/2006<br>Cassandra L. Kniffin - updated : 10/14/2003
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Creation Date:
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<span class="mim-text-font">
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Cassandra L. Kniffin : 10/7/2003
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 11/03/2020
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<span class="mim-text-font">
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mgross : 05/11/2018<br>mgross : 05/11/2018<br>carol : 01/27/2017<br>carol : 10/19/2016<br>carol : 06/06/2016<br>alopez : 6/3/2016<br>carol : 3/8/2016<br>alopez : 4/24/2015<br>mcolton : 4/21/2015<br>carol : 12/30/2014<br>alopez : 11/10/2014<br>alopez : 11/17/2011<br>terry : 11/10/2011<br>carol : 8/18/2011<br>terry : 8/16/2011<br>alopez : 1/3/2011<br>terry : 12/28/2010<br>wwang : 2/2/2010<br>terry : 1/28/2010<br>carol : 12/24/2009<br>wwang : 11/3/2009<br>terry : 10/23/2009<br>carol : 1/6/2009<br>terry : 1/6/2009<br>terry : 12/23/2008<br>carol : 11/12/2008<br>carol : 11/12/2008<br>carol : 7/22/2008<br>carol : 5/1/2008<br>carol : 4/22/2008<br>alopez : 2/22/2008<br>alopez : 2/22/2008<br>terry : 2/19/2008<br>carol : 12/17/2007<br>wwang : 10/12/2006<br>terry : 10/6/2006<br>wwang : 10/6/2006<br>terry : 9/29/2006<br>joanna : 9/8/2006<br>joanna : 9/8/2006<br>carol : 10/28/2003<br>carol : 10/19/2003<br>ckniffin : 10/14/2003
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<span class="mim-font">
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<strong>*</strong> 607854
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<div>
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<h3>
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<span class="mim-font">
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BESTROPHIN 1; BEST1
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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VMD2 GENE<br />
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TU15B
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<strong><em>HGNC Approved Gene Symbol: BEST1</em></strong>
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<strong>SNOMEDCT:</strong> 711162004, 723828008, 763387005;
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 11q12.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:61,949,821-61,965,515 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="6">
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<span class="mim-font">
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11q12.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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?Microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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193220
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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|
3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Bestrophinopathy, autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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611809
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Macular dystrophy, vitelliform, 2
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</span>
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</td>
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<td>
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<span class="mim-font">
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153700
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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Autosomal dominant
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</span>
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</td>
|
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<td>
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|
<span class="mim-font">
|
|
3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Retinitis pigmentosa-50
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|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613194
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|
</span>
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</td>
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|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
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</td>
|
|
<td>
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|
<span class="mim-font">
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3
|
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</span>
|
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</td>
|
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Retinitis pigmentosa, concentric
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
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613194
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Vitreoretinochoroidopathy
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</span>
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</td>
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<td>
|
|
<span class="mim-font">
|
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193220
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
|
