3332 lines
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Entry
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- *604032 - EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE 3; EIF2AK3
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- OMIM
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<p>
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<span class="h4">*604032</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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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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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/604032">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 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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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000172071;t=ENST00000303236" 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=9451" 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=604032" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000172071;t=ENST00000303236" 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_001313915,NM_004836,XM_047446428,XM_047446429,XM_047446430" 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_004836" 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=604032" 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=04942&isoform_id=04942_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/EIF2AK3" 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/4406380,7341091,9652337,51476489,62822228,62988944,116497041,116497199,119597474,119597475,134304838,189054855,193785920,296439367,927028872,1808808576,1808808578,2217332276,2217332278,2217332280,2462578700,2462578703,2462578705" 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/Q9NZJ5" 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=9451" 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=ENSG00000172071;t=ENST00000303236" 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=EIF2AK3" 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=EIF2AK3" 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+9451" 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/EIF2AK3" 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:9451" 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/9451" 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=chr2&hgg_gene=ENST00000303236.9&hgg_start=88556741&hgg_end=88628145&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:3255" 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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604032[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 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=604032[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/ENSG00000172071" 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=EIF2AK3" 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=EIF2AK3" 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=EIF2AK3" 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="http://www.euro-wabb.org/en/lovd-genetic-variation-database" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=EIF2AK3&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/PA27687" 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:3255" 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/FBgn0037327.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:1341830" 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/EIF2AK3#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:1341830" 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/9451/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=9451" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00003970;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00003970 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00012586;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00012586 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-050414-2" 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:9451" 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=EIF2AK3&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 254066006<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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604032
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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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EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE 3; EIF2AK3
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</span>
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</h3>
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</div>
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<div>
|
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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PANCREATIC EIF2-ALPHA KINASE; PEK<br />
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PERK
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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=EIF2AK3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EIF2AK3</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/2/456?start=-3&limit=10&highlight=456">2p11.2</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:88556741-88628145&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'})">2:88,556,741-88,628,145</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>
|
|
<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/2/456?start=-3&limit=10&highlight=456">
|
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2p11.2
|
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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">
|
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Wolcott-Rallison syndrome
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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/226980"> 226980 </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">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/604032" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/604032" 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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<p>In response to various environmental stresses, eukaryotic cells downregulate protein synthesis by phosphorylation of the alpha subunit of eukaryotic translation initiation factor-2 (eIF2-alpha; <a href="/entry/603907">603907</a>). Phosphorylation of eIF2-alpha results in inhibition of the guanine nucleotide exchange factor eIF-2B (see EIF2B5; <a href="/entry/603945">603945</a>), thereby reducing the rate of the GDP to GTP exchange that is required for eIF2 to carry out additional rounds of translation initiation. The eukaryotic eIF2-alpha kinases PKR (<a href="/entry/176871">176871</a>), HRI (EIF2AK1; <a href="/entry/613635">613635</a>) , and yeast GCN2 share extensive homology within their catalytic domains, but have distinct regulatory domains allowing for different physiologic signals to regulate phosphorylation of eIF2-alpha. <a href="#14" class="mim-tip-reference" title="Shi, Y., Vattem, K. M., Sood, R., An, J., Liang, J., Stramm, L., Wek, R. C. <strong>Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control.