3488 lines
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Entry
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- *605537 - ACTIVATING TRANSCRIPTION FACTOR 6; ATF6
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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">*605537</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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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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<a href="#text"><strong>Text</strong></a>
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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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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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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 role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605537">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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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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</ul>
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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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<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=ENSG00000118217;t=ENST00000367942" 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=22926" 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=605537" 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 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=ENSG00000118217;t=ENST00000367942" 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_001410890,NM_007348,XM_011509308,XM_011509309,XM_011509310,XM_047449542" 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_007348" 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=605537" 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=16118&isoform_id=16118_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/ATF6" 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/2245630,3953531,15929022,48734789,56786157,62087438,66774203,119611100,158254428,767908712,767908714,767908716,2217265248,2287478723,2462506316,2462506318,2462506320,2462506322" 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/P18850" 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=22926" 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=ENSG00000118217;t=ENST00000367942" 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=ATF6" 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=ATF6" 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+22926" 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/ATF6" 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:22926" 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/22926" 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=chr1&hgg_gene=ENST00000367942.4&hgg_start=161766320&hgg_end=161964070&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>
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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="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/gene-dosage/HGNC:791" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:791" 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=605537[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>
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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=605537[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/ENSG00000118217" 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=ATF6" 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=ATF6" 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=ATF6" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ATF6&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/PA25091" 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:791" 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/FBgn0033010.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:1926157" 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/ATF6#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:1926157" 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/22926/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://www.orthodb.org/?ncbi=22926" 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="https://wormbase.org/db/gene/gene?name=WBGene00000222;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-041014-328" 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://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:22926" 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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<div><a href="https://reactome.org/content/query?q=ATF6&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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</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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605537
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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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ACTIVATING TRANSCRIPTION FACTOR 6; ATF6
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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">
|
|
ACTIVATING TRANSCRIPTION FACTOR 6, ALPHA; ATF6A
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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=ATF6" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ATF6</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/1/1361?start=-3&limit=10&highlight=1361">1q23.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr1:161766320-161964070&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'})">1:161,766,320-161,964,070</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>
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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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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover 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="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/1/1361?start=-3&limit=10&highlight=1361">
|
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1q23.3
|
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</a>
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Achromatopsia 7
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
|
|
<a href="/entry/616517"> 616517 </a>
|
|
|
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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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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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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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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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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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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/605537" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/605537" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<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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</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="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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</span>
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</span>
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</h4>
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<p>ATF6 is an endoplasmic reticulum (ER) stress-regulated transmembrane transcription factor that activates the transcription of ER molecules (summary by <a href="#9" class="mim-tip-reference" title="Shen, J., Chen, X., Hendershot, L., Prywes, R. <strong>ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals.</strong> Dev. Cell 3: 99-111, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110171</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00203-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12110171">Shen et al., 2002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12110171" 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>An activating transcription factor (ATF)-binding site is a promoter element present in a wide range of viral and cellular genes. By screening a lambda-expression library with a DNA probe containing 3 tandem ATF-binding sites, <a href="#2" class="mim-tip-reference" title="Hai, T. W., Liu, F., Coukos, W. J., Green, M. R. <strong>Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers.</strong> Genes Dev. 3: 2083-2090, 1989. Note: Erratum: Genes Dev. 4: 682 only, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2516827/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2516827</a>] [<a href="https://doi.org/10.1101/gad.3.12b.2083" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2516827">Hai et al. (1989)</a> obtained cDNAs encoding ATF1 through ATF8. Binding analysis showed that the incomplete ATF6 protein bound to a triplicated ATF site with low affinity but did not bind to a single ATF site. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2516827" 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 a yeast interaction assay to screen a HeLa cell cDNA library for serum response factor (SRF; <a href="/entry/600589">600589</a>)-interacting proteins, <a href="#14" class="mim-tip-reference" title="Zhu, C., Johansen, F.-E., Prywes, R. <strong>Interaction of ATF6 and serum response factor.</strong> Molec. Cell. Biol. 17: 4957-4966, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9271374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9271374</a>] [<a href="https://doi.org/10.1128/MCB.17.9.4957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9271374">Zhu et al. (1997)</a> cloned a sequence identical to a region of ATF6. The ATF6 sequence bound to the C terminus of SRF, outside the DNA-binding region. By 5-prime and 3-prime RACE, <a href="#14" class="mim-tip-reference" title="Zhu, C., Johansen, F.-E., Prywes, R. <strong>Interaction of ATF6 and serum response factor.</strong> Molec. Cell. Biol. 17: 4957-4966, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9271374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9271374</a>] [<a href="https://doi.org/10.1128/MCB.17.9.4957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9271374">Zhu et al. (1997)</a> obtained a full-length cDNA encoding ATF6. Sequence analysis predicted that the 670-amino acid protein contains an N-terminal serine-rich domain and a central DNA-binding domain followed by a leucine zipper sequence. Northern blot analysis revealed expression of a 2.5-kb transcript in HeLa cells and 4.5- and 8.0-kb transcripts in all mouse tissues tested, with the exception of spleen. Immunoblot analysis detected expression of a 90-kD protein in HeLa and COS cell lysates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9271374" 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="#1" class="mim-tip-reference" title="Ansar, M., Santos-Cortez, R. L. P., Saqib, M. A. N., Zulfiqar, F., Lee, K., Ashraf, N. M., Ullah, E., Wang, X., Sajid, S., Khan, F. S., Amin-ud-Din, M., University of Washington Center for Mendelian Genomics, and 9 others. <strong>Mutation of ATF6 causes autosomal recessive achromatopsia.