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>BEST1 belongs to the bestrophin family of anion channels, which includes BEST2 (607335), BEST3 (607337), and BEST4 (607336). Bestrophins are transmembrane (TM) proteins that share a homology region containing a high content of aromatic residues, including an invariant arg-phe-pro (RFP) motif. The bestrophin genes share a conserved gene structure, with almost identical sizes of the 8 RFP-TM domain-encoding exons and highly conserved exon-intron boundaries. Each of the 4 bestrophin genes has a unique 3-prime end of variable length (Stohr et al., 2002; Tsunenari et al., 2003). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To identify the gene that is mutant in an early-onset form of vitelliform macular dystrophy (VMD2; 153700), also known as Best macular dystrophy, Petrukhin et al. (1998) defined the minimum genetic region on chromosome 11 by recombination breakpoint analysis, and scanned PAC clones of the region. They identified a novel retina-specific gene, designated VMD2, that encodes a 585-amino acid protein with a molecular mass of 68 kD and an isoelectric point of 6.9. The hydropathy profile predicted the presence of at least 4 putative transmembrane domains. Alternatively, these stretches of hydrophobic amino acids may be involved in the formation of hydrophobic pockets or may interact tightly with the membrane without crossing it. The 3-prime untranslated region (UTR) of the gene contains a region of antisense complementarity to the 3-prime UTR of the ferritin heavy-chain gene (FTH1; 134770), suggesting the possibility of antisense interaction between VMD2 and FTH1 transcripts. A mouse VMD2 probe representing a protein fragment with 89% identity to human VMD2 demonstrated exquisitely specific expression in the retinal pigment epithelium (RPE) of the adult mouse eye; similar results were seen in the human retina. The only other site of VMD2 gene expression identified by in situ hybridization was Sertoli cells in mouse testis. Petrukhin et al. (1998) proposed the name 'bestrophin' for the protein encoded by the VMD2 gene. </p><p>Marquardt et al. (1998) pursued further the work of Stohr et al. (1998) in identifying novel genes located within the critical region for Best disease on 11q13. They characterized 9 novel genes, determining their expression profiles as well as their genomic organizations, and analyzed their exonic sequences for the presence of mutations in patients from multigenerational Best disease pedigrees. By Northern blot analysis, one of the genes, termed TU15B, was found to be expressed exclusively in retinal pigment epithelium (RPE) as a single 2.4-kb transcript. Database analysis of the putative translation product of TU15B revealed a high degree of sequence conservation throughout evolution. </p>
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</span>
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<div>
|
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<br />
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</div>
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<div>
|
|
<h4>
|
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<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Using rabbit polyclonal and mouse monoclonal antibodies and immunocytochemical staining of macaque and porcine eyes, Marmorstein et al. (2000) found that bestrophin is localized at the basolateral plasma membrane of RPE cells. This localization suggested that bestrophin may play a role in generating the altered electrooculogram of individuals with Best disease. </p><p>Goodstadt and Ponting (2001) used the prediction of enzymatic activity for bestrophin as an example of how genetic databases can expand understanding of genes of unknown function by identifying homologies and functional motifs. </p><p>Using heterologous expression, Sun et al. (2002) showed that the human, Drosophila, and C. elegans bestrophin homologs form oligomeric chloride channels, and that human bestrophin is sensitive to intracellular calcium. Each of 15 missense mutations associated with vitelliform macular dystrophy greatly reduced or abolished the membrane current. Four of these mutant bestrophins were coexpressed with wildtype and each dominantly inhibited the wildtype membrane current, consistent with the dominant nature of the disorder. These experiments established the existence of a new chloride channel family and VMD as a channelopathy. </p><p>By whole-cell recordings of BEST1-transfected 293 cells, Sun et al. (2002) and Tsunenari et al. (2003) detected a weakly outward-rectifying current in response to a negative voltage step. Tsunenari et al. (2003) did not find new chloride currents in Xenopus oocytes following injection of BEST1 cRNA, suggesting that human cells contain a factor or subunit required for bestrophin function or plasma membrane localization. </p><p>Using Western blot analysis and confocal microscopy, Duta et al. (2004) showed that bestrophin was expressed in a human lung adenocarcinoma cell line. Bestrophin-directed small interfering RNA reduced the movement of radioactive chloride across cell monolayers. Duta et al. (2004) concluded that bestrophin contributes to the basolateral cell conductance in airway epithelial cells. </p><p>Although phasic GABA release arises from Ca(2+)-dependent exocytosis from neurons, the mechanism of tonic GABA release was unknown. Lee et al. (2010) reported that tonic inhibition in the cerebellum is due to GABA being released from glial cells by permeation of the bestrophin-1 (Best1) anion channel. They demonstrated that GABA directly permeates Best1 to yield GABA release and that tonic inhibition is eliminated by silencing of Best1. Glial cells express both GABA and Best1, and selective expression of Best1 in glial cells, after preventing general expression of Best1, fully rescues tonic inhibition. Lee et al. (2010) concluded that their results identified a molecular mechanism for tonic inhibition and established a role for interactions between glia and neurons in mediating tonic inhibition. </p><p>Moshfegh et al. (2016) found that mutations in BEST1 associated with VMD2 affected highly conserved residues. Structural modeling predicted that these BEST1 mutations would disrupt stability of pentamer formation and affect channel function. Studies of wildtype and patient stem cell-derived RPE cells suggested that BEST1 mediates chloride ion efflux in RPE cells. </p>
|
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</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Biochemical Features</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