</strong> Molec. Cell. Biol. 18: 7499-7509, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9819435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9819435</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9819435[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.18.12.7499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9819435">Shi et al. (1998)</a> identified a rat eIF2-alpha kinase that they designated PEK (pancreatic eIF2-alpha kinase). The authors demonstrated that PEK regulated protein synthesis both in vitro and in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9819435" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By searching an EST database for sequences related to rat PEK, <a href="#13" class="mim-tip-reference" title="Shi, Y., An, J., Liang, J., Hayes, S. E., Sandusky, G. E., Stramm, L. E., Yang, N. N. <strong>Characterization of a mutant pancreatic eIF-2-alpha kinase, PEK, and co-localization with somatostatin in islet delta cells.</strong> J. Biol. Chem. 274: 5723-5730, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10026192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10026192</a>] [<a href="https://doi.org/10.1074/jbc.274.9.5723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10026192">Shi et al. (1999)</a> identified partial cDNAs encoding human PEK. Using a combination of techniques, they cloned additional cDNAs and genomic fragments corresponding to the entire human PEK coding region. The predicted 1,115-amino acid human protein is 88% identical to rat PEK. PEK contains an N-terminal signal peptide and a hydrophobic region. The kinase domain of human PEK is similar to that of the other eIF2-alpha kinases, but the 550-residue N-terminal region is unique, perhaps reflecting the different physiologic signals that regulate its activity. Like rat PEK, recombinant human PEK was autophosphorylated and specifically phosphorylated eIF2-alpha. Northern blot analysis revealed that the 5.2-kb PEK mRNA was expressed in all human tissues tested, with the highest expression in pancreas and placenta. However, using immunohistochemistry and immunofluorescence, <a href="#13" class="mim-tip-reference" title="Shi, Y., An, J., Liang, J., Hayes, S. E., Sandusky, G. E., Stramm, L. E., Yang, N. N. <strong>Characterization of a mutant pancreatic eIF-2-alpha kinase, PEK, and co-localization with somatostatin in islet delta cells.</strong> J. Biol. Chem. 274: 5723-5730, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10026192/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10026192</a>] [<a href="https://doi.org/10.1074/jbc.274.9.5723" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10026192">Shi et al. (1999)</a> detected PEK protein only in pancreatic delta cells. They concluded that PEK may play a role in regulating protein synthesis in the pancreatic islet, especially in delta cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10026192" 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>By fluorescence in situ hybridization and radiation hybrid analysis, <a href="#9" class="mim-tip-reference" title="Hayes, S. E., Conner, L. J., Stramm, L. E., Shi, Y. <strong>Assignment of pancreatic eIF-2a kinase (EIF2AK3) to human chromosome band 2p12 by radiation hybrid mapping and in situ hybridization.</strong> Cytogenet. Cell Genet. 86: 327-328, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10575235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10575235</a>] [<a href="https://doi.org/10.1159/000015328" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10575235">Hayes et al. (1999)</a> mapped the EIF2AK3 gene to chromosome 2p12. <a href="#6" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 2/17/2016."None>Gross (2016)</a> mapped the EIF2AK3 gene to chromosome 2p11.2 based on an alignment of the EIF2AK3 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=AF110146" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">AF110146</a>) with the genomic sequence (GRCh38). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10575235" 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>Malfolded proteins in the endoplasmic reticulum (ER) inhibit translation initiation. This response is likely mediated by increased phosphorylation of eIF2-alpha and is thought to reduce the workload imposed on the folding machinery during stress. <a href="#8" class="mim-tip-reference" title="Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H., Ron, D. <strong>Perk is essential for translational regulation and cell survival during the unfolded protein response.</strong> Molec. Cell 5: 897-904, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10882126/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10882126</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80330-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10882126">Harding et al. (2000)</a> reported that a targeted mutation of the mouse Eif2ak3 gene, which they called Perk, abolished the phosphorylation of eIF2-alpha in response to accumulation of malfolded proteins in the ER, resulting in abnormally elevated protein synthesis and higher levels of ER stress. Mutant cells were markedly impaired in their ability to survive ER stress, and inhibition of protein synthesis by cycloheximide treatment during ER stress ameliorated this impairment. The authors therefore concluded that PERK plays a major role in the ability of cells to adapt to ER stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10882126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Blais, J. D., Filipenko, V., Bi, M., Harding, H. P., Ron, D., Koumenis, C., Wouters, B. G., Bell, J. C. <strong>Activating transcription factor 4 is translationally regulated by hypoxic stress.</strong> Molec. Cell. Biol. 24: 7469-7482, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15314157/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15314157</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15314157[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.24.17.7469-7482.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15314157">Blais et al. (2004)</a> determined that EIF2-alpha, PERK, ATF4 (<a href="/entry/604064">604064</a>), and GADD34 (PPP1R15A; <a href="/entry/611048">611048</a>) are involved in an integrated adaptive response to hypoxic stress in HeLa cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15314157" 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 library of endoribonuclease-prepared short interfering RNAs (esiRNAs), <a href="#10" class="mim-tip-reference" title="Kittler, R., Putz, G., Pelletier, L., Poser, I., Heninger, A.-K., Drechsel, D., Fischer, S., Konstantinova, I., Habermann, B., Grabner, H., Yaspo, M.-L., Himmelbauer, H., Korn, B., Neugebauer, K., Pisabarro, M. T., Buchholz, F. <strong>An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division.</strong> Nature 432: 1036-1040, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15616564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15616564</a>] [<a href="https://doi.org/10.1038/nature03159" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15616564">Kittler et al. (2004)</a> identified 37 genes required for cell division, one of which was EIF2AK3. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15616564" 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 unfolded protein response (UPR) branches, governed by the ER stress sensors IRE1 (<a href="/entry/604033">604033</a>), PERK, and ATF6 (<a href="/entry/605537">605537</a>), promote cell survival by reducing misfolded protein levels. UPR signaling also promotes apoptotic cell death if ER stress is not alleviated. <a href="#11" 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 inhibitions 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>