</strong> Hum. Genet. 134: 941-950, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063662</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26063662[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/10.1007/s00439-015-1571-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063662">Ansar et al. (2015)</a> identified 3 alternatively spliced isoforms of human ATF6: AK290498 and AF005887, both with 16 exons, and AB208929, with 14 exons. By RT-PCR, they demonstrated expression of all 3 isoforms in the human eye, particularly in retinal pigment epithelium (RPE) cells. The occurrence of multiple ATF6 isoforms was confirmed by Western blot analysis in adult C57BL/6J mouse retina. In CD1 mouse retina, ATF6 immunoreactivity was most prominent in the retinal ganglion cells, and staining was also observed in the RPE, outer and inner segments of photoreceptor cells, and inner and outer plexiform layers, as well as in the inner nuclear layer of neuronal retina. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26063662" 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="#8" class="mim-tip-reference" title="Meex, S. J. R., van Greevenbroek, M. M. J., Ayoubi, T. A., Vlietinck, R., van Vliet-Ostaptchouk, J. V., Hofker, M. H., Vermeulen, V. M. M.-J., Schalkwijk, C. G., Feskens, E. J. M., Boer, J. M. A., Stehouwer, C. D. A., van der Kallen, C. J. H., de Bruin, T. W. A. <strong>Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in Dutch Caucasians.</strong> J. Clin. Endocr. Metab. 92: 2720-2725, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17440018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17440018</a>] [<a href="https://doi.org/10.1210/jc.2006-2280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17440018">Meex et al. (2007)</a> stated that the ATF6 gene maps to chromosome 1q23.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17440018" 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="#1" class="mim-tip-reference" title="Ansar, M., Santos-Cortez, R. L. P., Saqib, M. A. N., Zulfiqar, F., Lee, K., Ashraf, N. M., Ullah, E., Wang, X., Sajid, S., Khan, F. S., Amin-ud-Din, M., University of Washington Center for Mendelian Genomics, and 9 others. <strong>Mutation of ATF6 causes autosomal recessive achromatopsia.</strong> Hum. Genet. 134: 941-950, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063662</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26063662[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/10.1007/s00439-015-1571-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063662">Ansar et al. (2015)</a> determined that the ATF6 gene comprises 16 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26063662" 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>When unfolded proteins accumulate in the endoplasmic reticulum, transcription of glucose-regulated proteins (GRPs) representing ER-resident molecular chaperones is markedly induced via the unfolded protein response (UPR) pathway. <a href="#13" class="mim-tip-reference" title="Yoshida, H., Haze, K., Yanagi, H., Yura, T., Mori, K. <strong>Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins: involvement of basic leucine zipper transcription factors.</strong> J. Biol. Chem. 273: 33741-33749, 1998. Note: Erratum: J. Biol. Chem. 274: 2592 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9837962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9837962</a>] [<a href="https://doi.org/10.1074/jbc.273.50.33741" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9837962">Yoshida et al. (1998)</a> analyzed the promoter regions of the human GRP78 (HSPA5; <a href="/entry/138120">138120</a>), GRP94 (<a href="/entry/191175">191175</a>), and calreticulin (CALR; <a href="/entry/109091">109091</a>) genes and identified a novel element designated the 'ER stress response element,' or ERSE. ERSE, with a consensus of CCAATN9CCACG, was shown to be necessary and sufficient for induction of these GRPs. Using yeast 1-hybrid screening, <a href="#13" class="mim-tip-reference" title="Yoshida, H., Haze, K., Yanagi, H., Yura, T., Mori, K. <strong>Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins: involvement of basic leucine zipper transcription factors.</strong> J. Biol. Chem. 273: 33741-33749, 1998. Note: Erratum: J. Biol. Chem. 274: 2592 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9837962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9837962</a>] [<a href="https://doi.org/10.1074/jbc.273.50.33741" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9837962">Yoshida et al. (1998)</a> isolated a human cDNA encoding a basic leucine zipper (bZIP) protein, ATF6, as a putative ERSE-binding protein. When overexpressed in HeLa cells, ATF6 enhanced transcription of GRP genes in an ERSE-dependent manner, whereas CREB-related protein (CREBRP; <a href="/entry/600984">600984</a>), another bZIP protein closely related to ATF6, specifically inhibited GRP induction. Endogenous ATF6 constitutively expressed as a 90-kD protein was converted to a 50-kD protein in ER-stressed cells, which appeared to be important for the cellular response to ER stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9837962" 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="#3" class="mim-tip-reference" title="Haze, K., Yoshida, H., Yanagi, H., Yura, T., Mori, K. <strong>Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress.</strong> Molec. Biol. Cell 10: 3787-3799, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10564271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10564271</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10564271[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/10.1091/mbc.10.11.3787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10564271">Haze et al. (1999)</a> found that in response to ER stress induced by thapsigargin, the 90-kD type II transmembrane glycoprotein form of ATF6 was converted to a 50-kD soluble nuclear form that retained only the N terminus, including the leucine zipper. Immunofluorescence analysis demonstrated that the subcellular localization altered from the ER to the nucleus for the form lacking the C terminus. <a href="#3" class="mim-tip-reference" title="Haze, K., Yoshida, H., Yanagi, H., Yura, T., Mori, K. <strong>Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress.</strong> Molec. Biol. Cell 10: 3787-3799, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10564271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10564271</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10564271[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/10.1091/mbc.10.11.3787" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10564271">Haze et al. (1999)</a> determined that the transmembrane domain is located near the center of the protein, C terminal to the leucine zipper, at amino acids 378 to 398. Expression of the N-terminal 373 residues enhanced the levels of HSPA5 mRNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10564271" 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>When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. <a href="#12" class="mim-tip-reference" title="Ye, J., Rawson, R. B., Komuro, R., Chen, X., Dave, U. P., Prywes, R., Brown, M. S., Goldstein, J. L. <strong>ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.</strong> Molec. Cell 6: 1355-1364, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163209</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)00133-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11163209">Ye et al. (2000)</a> showed that ATF6 is processed by site-1 protease (S1P; <a href="/entry/603355">603355</a>) and site-2 protease (S2P; <a href="/entry/300294">300294</a>), the enzymes that process sterol regulatory element-binding proteins (SREBPs; see <a href="/entry/184756">184756</a>) in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce HSPA5, an ATF6 target, in response to ER stress. ATF6 processing did not require SREBP cleavage-activating protein (SCAP; <a href="/entry/601510">601510</a>), which is essential for SREBP processing. <a href="#12" class="mim-tip-reference" title="Ye, J., Rawson, R. B., Komuro, R., Chen, X., Dave, U. P., Prywes, R., Brown, M. S., Goldstein, J. L. <strong>ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.</strong> Molec. Cell 6: 1355-1364, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163209</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)00133-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11163209">Ye et al. (2000)</a> concluded that S1P and S2P are required for the ER stress response as well as for lipid synthesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11163209" 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="#6" class="mim-tip-reference" title="Li, M., Baumeister, P., Roy, B., Phan, T., Foti, D., Luo, S., Lee, A. S. <strong>ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1.</strong> Molec. Cell. Biol. 20: 5096-5106, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10866666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10866666</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10866666[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/10.1128/MCB.20.14.5096-5106.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10866666">Li et al. (2000)</a> found that in addition to its possible cleavage upon ER stress, optimal ATF6 stimulation requires at least 2 copies of the ERSEs and a functional NF-Y (see NFYA; <a href="/entry/189903">189903</a>) complex with a high-affinity NF-Y-binding site that confers selectivity among different ERSEs. In thapsigargin-stressed cells, ATF6 interacted with YY1 (<a href="/entry/600013">600013</a>), which further enhanced and sustained the activity of ATF6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10866666" 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 immunoprecipitation, <a href="#9" class="mim-tip-reference" title="Shen, J., Chen, X., Hendershot, L., Prywes, R. <strong>ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals.</strong> Dev. Cell 3: 99-111, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110171</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00203-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12110171">Shen et al. (2002)</a> detected ATF6 binding to HSPA5, which dissociated in response to ER stress. Deletion of luminal HSPA5 binding sites or Golgi localization signals in ATF6 disrupted proper transport to the Golgi complex. The authors concluded that HSPA5 retains ATF6 in the ER by inhibiting its Golgi localization signals and that dissociation of HSPA5 during ER stress allows ATF6 to be transported to the Golgi. <a href="#10" class="mim-tip-reference" title="Sommer, T., Jarosch, E. <strong>BiP binding keeps ATF6 at bay.</strong> Dev. Cell 3: 1-2, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110159</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00210-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12110159">Sommer and Jarosch (2002)</a> summarized the findings of <a href="#9" class="mim-tip-reference" title="Shen, J., Chen, X., Hendershot, L., Prywes, R. <strong>ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals.</strong> Dev. Cell 3: 99-111, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110171</a>] [<a href="https://doi.org/10.1016/s1534-5807(02)00203-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12110171">Shen et al. (2002)</a> and presented a discussion of the proteins involved in regulating levels of aberrant proteins within the ER. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12110171+12110159" 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>The 3 UPR branches, governed by the ER stress sensors IRE1 (<a href="/entry/604033">604033</a>), PERK (<a href="/entry/604032">604032</a>), and ATF6, promote cell survival by reducing misfolded protein levels. UPR signaling also promotes apoptotic cell death if ER stress is not alleviated. <a href="#7" class="mim-tip-reference" title="Lin, J. H., Li, H., Yasumura, D., Cohen, H. R., Zhang, C., Panning, B., Shokat, K. M., LaVail, M. M., Walter, P. <strong>IRE1 signaling affects cell fate during the unfolded protein response.</strong> Science 318: 944-949, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17991856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17991856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17991856[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.1146361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17991856">Lin et al. (2007)</a> found that IRE1 and ATF6 activities were attenuated by persistent ER stress in human cells. By contrast, PERK signaling, including translational inhibition and induction of the proapoptotic transcription regulator CHOP (<a href="/entry/126337">126337</a>), was maintained. When IRE1 activity was sustained artificially, cell survival was enhanced, suggesting a causal link between the duration of UPR branch signaling and life or death cell fate after ER stress. Key findings from their studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin (<a href="/entry/180380">180380</a>) in animal models of retinitis pigmentosa. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17991856" 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 HeLa cells, <a href="#4" class="mim-tip-reference" title="Higa, A., Taouji, S., Lhomond, S., Jensen, D., Fernandez-Zapico, M. E., Simpson, J. C., Pasquet, J.-M., Schekman, R., Chevet, E. <strong>Endoplasmic reticulum stress-activated transcription factor ATF6-alpha requires the disulfide isomerase PDIA5 to modulate chemoresistance.</strong> Molec. Cell. Biol. 34: 1839-1849, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24636989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24636989</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24636989[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/10.1128/MCB.01484-13" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24636989">Higa et al. (2014)</a> found that PDIA5 (<a href="/entry/616942">616942</a>) played a crucial role in disulfide bond rearrangement and activation of ATF6 upon imatinib-induced ER stress. In leukemia cell lines, knockdown of ATF6 or PDIA5 via small interfering RNA, or pharmacologic inhibition of PDI, blocked ATF6 activation and release from the ER and restored cell sensitivity to imatinib. Silencing of PDIA5 did not significantly affect activation of other arms of the unfolded protein response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24636989" 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><strong><em>Achromatopsia 7</em></strong></p><p>
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In affected individuals from a consanguineous Pakistani family with achromatopsia (ACHM7; <a href="/entry/616517">616517</a>), <a href="#1" class="mim-tip-reference" title="Ansar, M., Santos-Cortez, R. L. P., Saqib, M. A. N., Zulfiqar, F., Lee, K., Ashraf, N. M., Ullah, E., Wang, X., Sajid, S., Khan, F. S., Amin-ud-Din, M., University of Washington Center for Mendelian Genomics, and 9 others. <strong>Mutation of ATF6 causes autosomal recessive achromatopsia.</strong> Hum. Genet. 134: 941-950, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063662</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26063662[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/10.1007/s00439-015-1571-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063662">Ansar et al. (2015)</a> identified homozygosity for a 1-bp duplication in the ATF6 gene (<a href="#0001">605537.0001</a>). The mutation, which segregated with disease in the family, was not found in ethnically matched controls or public databases. Functional studies showed mislocalization of the mutant protein compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26063662" 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>From a cohort of 304 patients with achromatopsia, <a href="#5" class="mim-tip-reference" title="Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others. <strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong> Nature Genet. 47: 757-765, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26029869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26029869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26029869[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/10.1038/ng.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26029869">Kohl et al. (2015)</a> identified 18 patients from 10 independent families who were homozygous or compound heterozygous for mutations in the ATF6 gene (see, e.g., <a href="#0002">605537.0002</a>-<a href="#0006">605537.0006</a>). Functional analysis demonstrated that the mutations attenuate ATF6 transcriptional activity in response to ER stress. <a href="#5" class="mim-tip-reference" title="Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others. <strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong> Nature Genet. 47: 757-765, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26029869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26029869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26029869[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/10.1038/ng.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26029869">Kohl et al. (2015)</a> concluded that mutations in ATF6 are a rare cause of achromatopsia and, noting that all 18 mutation-positive patients exhibited marked foveal hypoplasia, suggested that severe foveal hypoplasia with a poorly formed or absent foveal pit could be a hallmark of ATF6-related disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26029869" 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>Type 2 Diabetes</em></strong></p><p>
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<a href="#11" class="mim-tip-reference" title="Thameem, F., Farook, V. S., Bogardus, C., Prochazka, M. <strong>Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians.</strong> Diabetes 55: 839-842, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16505252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16505252</a>] [<a href="https://doi.org/10.2337/diabetes.55.03.06.db05-1002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16505252">Thameem et al. (2006)</a> reported a nominal association between variants of the ATF6 gene and type 2 diabetes (<a href="/entry/125853">125853</a>) in Pima Indians (p less than 0.05). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16505252" 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="#8" class="mim-tip-reference" title="Meex, S. J. R., van Greevenbroek, M. M. J., Ayoubi, T. A., Vlietinck, R., van Vliet-Ostaptchouk, J. V., Hofker, M. H., Vermeulen, V. M. M.-J., Schalkwijk, C. G., Feskens, E. J. M., Boer, J. M. A., Stehouwer, C. D. A., van der Kallen, C. J. H., de Bruin, T. W. A. <strong>Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in Dutch Caucasians.</strong> J. Clin. Endocr. Metab. 92: 2720-2725, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17440018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17440018</a>] [<a href="https://doi.org/10.1210/jc.2006-2280" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17440018">Meex et al. (2007)</a> investigated 16 ATF6 polymorphisms for their contribution to disturbed glucose homeostasis and type 2 diabetes in Dutch Caucasians. They found that common ATF variants were associated with elevated glucose levels in the general population (p = 0.005-0.5), and that the majority of these variants, and haplotypes thereof, were significantly associated with impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes (p = 0.006-0.05). They noted that the associated variants differed from those identified by <a href="#11" class="mim-tip-reference" title="Thameem, F., Farook, V. S., Bogardus, C., Prochazka, M. <strong>Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians.</strong> Diabetes 55: 839-842, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16505252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16505252</a>] [<a href="https://doi.org/10.2337/diabetes.55.03.06.db05-1002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16505252">Thameem et al. (2006)</a> in Pima Indians and that the variants identified by <a href="#11" class="mim-tip-reference" title="Thameem, F., Farook, V. S., Bogardus, C., Prochazka, M. <strong>Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians.</strong> Diabetes 55: 839-842, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16505252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16505252</a>] [<a href="https://doi.org/10.2337/diabetes.55.03.06.db05-1002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16505252">Thameem et al. (2006)</a> were not significantly associated with fasting glucose levels, disturbed glucose homeostasis, or type 2 diabetes in their Dutch Caucasian cohorts. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17440018+16505252" 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="#5" class="mim-tip-reference" title="Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others. <strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong> Nature Genet. 