Yang et al. (2014) described the structure of a bacterial homolog (KpBest) of BEST1 as well as functional characterizations of both channels. KpBest is a pentamer that forms a 5-helix transmembrane pore, closed by 3 rings of conserved hydrophobic residues, and has a cytoplasmic cavern with a restricted exit. From electrophysiologic analysis of structure-inspired mutations in KpBest and BEST1, Yang et al. (2014) found a sensitive control of ion selectivity in the bestrophins, including reversal of anion/cation selectivity, and dramatic activation by mutations at the cytoplasmic exit. Yang et al. (2014) also created a homology model of BEST1 that shows the locations of disease-causing mutations and suggests possible roles in regulation. </p><p>Dickson et al. (2014) presented the x-ray crystal structures of chicken BEST1-Fab complexes at 2.85-angstrom resolution with permeant anions and Ca(2+). Representing the first structure of a calcium-activated chloride channel, the eukaryotic BEST1 channel is formed from a pentameric assembly of subunits. Ca(2+) binds to the channels large cytosolic region. A single ion pore approximately 95 angstroms in length is located along the central axis and contains at least 15 binding sites for anions. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Vitelliform Macular Dystrophy 2</em></strong></p><p>
|
|
In several Swedish and Dutch families with Best macular dystrophy (VMD2; 153700), including a large Swedish family reported by Nordstrom and Barkman (1977) and studied by Graff et al. (1997), Petrukhin et al. (1998) identified 5 different heterozygous mutations in the VMD2 gene (607854.0001-607854.0005) that segregated with the disease. </p><p>In 12 patients with Best macular dystrophy, Marquardt et al. (1998) identified heterozygous sequence changes in the TU15B gene (see, e.g., 607854.0006). For 10 sequence changes, segregation with the disease was shown in multigenerational families. These data provided strong evidence that TU15B is the VMD2 gene. </p><p>Bakall et al. (1999) analyzed the bestrophin gene in 14 unrelated Swedish, Dutch, Danish, and Moroccan families with Best macular dystrophy and identified 8 previously unreported mutations. No mutations were detected in 3 families. The authors noted that the 19 mutations identified to date were missense mutations aggregating in 4 regions of the gene, and suggested that null alleles might result in other ocular diseases. </p><p>In 2 unrelated women who had vitelliform macular dystrophy diagnosed in the sixth decade of life, Allikmets et al. (1999) identified heterozygous missense mutations in the BEST1 gene (E119Q, 607854.0008; A146K, 607854.0009). </p><p>Caldwell et al. (1999) analyzed the bestrophin gene in 13 families with Best macular dystrophy and identified mutations in 9 families, including 6 missense mutations and a 2-bp deletion (607854.0012). The deletion occurred in exon 10; the authors stated that this was the first mutation reported in the 3-prime half of the bestrophin gene, beyond exon 8. In 3 of the families, there was a parent carrying the mutation who lacked the clinical phenotype, suggesting variable expression of the disease gene. </p><p>Kramer et al. (2000) identified several mutations in the VMD2 gene in German patients with macular dystrophy of juvenile onset as well as in 8 of 32 patients with adult-onset disease who were negative for mutation in the PRPH2 gene (see, e.g., 607854.0005 and 607854.0010-607854.0011). The authors suggested that the adult-onset patients represented a mild form of Best disease. </p><p>White et al. (2000) stated that 48 different mutations, predominantly missense mutations, had been described in the VMD2 gene in Best disease families. For the most part, these mutations affected amino acids in the first 50% of the protein and occurred in 4 distinct clusters possibly representing regions of functional importance. Results of analysis in 2 large series of patients with age-related macular degeneration (see 603785) suggested that the VMD2 gene does not play a major role in this disorder (Kramer et al., 2000; Allikmets et al., 1999). </p><p>Schatz et al. (2006) reported 6 affected members of a Swedish family with Best macular dystrophy who had mutations in the BEST1 gene. Four were heterozygous for either an R141H (607854.0013) or a Y29X (607854.0014) mutation and 2 were compound heterozygous for these mutations. The latter 2 patients presented with a variant form of the disorder. Both had onset of visual symptoms in early childhood and markedly reduced visual acuities. Fundus examination and OCT scan showed degenerative yellowish changes in the macula, thickening and elevation of the outer retina-RPE-choroid complex, and cystic edema of the macula. </p><p>Katagiri et al. (2015) performed a mutation analysis of the BEST1 and PRPH2 genes in 16 Japanese families with typical features of VMD and identified 12 different BEST1 variants in 13 probands (81%). Two of the variants were novel and 10 had previously been reported. Twelve probands had heterozygous mutations and 1 proband had compound heterozygous mutations. No mutations were identified in the PRPH2 gene. </p><p><strong><em>Bestrophinopathy, Autosomal Recessive</em></strong></p><p>
|
|
Burgess et al. (2008) described a retinal disorder, which they designated autosomal recessive bestrophinopathy (ARB; 611809), caused by biallelic mutation in BEST1 (e.g., 607854.0013 and 607854.0017) and associated with central visual loss, a characteristic retinopathy, an absent electrooculogram light rise, and a reduced electroretinogram. In 5 families, DNA variants were identified in each of 10 alleles. These encoded 6 different missense variants and 1 nonsense variant. No clinical or electrophysiologic abnormalities were found in heterozygotes. Two ARB missense isoforms severely reduced chloride channel activity. However, unlike 2 other alleles previously associated with Best disease, cotransfection with wildtype bestrophin-1 did not impair the formation of active wildtype bestrophin-1 channels, consistent with the recessive nature of the condition. Burgess et al. (2008) proposed that ARB is a null phenotype of bestrophin-1 in humans. </p><p><strong><em>Vitreoretinochoroidopathy</em></strong></p><p>