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<p>On the basis of 2 consanguineous families with Wolcott-Rallison syndrome (<a href="/entry/226980">226980</a>), <a href="#4" class="mim-tip-reference" title="Delepine, M., Nicolino, M., Barrett, T., Golamaully, M., Lathrop, G. M., Julier, C. <strong>EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome.</strong> Nature Genet. 25: 406-409, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932183</a>] [<a href="https://doi.org/10.1038/78085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932183">Delepine et al. (2000)</a> mapped the syndrome to a region of less than 3 cM on chromosome 2p12. Because the EIF2AK3 gene resides in this interval and is highly expressed in pancreatic islet cells, they explored it as a candidate and identified distinct homozygous mutations (<a href="#0001">604032.0001</a> and <a href="#0002">604032.0002</a>) segregating with the disorder in each of the 2 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated patients with Wolcott-Rallison syndrome, <a href="#3" class="mim-tip-reference" title="Brickwood, S., Bonthron, D. T., Al-Gazali, L. I., Piper, K., Hearn, T., Wilson, D. I., Hanley, N. A. <strong>Wolcott-Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3.</strong> J. Med. Genet. 40: 685-689, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960215</a>] [<a href="https://doi.org/10.1136/jmg.40.9.685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12960215">Brickwood et al. (2003)</a> identified 2 mutations in the EIF2AK3 gene (<a href="#0003">604032.0003</a>-<a href="#0004">604032.0004</a>). Additional phenotypic features included a predilection to severe unexplained hypoglycemic episodes suggestive of hepatic impairment, and to renal failure. It was noted that these features are not seen in Eif2ak3 knockout mice. Immunohistochemical analysis of human adult and fetal tissues showed that EIF2AK3 is widely expressed in the epithelial cells of the early fetal pancreas, and is present in adult beta cells and exocrine tissue. It is also expressed in developing bone, kidney, and adult liver, consistent with the extended phenotype of Wolcott-Rallison syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12960215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 unrelated children with Wolcott-Rallison syndrome, <a href="#5" class="mim-tip-reference" title="Durocher, F., Faure, R., Labrie, Y., Pelletier, L., Bouchard, I., Laframboise, R. <strong>A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome.</strong> Clin. Genet. 70: 34-38, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16813601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16813601</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00632.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16813601">Durocher et al. (2006)</a> identified homozygosity for a nonsense mutation in the EIF2AK3 gene (<a href="#0005">604032.0005</a>). The children exhibited disparate phenotypes; the authors suggested that there may be alternative pathways that can take over or supplement a defective metabolic pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16813601" 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>PERK couples protein folding in the ER to polypeptide biosynthesis by phosphorylating eIF2-alpha, attenuating translation initiation in response to ER stress. Perk is highly expressed in mouse pancreas, an organ active in protein secretion. <a href="#7" class="mim-tip-reference" title="Harding, H. P., Zeng, H., Zhang, Y., Jungries, R., Chung, P., Plesken, H., Sabatini, D. D., Ron, D. <strong>Diabetes mellitus and exocrine pancreatic dysfunction in Perk -/- mice reveals a role for translational control in secretory cell survival.</strong> Molec. Cell 7: 1153-1163, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11430819/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11430819</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00264-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11430819">Harding et al. (2001)</a> presented a phenotypic characterization of Perk -/- mice. They found that under physiologic conditions, Perk was partially activated, accounting for much of the phosphorylated eIF2-alpha in the pancreas. The exocrine and endocrine pancreas developed normally in Perk -/- mice. Postnatally, ER distention and activation of the ER stress transducer IRE1-alpha (<a href="/entry/604033">604033</a>) accompanied increased cell death and led to progressive diabetes mellitus and exocrine pancreatic insufficiency. These findings suggested a special role for translational control in protecting secretory cells from ER stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11430819" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Zhang, P., McGrath, B., Li, S., Frank, A., Zambito, F., Reinert, J., Gannon, M., Ma, K., McNaughton, K., Cavener, D. R. <strong>The PERK eukaryotic initiation factor 2-alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas.</strong> Molec. Cell. Biol. 22: 3864-3874, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997520</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11997520[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.22.11.3864-3874.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11997520">Zhang et al. (2002)</a> found that pancreata of Perk -/- mice were morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerated, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells. The exocrine pancreas showed reduced synthesis of several major digestive enzymes and succumbed to massive apoptosis after the fourth postnatal week. Perk -/- mice also exhibited skeletal dysplasia at birth and postnatal growth retardation. Skeletal defects included deficient mineralization, osteoporosis, and abnormal compact bone development. The skeletal and pancreatic defects were associated with defects in the rough ER of the major secretory cells of the skeletal system and pancreas. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11997520" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=604032[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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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869025178 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025178;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=rs869025178" 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=rs869025178" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 affected Tunisian sibs with Wolcott-Rallison syndrome, <a href="#4" class="mim-tip-reference" title="Delepine, M., Nicolino, M., Barrett, T., Golamaully, M., Lathrop, G. M., Julier, C. <strong>EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome.</strong> Nature Genet. 25: 406-409, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932183</a>] [<a href="https://doi.org/10.1038/78085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932183">Delepine et al. (2000)</a> identified homozygosity for an insertion (T) at nucleotide position 1103 (1103insT) in the EIF2AK3 gene, creating a frameshift at amino acid position 345 and a premature termination at lys345. The mutation was not found in their unaffected parents, who were related as first cousins, or in their unaffected sib. The family had previously been reported by <a href="#12" class="mim-tip-reference" title="Nicolino, P. M., Dupin, H., Macebeo, V., Treppoz, S., Chatelain, P. G. <strong>Wolcott-Rallison syndrome (diabetes mellitus and spondyloepiphyseal dysplasia) : a plausible existence of a gene(s) important for the mutation of neonatal pancreatic beta cell function. (Abstract)</strong> Hormone Res. 50 (suppl. 