47: 757-765, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26029869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26029869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26029869[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/10.1038/ng.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26029869">Kohl et al. (2015)</a> observed no significant differences in retinal morphology and function in young Atf6-null mice compared to heterozygous or wildtype littermates. However, at 18 months of age, both rod and cone single-flash electroretinography (ERG) responses were markedly reduced in the Atf6-null mice compared to wildtype mice; fundi of the mutant mice also showed retinal degeneration in areas that correlated with hyperfluorescent spots on confocal scanning-laser ophthalmoscopy. Retinal vasculature appeared unaffected in the mouse model, as observed in human patients. Spectral-domain optical coherence tomography (SD-OCT) imaging showed disruption of the layers corresponding to the inner and outer segments; however, in contrast to human patients, the RPE was also affected in mice. Noting that mice do not develop foveas, <a href="#5" class="mim-tip-reference" title="Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others. <strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong> Nature Genet. 47: 757-765, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26029869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26029869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26029869[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/10.1038/ng.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26029869">Kohl et al. (2015)</a> suggested that there are profound differences in the function and impact of ATF6 in mouse and human retinal development and maintenance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26029869" 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="/allelicVariants/605537" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605537[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<strong>.0001 ACHROMATOPSIA 7</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">rs869320751 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869320751;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=rs869320751" 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=rs869320751" 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=RCV000190367" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190367" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190367</a>
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<p>In 4 affected individuals from a consanguineous Pakistani family with achromatopsia (ACHM7; <a href="/entry/616517">616517</a>), <a href="#1" class="mim-tip-reference" title="Ansar, M., Santos-Cortez, R. L. P., Saqib, M. A. N., Zulfiqar, F., Lee, K., Ashraf, N. M., Ullah, E., Wang, X., Sajid, S., Khan, F. S., Amin-ud-Din, M., University of Washington Center for Mendelian Genomics, and 9 others. <strong>Mutation of ATF6 causes autosomal recessive achromatopsia.</strong> Hum. Genet. 134: 941-950, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26063662/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26063662</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26063662[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/10.1007/s00439-015-1571-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26063662">Ansar et al. (2015)</a> identified homozygosity for a 1-bp duplication (c.355_356dupG, NM_007348.3) in exon 5 of the ATF6 gene, causing a frameshift predicted to result in a premature termination codon (Glu119GlyfsTer8) prior to the basic region leucine zipper (BRLZ) and transmembrane domains, affecting all 3 ATF6 isoforms. The mutation, which segregated with disease in the family, was not found in 470 ethnically matched control chromosomes, in exome sequence data from 130 unrelated Pakistani individuals without eye disease, or in the dbSNP or ExAC databases. Functional analysis in transfected COS-7 cells demonstrated expression of wildtype ATF6 throughout the cytoplasm with localization to the ER, whereas the Glu119GlyfsTer8 mutant had significantly reduced localization in the cytoplasm and was mainly confined to the nucleus. Western blot analysis confirmed that mutant ATF6 had a reduced protein size. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26063662" 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>.0002 ACHROMATOPSIA 7</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> rs761357250 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs761357250;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/rs761357250?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=rs761357250" 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=rs761357250" 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=RCV000190368 OR RCV001390414 OR RCV003390920 OR RCV004668839" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190368, RCV001390414, RCV003390920, RCV004668839" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190368...</a>
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<p>In 3 sibs from a nonconsanguineous Irish family and 3 sibs from a nonconsanguineous United Kingdom family, all exhibiting achromatopsia (ACHM7; <a href="/entry/616517">616517</a>), <a href="#5" class="mim-tip-reference" title="Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others. <strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong> Nature Genet. 47: 757-765, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26029869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26029869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26029869[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/10.1038/ng.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26029869">Kohl et al. (2015)</a> identified homozygosity for a c.970C-T transition in the ATF6 gene (c.970C-T, NM_007348.3), resulting in an arg324-to-cys (R324C) substitution at a highly conserved residue in the basic region of the bZIP domain, necessary for dimerization. The mutation, which segregated with disease in both families, was not found in an in-house database or the dbSNP or Exome Variant Server databases. However, the c.970C-T allele was observed in heterozygosity in 3 of 120,904 genotypes found in the ExAC browser. Haplotype reconstruction of SNP chip data from the 2 families indicated that all carriers of the R324C mutation shared a 0.7-Mb common homozygous haplotype flanked by <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4072409;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4072409</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs16840028;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs16840028</a>, suggestive of either a founder mutation in the Irish and UK population or identity by descent. Functional analysis in patient fibroblasts and in transfected HEK293 cells showed significantly reduced or absent mRNA induction of downstream transcriptional targets with the R324C mutant compared to wildtype ATF6. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26029869" 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="0003" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0003 ACHROMATOPSIA 7</strong>
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ATF6, IVS12, G-C, +1
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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> rs797045172 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045172;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/rs797045172?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=rs797045172" 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=rs797045172" 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=RCV000191038 OR RCV003556237" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191038, RCV003556237" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191038...</a>
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<p>In affected individuals from 3 French Canadian families with achromatopsia (AHM7; <a href="/entry/616517">616517</a>), <a href="#5" class="mim-tip-reference" title="Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others. <strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong> Nature Genet. 47: 757-765, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26029869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26029869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26029869[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/10.1038/ng.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26029869">Kohl et al. (2015)</a> identified homozygosity for a splice site mutation (c.1533+1G-C, NM_007348.3) in intron 12 of the ATF6 gene, resulting in 2 aberrantly spliced proteins. Sequencing revealed that the larger mutant protein was due to retention of 83 bp of intron 12, causing a premature termination codon (Gly512LeufsTer39), whereas the smaller mutation was due to skipping of exon 12, which also resulted in premature termination (Leu479ValfsTer11). The mutation, which segregated with disease in the families, was not found in an in-house database or the dbSNP, Exome Variant Server, or ExAC databases. All patients carrying the splice site mutation had the same homozygous SNP genotype based on 2 rare SNPs, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs371893818;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs371893818</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs374093774;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs374093774</a>, suggestive of a founder mutation in the French Canadian population. One of the French Canadian patients, a 17-year-old boy, exhibited incomplete achromatopsia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26029869" 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="0004" class="mim-anchor"></a>
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<strong>.0004 ACHROMATOPSIA 7</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">rs797045173 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045173;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=rs797045173" 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=rs797045173" 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=RCV000191039" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191039" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191039</a>