|
|
Yardley et al. (2004) sequenced the BEST1 gene in 5 families with autosomal dominant developmental eye abnormalities associated with retinal dystrophy (see vitreoretinochoroidopathy, or ADVIRC, 193220), and identified 3 different heterozygous missense mutations (V86M, 607854.0019; V239M, 607854.0020; and Y236C, 607854.0021). In vitro functional assays demonstrated that all 3 of these mutations disrupted splicing and caused exon skipping, whereas 2 mutations in close proximity that are known to cause Best disease, Y85H (607854.0002) and A243T, did not. Screening of the BEST1 gene in 18 unrelated individuals with microphthalmia/coloboma (see MCOPCB1, 300345) and 50 individuals with various forms of anterior segment dysgenesis revealed no pathogenic alterations. </p><p><strong><em>Retinitis Pigmentosa 50</em></strong></p><p>
|
|
In the proband of a nonconsanguineous family of European descent segregating autosomal dominant retinitis pigmentosa (adRP) mapping to chromosome 11 (RP50; 613194), Davidson et al. (2009) sequenced the BEST1 gene and identified heterozygosity for a missense mutation (I205T; 607854.0022) that segregated with disease in the family. Analysis of BEST1 in a panel of 95 adRP patients who were negative for mutation in 10 known RP genes and in 12 patients with concentric RP revealed heterozygosity for a D228N missense mutation (607854.0023) in affected members of 1 adRP family and 1 concentric RP family, and heterozygosity for a Y227C mutation (607854.0024) in another concentric RP family. Homozygosity for a missense mutation in BEST1 (L140V; 607854.0025) was found in affected members of a Pakistani family that appeared to be segregating adRP, but in which the parents were from the same village. </p>
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</span>
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<div>
|
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<br />
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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<strong>Genotype/Phenotype Correlations</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In an affected sister and brother from a family segregating autosomal dominant vitreoretinochoroidopathy (ADVIRC), Burgess et al. (2009) identified heterozygosity for a 704T-C transition in the BEST1 gene (V235A; 607854.0026). Analysis of exonic splice enhancer (ESE) activity in exon 6 of the BEST1 gene demonstrated that 2 ADVIRC-associated mutations, V235A and Y236C (607854.0021; 707A-G), weakened or abolished ESE site-dependent splicing, respectively, whereas a Best disease-associated mutation (V235L; 703G-C; see Yardley et al., 2004) strengthened ESE activity compared to wildtype. In addition, gel-shift assays involving serine/arginine (SR)-rich proteins, such as SFRS1 (600812), showed that SFRS1 had increased binding to the V235A- or V236C-mutant sequences compared to wildtype or V235L-mutant sequence. Given the exon skipping observed with the ADVIRC-associated mutations and their affinity for SFRS1, Burgess et al. (2009) suggested that the region encompassing V235A and Y236C mutations (nucleotides 704 to 709) may form part of a composite exonic regulatory elements of splicing (CERES) site. </p><p>Milenkovic et al. (2018) found that pathologic mutations affecting highly conserved residues in the N-terminal half of BEST1 likely affect protein stability. Analysis of BEST1 half-life in transfected canine MDCKII cells confirmed that BEST1 mutations enhanced protein instability. BEST1 proteins with autosomal recessive mutations were degraded more quickly than wildtype BEST1 or BEST1 proteins with autosomal dominant mutations due to the use of different degradation mechanisms. BEST1 proteins with autosomal recessive mutations were recognized by the endoplasmic reticulum (ER) and subsequently degraded, whereas BEST1 proteins with autosomal dominant mutations escaped the ER quality check and were degraded by a post-ER quality control mechanism at the Golgi complex. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Animal Model</strong>
|
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</span>
|
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Esumi et al. (2009) showed that the -154 to -104 bp region of the Best1 gene is necessary for retinal pigment epithelium (RPE) expression in transgenic mice. The Best1 promoter region contains a predicted canonical OTX-binding site (-127 to -122 bp) and a neighboring noncanonical OTX-binding site (-81 to -76 bp), and mutation of either OTX-binding site results in reduced promoter activity. The 3 OTX family proteins, OTX1 (600036), OTX2 (600037), and CRX (602225) bound to both OTX-binding sites in vitro, and all of them increased BEST1 promoter activity. Human and bovine RPE expressed not only OTX2 but also CRX, and both OTX2 and CRX bound to the BEST1 proximal promoter region in vivo. </p><p>Zhang et al. (2010) generated knockin mice carrying the Best vitelliform macular dystrophy-causing mutation W93C (607854.0001) in Best1. Both Best1(+/W93C) and Best1(W93C/W93C) mice had normal ERG a- and b-waves, but exhibited an altered light peak luminance response reminiscent of that observed in BVMD patients. Morphologic analysis identified fluid- and debris-filled retinal detachments in mice as young as 6 months of age. By 18 to 24 months of age, Best1(+/W93C) and Best1(W93C/W93C) mice exhibited enhanced accumulation of lipofuscin in the RPE, and a significant deposition of debris composed of unphagocytosed photoreceptor outer segments and lipofuscin granules in the subretinal space. The RPE cells from Best1(W93C) mice exhibited normal chloride conductances, and ATP-stimulated changes in calcium concentration in RPE cells from Best1(+/W93C) and Best1(W93C/W93C) mice were suppressed relative to Best1 +/+ littermates. The authors hypothesized that BVMD does not occur because of Best1 deficiency, as the phenotypes of Best1(+/W93C0) and Best1(W93C/W93C) mice are distinct from that of Best1 -/- mice with regard to lipofuscin accumulation and changes in the light peak and ATP calcium responses. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>26 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BEST1, TRP93CYS