3): 77 only, 1998."None>Nicolino et al. (1998)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932183" 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">rs121908569 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908569;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=rs121908569" 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=rs121908569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 children, born to consanguineous Pakistani parents, with Wolcott-Rallison syndrome (<a href="/entry/226980">226980</a>), <a href="#4" class="mim-tip-reference" title="Delepine, M., Nicolino, M., Barrett, T., Golamaully, M., Lathrop, G. M., Julier, C. <strong>EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome.</strong> Nature Genet. 25: 406-409, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932183</a>] [<a href="https://doi.org/10.1038/78085" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10932183">Delepine et al. (2000)</a> found homozygosity for a 1832G-A transition in the EIF2AK3 gene, resulting in a change of glutamine for arginine at position 587 (R587Q) within the catalytic domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932183" 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">rs869025179 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025179;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=rs869025179" 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=rs869025179" 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=RCV000006234 OR RCV005089188" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006234, RCV005089188" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006234...</a>
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<p><a href="#1" class="mim-tip-reference" title="Al-Gazali, L. I., Makia, S., Azzam, A., Hall, C. M. <strong>Wolcott-Rallison syndrome.</strong> Clin. Dysmorph. 4: 227-233, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7551159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7551159</a>]" pmid="7551159">Al-Gazali et al. (1995)</a> reported the clinical findings in a patient with Wolcott-Rallison syndrome (<a href="/entry/226980">226980</a>), including spondyloepiphyseal dysplasia and generalized osteoporosis, up to the age of 4.5 years. <a href="#3" class="mim-tip-reference" title="Brickwood, S., Bonthron, D. T., Al-Gazali, L. I., Piper, K., Hearn, T., Wilson, D. I., Hanley, N. A. <strong>Wolcott-Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3.</strong> J. Med. Genet. 40: 685-689, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960215</a>] [<a href="https://doi.org/10.1136/jmg.40.9.685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12960215">Brickwood et al. (2003)</a> identified a homozygous splice site mutation in the EIF2AK3 gene, IVS14+1G-A, in this patient. The mutation was predicted to result in a truncated protein that lacked the critical kinase domain. An offspring of consanguineous Saudi parents, the child was diagnosed at 2 months of age with diabetes requiring insulin therapy. The clinical course was marked by severe intellectual impairment and frequent unpredictable hypoglycemic episodes. A brother was also affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7551159+12960215" 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">rs1558652941 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1558652941;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=rs1558652941" 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=rs1558652941" 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=RCV000006235 OR RCV005000981" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006235, RCV005000981" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006235...</a>
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<p>In a patient with Wolcott-Rallison syndrome (<a href="/entry/226980">226980</a>), the offspring of consanguineous Saudi parents, <a href="#3" class="mim-tip-reference" title="Brickwood, S., Bonthron, D. T., Al-Gazali, L. I., Piper, K., Hearn, T., Wilson, D. I., Hanley, N. A. <strong>Wolcott-Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3.</strong> J. Med. Genet. 40: 685-689, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12960215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12960215</a>] [<a href="https://doi.org/10.1136/jmg.40.9.685" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12960215">Brickwood et al. (2003)</a> identified homozygosity for a 4-bp deletion (1563delGAAA) in the EIF2AK3 gene. The mutation caused a frameshift in exon 9 and a premature stop codon at amino acid 523. Both parents were heterozygous for the mutation. Management of this patient was complicated by recurrent hypoglycemia until death at age 2 years from severe diabetic ketoacidosis and infection. Skeletal features were consistent with spondyloepiphyseal dysplasia and included bilateral femoral fractures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12960215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 WOLCOTT-RALLISON SYNDROME</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> rs121908570 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908570;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/rs121908570?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=rs121908570" 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=rs121908570" 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=RCV000006236" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006236" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006236</a>
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<p>In 2 apparently unrelated children with Wolcott-Rallison syndrome (<a href="/entry/226980">226980</a>), born into 2 families from the same region of Quebec and sharing the same French surname, <a href="#5" class="mim-tip-reference" title="Durocher, F., Faure, R., Labrie, Y., Pelletier, L., Bouchard, I., Laframboise, R. <strong>A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome.</strong> Clin. Genet. 70: 34-38, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16813601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16813601</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2006.00632.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16813601">Durocher et al. (2006)</a> identified homozygosity for a 994G-T transversion in exon 5 of the EIF2AK3 gene, resulting in a glu331-to-ter (E331X) substitution predicted to lead to a truncated protein of 330 amino acids, missing the cytosol-oriented kinase domain. The 2 children had disparate phenotypes: although both developed diabetes in infancy and had bone demineralization by x-ray, 1 died at age 4 of multiorgan failure after repeated episodes of hepatitis, whereas the other exhibited no hepatic or renal problems at 8 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16813601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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[<a href="https://doi.org/10.1128/MCB.24.17.7469-7482.2004" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1136/jmg.40.9.685" target="_blank">Full Text</a>]
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Delepine, M., Nicolino, M., Barrett, T., Golamaully, M., Lathrop, G. M., Julier, C.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10932183/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10932183</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10932183" 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/10.1038/78085" target="_blank">Full Text</a>]
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Durocher, F., Faure, R., Labrie, Y., Pelletier, L., Bouchard, I., Laframboise, R.