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<p>In a German brother and sister with achromatopsia (ACHM7; <a href="/entry/616517">616517</a>), <a href="#5" class="mim-tip-reference" title="Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others. <strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong> Nature Genet. 47: 757-765, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26029869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26029869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26029869[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/10.1038/ng.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26029869">Kohl et al. (2015)</a> identified compound heterozygosity for 2 different 1-bp duplications in the ATF6 gene: c.797dupC (c.797dupC, NM_007348.3), resulting in an asn267-to-ter (N267X) substitution, and c.1110dupA (<a href="#0005">605537.0005</a>), causing a frameshift resulting in a premature termination codon (Val371SerfsTer3). The mutations, which segregated with disease in the family, were not found in an in-house database or the dbSNP, Exome Variant Server, or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26029869" 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">rs797045174 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797045174;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=rs797045174" 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=rs797045174" 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=RCV000191040" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000191040" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000191040</a>
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<p>For discussion of the c.1110dupA mutation in the ATF6 gene (c.1110dupA, NM_007348.3) that was found in compound heterozygous state in 2 German sibs with achromatopsia (ACHM7; <a href="/entry/616517">616517</a>) by <a href="#5" class="mim-tip-reference" title="Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others. <strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong> Nature Genet. 47: 757-765, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26029869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26029869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26029869[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/10.1038/ng.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26029869">Kohl et al. (2015)</a>, see <a href="#0004">605537.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26029869" 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 ACHROMATOPSIA 7</strong>
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ATF6, TYR567ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796065053 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065053;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=rs796065053" 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=rs796065053" 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=RCV000190372 OR RCV004668840" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190372, RCV004668840" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190372...</a>
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<p>In a 26-year-old Iranian woman with incomplete achromatopsia (ACHM7; <a href="/entry/616517">616517</a>), <a href="#5" class="mim-tip-reference" title="Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others. <strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong> Nature Genet. 47: 757-765, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26029869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26029869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26029869[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/10.1038/ng.3319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26029869">Kohl et al. (2015)</a> identified homozygosity for a c.1699T-A transversion in the ATF6 gene (c.1699T-A, NM_007348.3), resulting in a tyr567-to-asn (Y567N) substitution at a highly conserved residue within an 18-residue C-terminal sequence motif that is present in both ATF6A and ATF6B (<a href="/entry/600984">600984</a>). The mutation, which segregated with disease in the family, was not found in an in-house database or the dbSNP, Exome Variant Server, or ExAC databases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26029869" 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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<strong>Mutation of ATF6 causes autosomal recessive achromatopsia.</strong>
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Hum. Genet. 134: 941-950, 2015.
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[<a href="https://doi.org/10.1101/gad.3.12b.2083" target="_blank">Full Text</a>]
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<a id="Haze1999" class="mim-anchor"></a>
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Haze, K., Yoshida, H., Yanagi, H., Yura, T., Mori, K.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10564271/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10564271</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10564271[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=10564271" 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/10.1091/mbc.10.11.3787" target="_blank">Full Text</a>]
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Higa, A., Taouji, S., Lhomond, S., Jensen, D., Fernandez-Zapico, M. E., Simpson, J. C., Pasquet, J.-M., Schekman, R., Chevet, E.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24636989/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24636989</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24636989[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=24636989" 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/10.1128/MCB.01484-13" target="_blank">Full Text</a>]
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Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others.
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<strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong>
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Nature Genet. 47: 757-765, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26029869/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26029869</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26029869[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=26029869" 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/ng.3319" target="_blank">Full Text</a>]
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Li, M., Baumeister, P., Roy, B., Phan, T., Foti, D., Luo, S., Lee, A. S.
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<strong>ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10866666/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10866666</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10866666[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=10866666" 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/10.1128/MCB.20.14.5096-5106.2000" target="_blank">Full Text</a>]
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Lin, J. H., Li, H., Yasumura, D., Cohen, H. R., Zhang, C., Panning, B., Shokat, K. M., LaVail, M. M., Walter, P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17991856/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17991856</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17991856[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=17991856" 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.1146361" target="_blank">Full Text</a>]
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Meex, S. J. R., van Greevenbroek, M. M. J., Ayoubi, T. A., Vlietinck, R., van Vliet-Ostaptchouk, J. V., Hofker, M. H., Vermeulen, V. M. M.-J., Schalkwijk, C. G., Feskens, E. J. M., Boer, J. M. A., Stehouwer, C. D. A., van der Kallen, C. J. H., de Bruin, T. W. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17440018/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17440018</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17440018" 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/10.1210/jc.2006-2280" target="_blank">Full Text</a>]
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Shen, J., Chen, X., Hendershot, L., Prywes, R.
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<strong>ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110171</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12110171" 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/s1534-5807(02)00203-4" target="_blank">Full Text</a>]
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Sommer, T., Jarosch, E.
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<strong>BiP binding keeps ATF6 at bay.</strong>
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Dev. Cell 3: 1-2, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12110159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12110159</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12110159" 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/s1534-5807(02)00210-1" target="_blank">Full Text</a>]
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<a id="11" class="mim-anchor"></a>
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<a id="Thameem2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Thameem, F., Farook, V. S., Bogardus, C., Prochazka, M.
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<strong>Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians.</strong>
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Diabetes 55: 839-842, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16505252/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16505252</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16505252" 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/10.2337/diabetes.55.03.06.db05-1002" target="_blank">Full Text</a>]
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Ye2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ye, J., Rawson, R. B., Komuro, R., Chen, X., Dave, U. P., Prywes, R., Brown, M. S., Goldstein, J. L.
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<strong>ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.</strong>
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Molec. Cell 6: 1355-1364, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11163209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11163209</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11163209" 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/s1097-2765(00)00133-7" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Yoshida1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yoshida, H., Haze, K., Yanagi, H., Yura, T., Mori, K.
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<strong>Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins: involvement of basic leucine zipper transcription factors.</strong>
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J. Biol. Chem. 273: 33741-33749, 1998. Note: Erratum: J. Biol. Chem. 274: 2592 only, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9837962/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9837962</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9837962" 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.273.50.33741" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Zhu1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhu, C., Johansen, F.-E., Prywes, R.