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<br />
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SNP: rs28940273,
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gnomAD: rs28940273,
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ClinVar: RCV000002846, RCV000086116
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a large Swedish family with Best macular dystrophy (VMD2; 153700) first reported by Nordstrom and Barkman (1977), Petrukhin et al. (1998) identified heterozygosity for a 383G-C transversion in exon 4 of the VMD2 gene, resulting in a trp93-to-cys (W93C) amino acid substitution. The W93C mutation in this Swedish family was not found in 50 unrelated individuals of predominantly European descent or in 50 healthy Swedish blood donors. One of the affected family members was homozygous for W93C; Nordstrom and Barkman (1977) had noted that there was no difference in phenotype between heterozygotes and apparent homozygotes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BEST1, TYR85HIS
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<br />
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SNP: rs28940274,
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ClinVar: RCV000002847, RCV000086109, RCV001073456
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Swedish family with Best macular dystrophy (VMD2; 153700), Petrukhin et al. (1998) identified heterozygosity for a 357T-C transition in the VMD2 gene, resulting in a tyr85-to-his (Y85H) substitution. All related proteins from C. elegans contained tyrosine or isofunctional phenylalanine in this position; tyrosine is highly similar to phenylalanine in that it also is an aromatic hydrophobic amino acid. The Y85H mutation was found to cosegregate with the disease in all affected members of the pedigree and was not detected in 200 chromosomes from normal individuals of North American and Swedish descent. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BEST1, GLY299GLU
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<br />
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SNP: rs28941468,
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ClinVar: RCV000002848, RCV000086186, RCV004814806
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a Swedish family with Best macular dystrophy (VMD2; 153700), Petrukhin et al. (1998) identified heterozygosity for a 1000G-A transition in the VMD2 gene, resulting in a gly299-to-glu (G299E) substitution. The G299E mutation was found in all affected members of this Swedish pedigree and was not found in 94 normal chromosomes from the Swedish sample. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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BEST1, TYR227ASN
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<br />
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SNP: rs28941469,
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ClinVar: RCV000002850, RCV000086157, RCV001073354
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In all affected members of an Iowa family of Dutch ancestry with Best macular dystrophy (VMD2; 153700), originally reported by Braley and Spivey (1964), Petrukhin et al. (1998) identified a heterozygous 783T-A transversion in the VMD2 gene, resulting in a tyr227-to-asn (Y227N) substitution. All related proteins from C. elegans contained tyrosine or isofunctional phenylalanine in this position. </p><p>Mullins et al. (2005) restudied a male mutation carrier from this pedigree who had photographically documented normal maculae at age 51 years, but subsequently developed small vitelliform lesions at age 75 years, followed by widespread flecks in the midperiphery; 2 additional family members exhibited similar multifocal lesions. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, THR6PRO
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|
|
<br />
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|
|
SNP: rs28940275,
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|
|
|
|
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|
|
ClinVar: RCV000002851, RCV000086095
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members from 2 unrelated Dutch families with Best macular dystrophy (VMD2; 153700), Petrukhin et al. (1998) identified heterozygosity for a 120A-C transversion in the VMD2 gene, resulting in a thr6-to-pro (T6P) substitution. Analysis of this residue among 14 C. elegans proteins had not shown this threonine to be conserved. However, the authors classified the 120A-C change as a disease mutation because thr6 is located next to the evolutionarily conserved tyrosine at amino acid position 5, and a Chou-Fasman algorithm predicted a dramatic change in the secondary structure as a result of the threonine to proline substitution. </p><p>In a German patient with adult-onset vitelliform macular dystrophy, Kramer et al. (2000) identified heterozygosity for the T6P mutation in exon 2 of the VMD2 gene. There was no family history of the disorder. </p><p>In 2 patients with Best dystrophy who exhibited multifocal lesions, Boon et al. (2007) identified heterozygosity for the T6P mutation in the VMD2 gene. </p>
|
|
</span>
|
|
</div>
|
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, ILE295DEL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918283,