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<strong>A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome.</strong>
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Clin. Genet. 70: 34-38, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16813601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16813601</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16813601" 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/10.1111/j.1399-0004.2006.00632.x" target="_blank">Full Text</a>]
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Gross, M. B.
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Baltimore, Md. 2/17/2016.
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Harding, H. P., Zeng, H., Zhang, Y., Jungries, R., Chung, P., Plesken, H., Sabatini, D. D., Ron, D.
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[<a href="https://doi.org/10.1016/s1097-2765(01)00264-7" target="_blank">Full Text</a>]
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Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H., Ron, D.
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[<a href="https://doi.org/10.1016/s1097-2765(00)80330-5" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1146361" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1074/jbc.274.9.5723" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9819435/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9819435</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9819435[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=9819435" 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.18.12.7499" target="_blank">Full Text</a>]
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<a id="15" class="mim-anchor"></a>
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<a id="Zhang2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, P., McGrath, B., Li, S., Frank, A., Zambito, F., Reinert, J., Gannon, M., Ma, K., McNaughton, K., Cavener, D. R.
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<strong>The PERK eukaryotic initiation factor 2-alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas.</strong>
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Molec. Cell. Biol. 22: 3864-3874, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11997520/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11997520</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11997520[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=11997520" 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.22.11.3864-3874.2002" target="_blank">Full Text</a>]
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</ol>
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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>
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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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Matthew B. Gross - updated : 02/17/2016
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</span>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Patricia A. Hartz - updated : 1/17/2008<br>Ada Hamosh - updated : 11/26/2007<br>Marla J. F. O'Neill - updated : 9/8/2006<br>Patricia A. Hartz - updated : 8/5/2005<br>Ada Hamosh - updated : 3/8/2005<br>Patricia A. Hartz - updated : 9/23/2004<br>Victor A. McKusick - updated : 12/29/2003<br>Stylianos E. Antonarakis - updated : 7/3/2001<br>Victor A. McKusick - updated : 7/31/2000<br>Stylianos E. Antonarakis - updated : 6/21/2000<br>Carol A. Bocchini - updated : 12/15/1999
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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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</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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Rebekah S. Rasooly : 7/20/1999
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</span>
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</div>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </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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carol : 10/05/2017
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<span class="mim-text-font">
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mgross : 02/17/2016<br>carol : 2/16/2016<br>carol : 9/17/2012<br>mgross : 11/9/2010<br>mgross : 10/18/2010<br>mgross : 2/5/2008<br>terry : 1/17/2008<br>terry : 1/17/2008<br>alopez : 11/28/2007<br>terry : 11/26/2007<br>mgross : 5/21/2007<br>wwang : 9/12/2006<br>terry : 9/8/2006<br>mgross : 8/9/2005<br>terry : 8/5/2005<br>alopez : 3/8/2005<br>mgross : 9/23/2004<br>tkritzer : 1/2/2004<br>terry : 12/29/2003<br>cwells : 11/10/2003<br>mgross : 7/3/2001<br>mgross : 7/3/2001<br>mcapotos : 3/12/2001<br>alopez : 7/31/2000<br>terry : 7/31/2000<br>mgross : 6/21/2000<br>carol : 12/15/1999<br>carol : 12/15/1999<br>alopez : 7/20/1999
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</span>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 604032
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<div>
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<h3>
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<span class="mim-font">
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EUKARYOTIC TRANSLATION INITIATION FACTOR 2-ALPHA KINASE 3; EIF2AK3
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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PANCREATIC EIF2-ALPHA KINASE; PEK<br />
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PERK
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</span>
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</h4>
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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: EIF2AK3</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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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 254066006;
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</span>
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</p>
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<strong>
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<em>
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Cytogenetic location: 2p11.2
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:88,556,741-88,628,145 </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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<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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<th>
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Location
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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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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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2p11.2
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<td>
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<span class="mim-font">
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Wolcott-Rallison syndrome
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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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226980