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<strong>Interaction of ATF6 and serum response factor.</strong>
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Molec. Cell. Biol. 17: 4957-4966, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9271374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9271374</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9271374" 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/10.1128/MCB.17.9.4957" target="_blank">Full Text</a>]
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</ol>
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<br />
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<div>
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<a id="contributors" class="mim-anchor"></a>
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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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Patricia A. Hartz - updated : 05/09/2016
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</span>
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</div>
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</div>
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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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Marla J. F. O'Neill - updated : 8/13/2015<br>Marla J. F. O'Neill - updated : 2/19/2008<br>John A. Phillips, III - updated : 2/14/2008<br>Ada Hamosh - updated : 11/26/2007<br>Dawn Watkins-Chow - updated : 2/26/2003<br>Paul J. Converse - updated : 2/16/2001
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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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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Stylianos E. Antonarakis : 1/8/2001
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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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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alopez : 10/01/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 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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mgross : 05/09/2016<br>alopez : 8/13/2015<br>mcolton : 8/13/2015<br>terry : 11/29/2012<br>terry : 9/14/2012<br>mgross : 9/10/2009<br>carol : 2/19/2008<br>carol : 2/14/2008<br>alopez : 11/28/2007<br>terry : 11/26/2007<br>mgross : 7/31/2003<br>carol : 3/3/2003<br>tkritzer : 2/26/2003<br>tkritzer : 2/26/2003<br>mgross : 2/26/2001<br>terry : 2/16/2001<br>mgross : 1/8/2001
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</span>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605537
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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ACTIVATING TRANSCRIPTION FACTOR 6; ATF6
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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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<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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</div>
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<div>
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<h4>
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<span class="mim-font">
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ACTIVATING TRANSCRIPTION FACTOR 6, ALPHA; ATF6A
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ATF6</em></strong>
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</span>
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</p>
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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: 1q23.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 1:161,766,320-161,964,070 </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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<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="1">
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<span class="mim-font">
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1q23.3
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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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Achromatopsia 7
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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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616517
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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 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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3
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</span>
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</td>
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<div>
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<br />
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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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<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>ATF6 is an endoplasmic reticulum (ER) stress-regulated transmembrane transcription factor that activates the transcription of ER molecules (summary by Shen et al., 2002). </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>An activating transcription factor (ATF)-binding site is a promoter element present in a wide range of viral and cellular genes. By screening a lambda-expression library with a DNA probe containing 3 tandem ATF-binding sites, Hai et al. (1989) obtained cDNAs encoding ATF1 through ATF8. Binding analysis showed that the incomplete ATF6 protein bound to a triplicated ATF site with low affinity but did not bind to a single ATF site. </p><p>Using a yeast interaction assay to screen a HeLa cell cDNA library for serum response factor (SRF; 600589)-interacting proteins, Zhu et al. (1997) cloned a sequence identical to a region of ATF6. The ATF6 sequence bound to the C terminus of SRF, outside the DNA-binding region. By 5-prime and 3-prime RACE, Zhu et al. (1997) obtained a full-length cDNA encoding ATF6. Sequence analysis predicted that the 670-amino acid protein contains an N-terminal serine-rich domain and a central DNA-binding domain followed by a leucine zipper sequence. Northern blot analysis revealed expression of a 2.5-kb transcript in HeLa cells and 4.5- and 8.0-kb transcripts in all mouse tissues tested, with the exception of spleen. Immunoblot analysis detected expression of a 90-kD protein in HeLa and COS cell lysates. </p><p>Ansar et al. (2015) identified 3 alternatively spliced isoforms of human ATF6: AK290498 and AF005887, both with 16 exons, and AB208929, with 14 exons. By RT-PCR, they demonstrated expression of all 3 isoforms in the human eye, particularly in retinal pigment epithelium (RPE) cells. The occurrence of multiple ATF6 isoforms was confirmed by Western blot analysis in adult C57BL/6J mouse retina. In CD1 mouse retina, ATF6 immunoreactivity was most prominent in the retinal ganglion cells, and staining was also observed in the RPE, outer and inner segments of photoreceptor cells, and inner and outer plexiform layers, as well as in the inner nuclear layer of neuronal retina. </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>Mapping</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>Meex et al. (2007) stated that the ATF6 gene maps to chromosome 1q23.3. </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>Gene Structure</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>Ansar et al. (2015) determined that the ATF6 gene comprises 16 exons. </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>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">
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<p>When unfolded proteins accumulate in the endoplasmic reticulum, transcription of glucose-regulated proteins (GRPs) representing ER-resident molecular chaperones is markedly induced via the unfolded protein response (UPR) pathway. Yoshida et al. (1998) analyzed the promoter regions of the human GRP78 (HSPA5; 138120), GRP94 (191175), and calreticulin (CALR; 109091) genes and identified a novel element designated the 'ER stress response element,' or ERSE. ERSE, with a consensus of CCAATN9CCACG, was shown to be necessary and sufficient for induction of these GRPs. Using yeast 1-hybrid screening, Yoshida et al. (1998) isolated a human cDNA encoding a basic leucine zipper (bZIP) protein, ATF6, as a putative ERSE-binding protein. When overexpressed in HeLa cells, ATF6 enhanced transcription of GRP genes in an ERSE-dependent manner, whereas CREB-related protein (CREBRP; 600984), another bZIP protein closely related to ATF6, specifically inhibited GRP induction. Endogenous ATF6 constitutively expressed as a 90-kD protein was converted to a 50-kD protein in ER-stressed cells, which appeared to be important for the cellular response to ER stress. </p><p>Haze et al. (1999) found that in response to ER stress induced by thapsigargin, the 90-kD type II transmembrane glycoprotein form of ATF6 was converted to a 50-kD soluble nuclear form that retained only the N terminus, including the leucine zipper. Immunofluorescence analysis demonstrated that the subcellular localization altered from the ER to the nucleus for the form lacking the C terminus. Haze et al. (1999) determined that the transmembrane domain is located near the center of the protein, C terminal to the leucine zipper, at amino acids 378 to 398. Expression of the N-terminal 373 residues enhanced the levels of HSPA5 mRNA. </p><p>When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Ye et al. (2000) showed that ATF6 is processed by site-1 protease (S1P; 603355) and site-2 protease (S2P; 300294), the enzymes that process sterol regulatory element-binding proteins (SREBPs; see 184756) in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce HSPA5, an ATF6 target, in response to ER stress. ATF6 processing did not require SREBP