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|
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|
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|
|
ClinVar: RCV000002854, RCV000086179, RCV004814807
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated families with Best macular dystrophy (VMD2; 153700), 1 from Germany and 1 from Canada, Marquardt et al. (1998) found a heterozygous deletion of codon 295, an isoleucine, in the VMD2 gene. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, VAL9MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28940276,
|
|
|
|
|
|
|
|
ClinVar: RCV000002855, RCV000086110, RCV004814808
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Among 10 missense mutations identified in the VMD2 gene in association with Best macular dystrophy (VMD2; 153700), Marquardt et al. (1998) identified a val9-to-met (V9M) amino acid substitution in exon 2 of the VMD2 gene resulting from a GTG-to-ATG transition. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, GLU119GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1805142,
|
|
|
|
|
|
gnomAD: rs1805142,
|
|
|
|
|
|
ClinVar: RCV000002856, RCV000086129, RCV004814809
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 61-year-old woman with vitelliform macular dystrophy (VMD2; 153700) diagnosed at age 57 years, who had mottling of the retinal pigment epithelium in the right eye and exhibited a bull's-eye configuration in her left eye, Allikmets et al. (1999) identified heterozygosity for a 355G-C transversion in the VMD2 gene, resulting in a glu119-to-gln (E119Q) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, ALA146LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1800995,
|
|
|
|
|
|
|
|
ClinVar: RCV000002857, RCV000086136
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 60-year-old woman with vitelliform macular dystrophy (VMD2; 153700) diagnosed at age 54 years, Allikmets et al. (1999) identified a heterozygous 540GC-AA change in the VMD2 gene, resulting in an ala146-to-lys (A146K) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, ALA243VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28940570,
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|
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|
|
|
gnomAD: rs28940570,
|
|
|
|
|
|
ClinVar: RCV000002858, RCV000086167, RCV001075633, RCV003326112, RCV003448243
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 8 unrelated patients with vitelliform macular dystrophy (VMD2; 153700), 3 with onset of disease in childhood and 5 with onset in adulthood, Kramer et al. (2000) identified heterozygosity for a 728C-T transition in exon 7 of the BEST1 gene, resulting in an ala243-to-val (A243V) substitution. Four of the patients, 3 with childhood-onset disease and 1 with adult-onset, had a first-degree affected relative who also carried the mutation. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, ARG47HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28940278,
|
|
|
|
|
|
gnomAD: rs28940278,
|
|
|
|
|
|
ClinVar: RCV000002860, RCV000086086, RCV004795367, RCV004814810
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic patient with adult-onset vitelliform macular dystrophy (VMD2; 153700), Kramer et al. (2000) identified a heterozygous 140G-A transition in exon 2 of the VMD2 gene, resulting in an arg47-to-his (R47H) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
|
|
|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
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BEST1, 2-BP DEL, 1574CA
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|
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<br />
|
|
|
|
SNP: rs281865528,
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|
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ClinVar: RCV000002861, RCV000086087, RCV001074224, RCV003152665, RCV004732527
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Best macular dystrophy (VMD2; 153700), Caldwell et al. (1999) identified heterozygosity for a 2-bp deletion (1574delCA) in exon 10 of the VMD2 gene, causing a frameshift resulting in a premature termination codon 24 amino acids downstream that truncates the protein by 71 amino acids. The authors stated that this was the first mutation reported in the 3-prime half of the bestrophin gene, beyond exon 8. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
BESTROPHINOPATHY, AUTOSOMAL RECESSIVE, INCLUDED
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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|
BEST1, ARG141HIS
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|
<br />
|
|
|
|
SNP: rs121918284,
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|
|
|
|
|
gnomAD: rs121918284,
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|
|
|
|
ClinVar: RCV000002862, RCV000002863, RCV000086135, RCV000787541, RCV001075875, RCV004532276
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 6 affected members of Swedish family with Best macular dystrophy (VMD2; 153700), Schatz et al. (2006) identified mutations in the BEST1 gene. One was heterozygous for an arg141-to-his (R141H) mutation, 3 were heterozygous for a tyr29-to-ter (Y29X; 607854.0014) mutation, and 2 were compound heterozygous for these mutations. The 2 members who were compound heterozygous had a more severe phenotype. Neither mutation was found in 100 Swedish control individuals. </p><p>In a 15-year-old proband with multifocal Best vitelliform macular dystrophy, Wittstrom et al. (2011) identified compound heterozygosity for 2 mutations in the BEST1 gene: the R141H mutation and a de novo pro233-to-ala (P233A) substitution. The R141H mutation was present in heterozygous state in her mother and brother, neither of whom had any visual symptoms. However, both heterozygous carriers showed delayed implicit times in a- and b-waves of combined total rod and cone full-field ERG responses. </p><p>In 2 patients with a distinctive retinopathy, called bestrophinopathy (ARB; 611809), Burgess et al. (2008) identified compound heterozygosity for missense mutations in the BEST1 gene. Both patients carried a 442G-A transition that caused the R141H substitution; 1 patient also had a 949G-A transition resulting in a val317-to-met substitution (V317M; 607854.0017), and the other patient had a 122T-C transition causing a leu41-to-pro substitution (L41P; 607854.0018). </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