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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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</tr>
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</tbody>
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</table>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>In response to various environmental stresses, eukaryotic cells downregulate protein synthesis by phosphorylation of the alpha subunit of eukaryotic translation initiation factor-2 (eIF2-alpha; 603907). Phosphorylation of eIF2-alpha results in inhibition of the guanine nucleotide exchange factor eIF-2B (see EIF2B5; 603945), thereby reducing the rate of the GDP to GTP exchange that is required for eIF2 to carry out additional rounds of translation initiation. The eukaryotic eIF2-alpha kinases PKR (176871), HRI (EIF2AK1; 613635) , and yeast GCN2 share extensive homology within their catalytic domains, but have distinct regulatory domains allowing for different physiologic signals to regulate phosphorylation of eIF2-alpha. Shi et al. (1998) identified a rat eIF2-alpha kinase that they designated PEK (pancreatic eIF2-alpha kinase). The authors demonstrated that PEK regulated protein synthesis both in vitro and in vivo. </p><p>By searching an EST database for sequences related to rat PEK, Shi et al. (1999) identified partial cDNAs encoding human PEK. Using a combination of techniques, they cloned additional cDNAs and genomic fragments corresponding to the entire human PEK coding region. The predicted 1,115-amino acid human protein is 88% identical to rat PEK. PEK contains an N-terminal signal peptide and a hydrophobic region. The kinase domain of human PEK is similar to that of the other eIF2-alpha kinases, but the 550-residue N-terminal region is unique, perhaps reflecting the different physiologic signals that regulate its activity. Like rat PEK, recombinant human PEK was autophosphorylated and specifically phosphorylated eIF2-alpha. Northern blot analysis revealed that the 5.2-kb PEK mRNA was expressed in all human tissues tested, with the highest expression in pancreas and placenta. However, using immunohistochemistry and immunofluorescence, Shi et al. (1999) detected PEK protein only in pancreatic delta cells. They concluded that PEK may play a role in regulating protein synthesis in the pancreatic islet, especially in delta cells. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>By fluorescence in situ hybridization and radiation hybrid analysis, Hayes et al. (1999) mapped the EIF2AK3 gene to chromosome 2p12. Gross (2016) mapped the EIF2AK3 gene to chromosome 2p11.2 based on an alignment of the EIF2AK3 sequence (GenBank AF110146) with the genomic sequence (GRCh38). </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>Malfolded proteins in the endoplasmic reticulum (ER) inhibit translation initiation. This response is likely mediated by increased phosphorylation of eIF2-alpha and is thought to reduce the workload imposed on the folding machinery during stress. Harding et al. (2000) reported that a targeted mutation of the mouse Eif2ak3 gene, which they called Perk, abolished the phosphorylation of eIF2-alpha in response to accumulation of malfolded proteins in the ER, resulting in abnormally elevated protein synthesis and higher levels of ER stress. Mutant cells were markedly impaired in their ability to survive ER stress, and inhibition of protein synthesis by cycloheximide treatment during ER stress ameliorated this impairment. The authors therefore concluded that PERK plays a major role in the ability of cells to adapt to ER stress. </p><p>Blais et al. (2004) determined that EIF2-alpha, PERK, ATF4 (604064), and GADD34 (PPP1R15A; 611048) are involved in an integrated adaptive response to hypoxic stress in HeLa cells. </p><p>Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was EIF2AK3. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. </p><p>The 3 unfolded protein response (UPR) branches, governed by the ER stress sensors IRE1 (604033), PERK, and ATF6 (605537), 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 inhibitions 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>
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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>On the basis of 2 consanguineous families with Wolcott-Rallison syndrome (226980), Delepine et al. (2000) mapped the syndrome to a region of less than 3 cM on chromosome 2p12. Because the EIF2AK3 gene resides in this interval and is highly expressed in pancreatic islet cells, they explored it as a candidate and identified distinct homozygous mutations (604032.0001 and 604032.0002) segregating with the disorder in each of the 2 families. </p><p>In 2 unrelated patients with Wolcott-Rallison syndrome, Brickwood et al. (2003) identified 2 mutations in the EIF2AK3 gene (604032.0003-604032.0004). Additional phenotypic features included a predilection to severe unexplained hypoglycemic episodes suggestive of hepatic impairment, and to renal failure. It was noted that these features are not seen in Eif2ak3 knockout mice. Immunohistochemical analysis of human adult and fetal tissues showed that EIF2AK3 is widely expressed in the epithelial cells of the early fetal pancreas, and is present in adult beta cells and exocrine tissue. It is also expressed in developing bone, kidney, and adult liver, consistent with the extended phenotype of Wolcott-Rallison syndrome. </p><p>In 2 unrelated children with Wolcott-Rallison syndrome, Durocher et al. (2006) identified homozygosity for a nonsense mutation in the EIF2AK3 gene (604032.0005). The children exhibited disparate phenotypes; the authors suggested that there may be alternative pathways that can take over or supplement a defective metabolic pathway. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>PERK couples protein folding in the ER to polypeptide biosynthesis by phosphorylating eIF2-alpha, attenuating translation initiation in response to ER stress. Perk is highly expressed in mouse pancreas, an organ active in protein secretion. Harding et al. (2001) presented a phenotypic characterization of Perk -/- mice. They found that under physiologic conditions, Perk was partially activated, accounting for much of the phosphorylated eIF2-alpha in the pancreas. The exocrine and endocrine pancreas developed normally in Perk -/- mice. Postnatally, ER distention and activation of the ER stress transducer IRE1-alpha (604033) accompanied increased cell death and led to progressive diabetes mellitus and exocrine pancreatic insufficiency. These findings suggested a special role for translational control in protecting secretory cells from ER stress. </p><p>Zhang et al. (2002) found that pancreata of Perk -/- mice were morphologically and functionally normal at birth, but the islets of Langerhans progressively degenerated, resulting in loss of insulin-secreting beta cells and development of diabetes mellitus, followed later by loss of glucagon-secreting alpha cells. The exocrine pancreas showed reduced synthesis of several major digestive enzymes and succumbed to massive apoptosis after the fourth postnatal week. Perk -/- mice also exhibited skeletal dysplasia at birth and postnatal growth retardation. Skeletal defects included deficient mineralization, osteoporosis, and abnormal compact bone development. The skeletal and pancreatic defects were associated with defects in the rough ER of the major secretory cells of the skeletal system and pancreas. </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>5 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 WOLCOTT-RALLISON SYNDROME</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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EIF2AK3, 1-BP INS, 1103T