cleavage-activating protein (SCAP; 601510), which is essential for SREBP processing. Ye et al. (2000) concluded that S1P and S2P are required for the ER stress response as well as for lipid synthesis. </p><p>Li et al. (2000) found that in addition to its possible cleavage upon ER stress, optimal ATF6 stimulation requires at least 2 copies of the ERSEs and a functional NF-Y (see NFYA; 189903) complex with a high-affinity NF-Y-binding site that confers selectivity among different ERSEs. In thapsigargin-stressed cells, ATF6 interacted with YY1 (600013), which further enhanced and sustained the activity of ATF6. </p><p>Using immunoprecipitation, Shen et al. (2002) detected ATF6 binding to HSPA5, which dissociated in response to ER stress. Deletion of luminal HSPA5 binding sites or Golgi localization signals in ATF6 disrupted proper transport to the Golgi complex. The authors concluded that HSPA5 retains ATF6 in the ER by inhibiting its Golgi localization signals and that dissociation of HSPA5 during ER stress allows ATF6 to be transported to the Golgi. Sommer and Jarosch (2002) summarized the findings of Shen et al. (2002) and presented a discussion of the proteins involved in regulating levels of aberrant proteins within the ER. </p><p>The 3 UPR branches, governed by the ER stress sensors IRE1 (604033), PERK (604032), and ATF6, promote cell survival by reducing misfolded protein levels. UPR signaling also promotes apoptotic cell death if ER stress is not alleviated. Lin et al. (2007) found that IRE1 and ATF6 activities were attenuated by persistent ER stress in human cells. By contrast, PERK signaling, including translational inhibition and induction of the proapoptotic transcription regulator CHOP (126337), was maintained. When IRE1 activity was sustained artificially, cell survival was enhanced, suggesting a causal link between the duration of UPR branch signaling and life or death cell fate after ER stress. Key findings from their studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin (180380) in animal models of retinitis pigmentosa. </p><p>Using HeLa cells, Higa et al. (2014) found that PDIA5 (616942) played a crucial role in disulfide bond rearrangement and activation of ATF6 upon imatinib-induced ER stress. In leukemia cell lines, knockdown of ATF6 or PDIA5 via small interfering RNA, or pharmacologic inhibition of PDI, blocked ATF6 activation and release from the ER and restored cell sensitivity to imatinib. Silencing of PDIA5 did not significantly affect activation of other arms of the unfolded protein response. </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>Achromatopsia 7</em></strong></p><p>
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In affected individuals from a consanguineous Pakistani family with achromatopsia (ACHM7; 616517), Ansar et al. (2015) identified homozygosity for a 1-bp duplication in the ATF6 gene (605537.0001). The mutation, which segregated with disease in the family, was not found in ethnically matched controls or public databases. Functional studies showed mislocalization of the mutant protein compared to wildtype. </p><p>From a cohort of 304 patients with achromatopsia, Kohl et al. (2015) identified 18 patients from 10 independent families who were homozygous or compound heterozygous for mutations in the ATF6 gene (see, e.g., 605537.0002-605537.0006). Functional analysis demonstrated that the mutations attenuate ATF6 transcriptional activity in response to ER stress. Kohl et al. (2015) concluded that mutations in ATF6 are a rare cause of achromatopsia and, noting that all 18 mutation-positive patients exhibited marked foveal hypoplasia, suggested that severe foveal hypoplasia with a poorly formed or absent foveal pit could be a hallmark of ATF6-related disease. </p><p><strong><em>Type 2 Diabetes</em></strong></p><p>
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Thameem et al. (2006) reported a nominal association between variants of the ATF6 gene and type 2 diabetes (125853) in Pima Indians (p less than 0.05). </p><p>Meex et al. (2007) investigated 16 ATF6 polymorphisms for their contribution to disturbed glucose homeostasis and type 2 diabetes in Dutch Caucasians. They found that common ATF variants were associated with elevated glucose levels in the general population (p = 0.005-0.5), and that the majority of these variants, and haplotypes thereof, were significantly associated with impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes (p = 0.006-0.05). They noted that the associated variants differed from those identified by Thameem et al. (2006) in Pima Indians and that the variants identified by Thameem et al. (2006) were not significantly associated with fasting glucose levels, disturbed glucose homeostasis, or type 2 diabetes in their Dutch Caucasian cohorts. </p>
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</span>
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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>Kohl et al. (2015) observed no significant differences in retinal morphology and function in young Atf6-null mice compared to heterozygous or wildtype littermates. However, at 18 months of age, both rod and cone single-flash electroretinography (ERG) responses were markedly reduced in the Atf6-null mice compared to wildtype mice; fundi of the mutant mice also showed retinal degeneration in areas that correlated with hyperfluorescent spots on confocal scanning-laser ophthalmoscopy. Retinal vasculature appeared unaffected in the mouse model, as observed in human patients. Spectral-domain optical coherence tomography (SD-OCT) imaging showed disruption of the layers corresponding to the inner and outer segments; however, in contrast to human patients, the RPE was also affected in mice. Noting that mice do not develop foveas, Kohl et al. (2015) suggested that there are profound differences in the function and impact of ATF6 in mouse and human retinal development and maintenance. </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>6 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 ACHROMATOPSIA 7</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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ATF6, 1-BP DUP, 355G
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<br />
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SNP: rs869320751,
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ClinVar: RCV000190367
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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 4 affected individuals from a consanguineous Pakistani family with achromatopsia (ACHM7; 616517), Ansar et al. (2015) identified homozygosity for a 1-bp duplication (c.355_356dupG, NM_007348.3) in exon 5 of the ATF6 gene, causing a frameshift predicted to result in a premature termination codon (Glu119GlyfsTer8) prior to the basic region leucine zipper (BRLZ) and transmembrane domains, affecting all 3 ATF6 isoforms. The mutation, which segregated with disease in the family, was not found in 470 ethnically matched control chromosomes, in exome sequence data from 130 unrelated Pakistani individuals without eye disease, or in the dbSNP or ExAC databases. Functional analysis in transfected COS-7 cells demonstrated expression of wildtype ATF6 throughout the cytoplasm with localization to the ER, whereas the Glu119GlyfsTer8 mutant had significantly reduced localization in the cytoplasm and was mainly confined to the nucleus. Western blot analysis confirmed that mutant ATF6 had a reduced protein size. </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 ACHROMATOPSIA 7</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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ATF6, ARG324CYS
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<br />
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SNP: rs761357250,
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gnomAD: rs761357250,
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ClinVar: RCV000190368, RCV001390414, RCV003390920, RCV004668839
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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 3 sibs from a nonconsanguineous Irish family and 3 sibs from a nonconsanguineous United Kingdom family, all exhibiting achromatopsia (ACHM7; 616517), Kohl et al. (2015) identified homozygosity for a c.970C-T transition in the ATF6 gene (c.970C-T, NM_007348.3), resulting in an arg324-to-cys (R324C) substitution at a highly conserved residue in the basic region of the bZIP domain, necessary for dimerization. The mutation, which segregated with disease in both families, was not found in an in-house database or the dbSNP or Exome Variant Server databases. However, the c.970C-T allele was observed in heterozygosity in 3 of 120,904 genotypes found in the ExAC browser. Haplotype reconstruction of SNP chip data from the 2 families indicated that all carriers of the R324C mutation shared a 0.7-Mb common homozygous haplotype flanked by rs4072409 and rs16840028, suggestive of either a founder mutation in the Irish and UK population or identity by descent. Functional analysis in patient fibroblasts and in transfected HEK293 cells showed significantly reduced or absent mRNA induction of downstream transcriptional targets with the R324C mutant compared to wildtype ATF6. </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 ACHROMATOPSIA 7</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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ATF6, IVS12, G-C, +1
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<br />
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SNP: rs797045172,
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gnomAD: rs797045172,
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ClinVar: RCV000191038, RCV003556237