|
|
</div>
|
|
|
|
</div>
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|
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
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|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
BEST1, TYR29TER
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|
<br />
|
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|
|
SNP: rs121918285,
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|
|
gnomAD: rs121918285,
|
|
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|
|
|
ClinVar: RCV000002849, RCV001851591
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>For discussion of the tyr29-to-ter (Y29X) mutation in the BEST1 gene that was found in compound heterozygous state in patients with Best macular dystrophy (VMD2; 153700) by Schatz et al. (2006), see 607854.0013. </p>
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|
</span>
|
|
</div>
|
|
|
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|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 BESTROPHINOPATHY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, ARG200TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918286,
|
|
|
|
|
|
gnomAD: rs121918286,
|
|
|
|
|
|
ClinVar: RCV000002864, RCV001202565, RCV002490299, RCV004814811
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a brother and sister with a distinctive retinopathy, designated bestrophinopathy (ARB; 611809), Burgess et al. (2008) identified homozygosity for a 598C-T transition in the BEST1 gene that caused truncation of the protein (arg200 to ter; R200X). The age at visual deterioration was 30 years in the brother and 18 years in the sister. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0016 MOVED TO 607854.0013</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 BESTROPHINOPATHY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, VAL317MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918287,
|
|
|
|
|
|
|
|
ClinVar: RCV000002865
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient reported by Burgess et al. (2008) with autosomal recessive bestrophinopathy (ARB; 611809), a val317-to-met (V317M) mutation occurred in compound heterozygosity with R141H (607854.0013). Visual deterioration began at age 40 years. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 BESTROPHINOPATHY, AUTOSOMAL RECESSIVE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, LEU41PRO
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918288,
|
|
|
|
|
|
gnomAD: rs121918288,
|
|
|
|
|
|
ClinVar: RCV000002866, RCV000086085, RCV004814812
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient reported by Burgess et al. (2008) with autosomal recessive bestrophinopathy (ARB; 611809), a leu41-to-pro (L41P) mutation in the BEST1 gene occurred in compound heterozygosity with R141H (607854.0013). Visual deterioration began at age 4 years. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 VITREORETINOCHOROIDOPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, VAL86MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918289,
|
|
|
|
|
|
gnomAD: rs121918289,
|
|
|
|
|
|
ClinVar: RCV000002867, RCV001074078, RCV001851592
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 3 families segregating autosomal dominant vitreoretinochoroidopathy, microcornea, glaucoma, and cataract (VRCP; 193220), including the 4-generation Belgian family previously reported by Lafaut et al. (2001), a 6-generation French family originally reported by Hermann (1958), and another Belgian family, Yardley et al. (2004) identified heterozygosity for a 256G-A transition in exon 4 of the BEST1 gene, resulting in a val86-to-met (V86M) substitution at a conserved residue. In vitro functional assays demonstrated that V86M disrupts splicing and causes exon skipping. The mutation was not found in 400 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0020 MICROCORNEA, ROD-CONE DYSTROPHY, CATARACT, AND POSTERIOR STAPHYLOMA 2 (1 family)</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, VAL239MET
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918290,
|
|
|
|
|
|
|
|
ClinVar: RCV000002868, RCV002054410
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 3-generation English family with microcornea, rod-cone dystrophy, cataract, and posterior staphyloma (MRCS2; 193220), originally reported by Reddy et al. (2003), Yardley et al. (2004) identified heterozygosity for a 715G-A transition in exon 7 of the BEST1 gene, resulting in a val239-to-met (V239M) substitution at a conserved residue. In vitro functional assays demonstrated that V239M disrupts splicing and causes exon skipping. The mutation was not found in 400 control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0021 VITREORETINOCHOROIDOPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, TYR236CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121918291,
|
|
|
|
|
|
|
|
ClinVar: RCV000002869, RCV003555902
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a family segregating autosomal dominant vitreoretinochoroidopathy and nanophthalmos (VRCP; 193220), Yardley et al. (2004) identified heterozygosity for a 707A-G transition in exon 6 of the BEST1 gene, resulting in a tyr236-to-cys (Y236C) substitution at a conserved residue. In vitro functional assays demonstrated that Y236C disrupts splicing and causes exon skipping. The mutation was not found in 400 control chromosomes. </p><p>Burgess et al. (2009) analyzed exonic splice enhancer (ESE) activity in exon 6 of the BEST1 gene and found that the 707A-G variant abolished ESE site-dependent splicing. Gel-shift assays involving serine/arginine (SR)-rich proteins showed that SFRS1 (600812) had increased binding to 707A-G compared to wildtype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0022 RETINITIS PIGMENTOSA 50</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, ILE205THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606680,