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<br />
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SNP: rs869025178,
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ClinVar: RCV000006232
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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 affected Tunisian sibs with Wolcott-Rallison syndrome, Delepine et al. (2000) identified homozygosity for an insertion (T) at nucleotide position 1103 (1103insT) in the EIF2AK3 gene, creating a frameshift at amino acid position 345 and a premature termination at lys345. The mutation was not found in their unaffected parents, who were related as first cousins, or in their unaffected sib. The family had previously been reported by Nicolino et al. (1998). </p>
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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>
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<h4>
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<span class="mim-font">
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<strong>.0002 WOLCOTT-RALLISON SYNDROME</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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EIF2AK3, ARG587GLN
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<br />
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SNP: rs121908569,
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ClinVar: RCV000006233, RCV005089187
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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 2 children, born to consanguineous Pakistani parents, with Wolcott-Rallison syndrome (226980), Delepine et al. (2000) found homozygosity for a 1832G-A transition in the EIF2AK3 gene, resulting in a change of glutamine for arginine at position 587 (R587Q) within the catalytic domain. </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 WOLCOTT-RALLISON SYNDROME</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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EIF2AK3, IVS14DS, G-A, +1
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<br />
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SNP: rs869025179,
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ClinVar: RCV000006234, RCV005089188
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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>Al-Gazali et al. (1995) reported the clinical findings in a patient with Wolcott-Rallison syndrome (226980), including spondyloepiphyseal dysplasia and generalized osteoporosis, up to the age of 4.5 years. Brickwood et al. (2003) identified a homozygous splice site mutation in the EIF2AK3 gene, IVS14+1G-A, in this patient. The mutation was predicted to result in a truncated protein that lacked the critical kinase domain. An offspring of consanguineous Saudi parents, the child was diagnosed at 2 months of age with diabetes requiring insulin therapy. The clinical course was marked by severe intellectual impairment and frequent unpredictable hypoglycemic episodes. A brother was also affected. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 WOLCOTT-RALLISON SYNDROME</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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EIF2AK3, 4-BP DEL, 1563GAAA
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<br />
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SNP: rs1558652941,
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ClinVar: RCV000006235, RCV005000981
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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 a patient with Wolcott-Rallison syndrome (226980), the offspring of consanguineous Saudi parents, Brickwood et al. (2003) identified homozygosity for a 4-bp deletion (1563delGAAA) in the EIF2AK3 gene. The mutation caused a frameshift in exon 9 and a premature stop codon at amino acid 523. Both parents were heterozygous for the mutation. Management of this patient was complicated by recurrent hypoglycemia until death at age 2 years from severe diabetic ketoacidosis and infection. Skeletal features were consistent with spondyloepiphyseal dysplasia and included bilateral femoral fractures. </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>.0005 WOLCOTT-RALLISON SYNDROME</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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EIF2AK3, GLU331TER
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<br />
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SNP: rs121908570,
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gnomAD: rs121908570,
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ClinVar: RCV000006236
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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 2 apparently unrelated children with Wolcott-Rallison syndrome (226980), born into 2 families from the same region of Quebec and sharing the same French surname, Durocher et al. (2006) identified homozygosity for a 994G-T transversion in exon 5 of the EIF2AK3 gene, resulting in a glu331-to-ter (E331X) substitution predicted to lead to a truncated protein of 330 amino acids, missing the cytosol-oriented kinase domain. The 2 children had disparate phenotypes: although both developed diabetes in infancy and had bone demineralization by x-ray, 1 died at age 4 of multiorgan failure after repeated episodes of hepatitis, whereas the other exhibited no hepatic or renal problems at 8 years of age. </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>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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Al-Gazali, L. I., Makia, S., Azzam, A., Hall, C. M.
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<strong>Wolcott-Rallison syndrome.</strong>
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Clin. Dysmorph. 4: 227-233, 1995.
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[PubMed: 7551159]
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</li>
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<li>
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<p class="mim-text-font">
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Blais, J. D., Filipenko, V., Bi, M., Harding, H. P., Ron, D., Koumenis, C., Wouters, B. G., Bell, J. C.
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<strong>Activating transcription factor 4 is translationally regulated by hypoxic stress.</strong>
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|
Molec. Cell. Biol. 24: 7469-7482, 2004.