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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 individuals from 3 French Canadian families with achromatopsia (AHM7; 616517), Kohl et al. (2015) identified homozygosity for a splice site mutation (c.1533+1G-C, NM_007348.3) in intron 12 of the ATF6 gene, resulting in 2 aberrantly spliced proteins. Sequencing revealed that the larger mutant protein was due to retention of 83 bp of intron 12, causing a premature termination codon (Gly512LeufsTer39), whereas the smaller mutation was due to skipping of exon 12, which also resulted in premature termination (Leu479ValfsTer11). The mutation, which segregated with disease in the families, was not found in an in-house database or the dbSNP, Exome Variant Server, or ExAC databases. All patients carrying the splice site mutation had the same homozygous SNP genotype based on 2 rare SNPs, rs371893818 and rs374093774, suggestive of a founder mutation in the French Canadian population. One of the French Canadian patients, a 17-year-old boy, exhibited incomplete achromatopsia. </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">
|
|
<strong>.0004 ACHROMATOPSIA 7</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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ATF6, 1-BP DUP, 797C
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<br />
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|
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SNP: rs797045173,
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|
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ClinVar: RCV000191039
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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 a German brother and sister with achromatopsia (ACHM7; 616517), Kohl et al. (2015) identified compound heterozygosity for 2 different 1-bp duplications in the ATF6 gene: c.797dupC (c.797dupC, NM_007348.3), resulting in an asn267-to-ter (N267X) substitution, and c.1110dupA (605537.0005), causing a frameshift resulting in a premature termination codon (Val371SerfsTer3). The mutations, which segregated with disease in the family, were not found in an in-house database or the dbSNP, Exome Variant Server, or ExAC databases. </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">
|
|
<strong>.0005 ACHROMATOPSIA 7</strong>
|
|
</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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ATF6, 1-BP DUP, 1110A
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<br />
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|
|
SNP: rs797045174,
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|
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ClinVar: RCV000191040
|
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|
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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>For discussion of the c.1110dupA mutation in the ATF6 gene (c.1110dupA, NM_007348.3) that was found in compound heterozygous state in 2 German sibs with achromatopsia (ACHM7; 616517) by Kohl et al. (2015), see 605537.0004. </p>
|
|
</span>
|
|
</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>
|
|
<span class="mim-font">
|
|
<strong>.0006 ACHROMATOPSIA 7</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
ATF6, TYR567ASN
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<br />
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|
|
SNP: rs796065053,
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|
|
ClinVar: RCV000190372, RCV004668840
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 26-year-old Iranian woman with incomplete achromatopsia (ACHM7; 616517), Kohl et al. (2015) identified homozygosity for a c.1699T-A transversion in the ATF6 gene (c.1699T-A, NM_007348.3), resulting in a tyr567-to-asn (Y567N) substitution at a highly conserved residue within an 18-residue C-terminal sequence motif that is present in both ATF6A and ATF6B (600984). The mutation, which segregated with disease in the family, was not found in an in-house database or the dbSNP, Exome Variant Server, or ExAC databases. </p>
|
|
</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">
|
|
<strong>REFERENCES</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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<ol>
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<li>
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<p class="mim-text-font">
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Ansar, M., Santos-Cortez, R. L. P., Saqib, M. A. N., Zulfiqar, F., Lee, K., Ashraf, N. M., Ullah, E., Wang, X., Sajid, S., Khan, F. S., Amin-ud-Din, M., University of Washington Center for Mendelian Genomics, and 9 others.
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<strong>Mutation of ATF6 causes autosomal recessive achromatopsia.</strong>
|
|
Hum. Genet. 134: 941-950, 2015.
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[PubMed: 26063662]
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[Full Text: https://doi.org/10.1007/s00439-015-1571-4]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Hai, T. W., Liu, F., Coukos, W. J., Green, M. R.
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<strong>Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers.</strong>
|
|
Genes Dev. 3: 2083-2090, 1989. Note: Erratum: Genes Dev. 4: 682 only, 1990.
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[PubMed: 2516827]
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[Full Text: https://doi.org/10.1101/gad.3.12b.2083]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Haze, K., Yoshida, H., Yanagi, H., Yura, T., Mori, K.
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<strong>Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress.</strong>
|
|
Molec. Biol. Cell 10: 3787-3799, 1999.
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[PubMed: 10564271]
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[Full Text: https://doi.org/10.1091/mbc.10.11.3787]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Higa, A., Taouji, S., Lhomond, S., Jensen, D., Fernandez-Zapico, M. E., Simpson, J. C., Pasquet, J.-M., Schekman, R., Chevet, E.
|
|
<strong>Endoplasmic reticulum stress-activated transcription factor ATF6-alpha requires the disulfide isomerase PDIA5 to modulate chemoresistance.</strong>
|
|
Molec. Cell. Biol. 34: 1839-1849, 2014.
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[PubMed: 24636989]
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[Full Text: https://doi.org/10.1128/MCB.01484-13]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Kohl, S., Zobor, D., Chiang, W.-C., Weisschuh, N., Staller, J., Gonzalez Menendez, I., Chang, S., Beck, S. C., Garcia Garrido, M., Sothilingam, V., Seeliger, M. W., Stanzial, F., and 21 others.
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|
<strong>Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia.</strong>
|
|
Nature Genet. 47: 757-765, 2015.
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[PubMed: 26029869]
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[Full Text: https://doi.org/10.1038/ng.3319]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Li, M., Baumeister, P., Roy, B., Phan, T., Foti, D., Luo, S., Lee, A. S.
|
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<strong>ATF6 as a transcription activator of the endoplasmic reticulum stress element: thapsigargin stress-induced changes and synergistic interactions with NF-Y and YY1.</strong>
|
|
Molec. Cell. Biol. 20: 5096-5106, 2000.
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[PubMed: 10866666]
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[Full Text: https://doi.org/10.1128/MCB.20.14.5096-5106.2000]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Lin, J. H., Li, H., Yasumura, D., Cohen, H. R., Zhang, C., Panning, B., Shokat, K. M., LaVail, M. M., Walter, P.
|
|
<strong>IRE1 signaling affects cell fate during the unfolded protein response.</strong>
|
|
Science 318: 944-949, 2007.
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[PubMed: 17991856]
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[Full Text: https://doi.org/10.1126/science.1146361]
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Meex, S. J. R., van Greevenbroek, M. M. J., Ayoubi, T. A., Vlietinck, R., van Vliet-Ostaptchouk, J. V., Hofker, M. H., Vermeulen, V. M. M.-J., Schalkwijk, C. G., Feskens, E. J. M., Boer, J. M. A., Stehouwer, C. D. A., van der Kallen, C. J. H., de Bruin, T. W. A.
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<strong>Activating transcription factor 6 polymorphisms and haplotypes are associated with impaired glucose homeostasis and type 2 diabetes in Dutch Caucasians.</strong>
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Shen, J., Chen, X., Hendershot, L., Prywes, R.
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<strong>ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals.</strong>
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Sommer, T., Jarosch, E.
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<strong>BiP binding keeps ATF6 at bay.</strong>
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Dev. Cell 3: 1-2, 2002.
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Thameem, F., Farook, V. S., Bogardus, C., Prochazka, M.
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<strong>Association of amino acid variants in the activating transcription factor 6 gene (ATF6) on 1q21-q23 with type 2 diabetes in Pima Indians.</strong>
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Ye, J., Rawson, R. B., Komuro, R., Chen, X., Dave, U. P., Prywes, R., Brown, M. S., Goldstein, J. L.
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<strong>ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.</strong>
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Yoshida, H., Haze, K., Yanagi, H., Yura, T., Mori, K.
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<strong>Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins: involvement of basic leucine zipper transcription factors.</strong>
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