|
|
|
|
|
|
|
|
ClinVar: RCV000002870, RCV001382239
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 10 affected members of a family with retinitis pigmentosa-50 (RP50; 613194), Davidson et al. (2009) identified heterozygosity for a 614T-C transition in exon 5 of the BEST1 gene, resulting in an ile205-to-thr (I205T) substitution. The mutation was not found in 5 unaffected family members or in 210 ethnically matched control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0023 RETINITIS PIGMENTOSA 50</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
RETINITIS PIGMENTOSA, CONCENTRIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, ASP228ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606676,
|
|
|
|
|
|
gnomAD: rs267606676,
|
|
|
|
|
|
ClinVar: RCV000002871, RCV000417725, RCV000787545, RCV001073474
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and son with retinitis pigmentosa-50 (RP50; 613194) and a brother and sister with concentric RP (see 613194), Davidson et al. (2009) identified heterozygosity for a 682G-A transition in exon 6 of the BEST1 gene, resulting in an asp228-to-asn (D228N) substitution. The mutation was not found in 210 ethnically matched control chromosomes. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0024 MACULAR DYSTROPHY, VITELLIFORM, 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
RETINITIS PIGMENTOSA, CONCENTRIC, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, TYR227CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606677,
|
|
|
|
|
|
|
|
ClinVar: RCV000002873, RCV000002874, RCV000086158
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a German family with vitelliform macular dystrophy (VMD2; 153700), Marquardt et al. (1998) identified heterozygosity for a 680A-G transition in exon 6 of the BEST1 gene, resulting in a tyr227-to-cys (Y227C) substitution at a highly conserved residue. The mutation, which segregated with disease, was not found in 84 control chromosomes. </p><p>In a 45-year-old woman with concentric retinitis pigmentosa (see 613194), Davidson et al. (2009) identified heterozygosity for the BEST1 Y227C mutation. Funduscopic examination revealed an abrupt change from normal to abnormal retina in the periphery, suggestive of a bestrophinopathy (611809), but after detection of the Y227C mutation, adjacent to the D228N (607854.0023) mutation that had been found in a family with concentric RP, the fundus images were considered to be consistent with concentric RP. The patient had 2 affected daughters with a similar phenotype who were unavailable for molecular testing. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0025 RETINITIS PIGMENTOSA 50</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, LEU140VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606678,
|
|
|
|
|
|
gnomAD: rs267606678,
|
|
|
|
|
|
ClinVar: RCV000002875, RCV000726591, RCV000787540
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and 2 daughters from a Pakistani family with retinitis pigmentosa-50 (RP50; 613194), Davidson et al. (2009) identified homozygosity for a 418C-G transversion in exon 4 of the BEST1 gene, resulting in a leu140-to-val (L140V) substitution. Davidson et al. (2009) stated that in unpublished results, they had previously found the L140V mutation in patients diagnosed with autosomal recessive bestrophinopathy (ARB; 611809). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 VITREORETINOCHOROIDOPATHY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
BEST1, VAL235ALA
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267606679,
|
|
|
|
|
|
|
|
ClinVar: RCV000002876
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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<span class="mim-text-font">
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<p>In an affected sister and brother from a family segregating autosomal dominant vitreoretinochoroidopathy (VRCP; 193220), Burgess et al. (2009) identified heterozygosity for a 704T-C transition in exon 6 of the BEST1 gene, predicted to result in a val235-to-ala (V235A) substitution. The mutation was not found in 210 control chromosomes. Splicing assay in HEK293 cells demonstrated the generation of both wildtype product and a larger splice product including an extra copy of exon 6, spliced between exons 6 and 7. Analysis of exonic splice enhancer (ESE) activity in exon 6 of the BEST1 gene demonstrated that the 704T-C variant weakened ESE site-dependent splicing compared to wildtype, and gel-shift assays involving serine/arginine (SR)-rich proteins showed that SFRS1 (600812) had increased binding to 704T-C compared to wildtype. </p>
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Wittstrom, E., Ekvall, S., Schatz, P., Bondeson, M.-L., Ponjavic, V., Andreasson, S.
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Yang, T., Liu, Q., Kloss, B., Bruni, R., Kalathur, R. C., Guo, Y., Kloppmann, E., Rost, B., Colecraft, H. M., Hendrickson, W. A.
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Yardley, J., Leroy, B. P., Hart-Holden, N., Lafaut, B. A., Loeys, B., Messiaen, L. M., Perveen, R., Reddy, M. A., Bhattacharya, S. S., Traboulsi, E., Baralle, D., De Laey, J.-J., Puech, B., Kestelyn, P., Moore, A. T., Manson, F. D. C., Black, G. C. M.
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Zhang, Y., Stanton, J. B., Wu, J., Yu, K., Hartzell, H. C., Peachey, N. S., Marmorstein, L. Y., Marmorstein, A. D.
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