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[PubMed: 15314157]
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[Full Text: https://doi.org/10.1128/MCB.24.17.7469-7482.2004]
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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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Brickwood, S., Bonthron, D. T., Al-Gazali, L. I., Piper, K., Hearn, T., Wilson, D. I., Hanley, N. A.
|
|
<strong>Wolcott-Rallison syndrome: pathogenic insights into neonatal diabetes from new mutation and expression studies of EIF2AK3.</strong>
|
|
J. Med. Genet. 40: 685-689, 2003.
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[PubMed: 12960215]
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[Full Text: https://doi.org/10.1136/jmg.40.9.685]
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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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Delepine, M., Nicolino, M., Barrett, T., Golamaully, M., Lathrop, G. M., Julier, C.
|
|
<strong>EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome.</strong>
|
|
Nature Genet. 25: 406-409, 2000.
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[PubMed: 10932183]
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[Full Text: https://doi.org/10.1038/78085]
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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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Durocher, F., Faure, R., Labrie, Y., Pelletier, L., Bouchard, I., Laframboise, R.
|
|
<strong>A novel mutation in the EIF2AK3 gene with variable expressivity in two patients with Wolcott-Rallison syndrome.</strong>
|
|
Clin. Genet. 70: 34-38, 2006.
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[PubMed: 16813601]
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[Full Text: https://doi.org/10.1111/j.1399-0004.2006.00632.x]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Gross, M. B.
|
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<strong>Personal Communication.</strong>
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|
Baltimore, Md. 2/17/2016.
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Harding, H. P., Zeng, H., Zhang, Y., Jungries, R., Chung, P., Plesken, H., Sabatini, D. D., Ron, D.
|
|
<strong>Diabetes mellitus and exocrine pancreatic dysfunction in Perk -/- mice reveals a role for translational control in secretory cell survival.</strong>
|
|
Molec. Cell 7: 1153-1163, 2001.
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[PubMed: 11430819]
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[Full Text: https://doi.org/10.1016/s1097-2765(01)00264-7]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Harding, H. P., Zhang, Y., Bertolotti, A., Zeng, H., Ron, D.
|
|
<strong>Perk is essential for translational regulation and cell survival during the unfolded protein response.</strong>
|
|
Molec. Cell 5: 897-904, 2000.
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|
|
[PubMed: 10882126]
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[Full Text: https://doi.org/10.1016/s1097-2765(00)80330-5]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Hayes, S. E., Conner, L. J., Stramm, L. E., Shi, Y.
|
|
<strong>Assignment of pancreatic eIF-2a kinase (EIF2AK3) to human chromosome band 2p12 by radiation hybrid mapping and in situ hybridization.</strong>
|
|
Cytogenet. Cell Genet. 86: 327-328, 1999.
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[PubMed: 10575235]
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[Full Text: https://doi.org/10.1159/000015328]
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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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Kittler, R., Putz, G., Pelletier, L., Poser, I., Heninger, A.-K., Drechsel, D., Fischer, S., Konstantinova, I., Habermann, B., Grabner, H., Yaspo, M.-L., Himmelbauer, H., Korn, B., Neugebauer, K., Pisabarro, M. T., Buchholz, F.
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<strong>An endoribonuclease-prepared siRNA screen in human cells identifies genes essential for cell division.</strong>
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Nature 432: 1036-1040, 2004.
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[PubMed: 15616564]
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[Full Text: https://doi.org/10.1038/nature03159]
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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.
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<strong>IRE1 signaling affects cell fate during the unfolded protein response.</strong>
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|
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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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Nicolino, P. M., Dupin, H., Macebeo, V., Treppoz, S., Chatelain, P. G.
|
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<strong>Wolcott-Rallison syndrome (diabetes mellitus and spondyloepiphyseal dysplasia) : a plausible existence of a gene(s) important for the mutation of neonatal pancreatic beta cell function. (Abstract)</strong>
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|
Hormone Res. 50 (suppl. 3): 77 only, 1998.
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</p>
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<li>
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<p class="mim-text-font">
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Shi, Y., An, J., Liang, J., Hayes, S. E., Sandusky, G. E., Stramm, L. E., Yang, N. N.
|
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<strong>Characterization of a mutant pancreatic eIF-2-alpha kinase, PEK, and co-localization with somatostatin in islet delta cells.</strong>
|
|
J. Biol. Chem. 274: 5723-5730, 1999.
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[PubMed: 10026192]
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[Full Text: https://doi.org/10.1074/jbc.274.9.5723]
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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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Shi, Y., Vattem, K. M., Sood, R., An, J., Liang, J., Stramm, L., Wek, R. C.
|
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<strong>Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control.</strong>
|
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Molec. Cell. Biol. 18: 7499-7509, 1998.
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[PubMed: 9819435]
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[Full Text: https://doi.org/10.1128/MCB.18.12.7499]
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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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Zhang, P., McGrath, B., Li, S., Frank, A., Zambito, F., Reinert, J., Gannon, M., Ma, K., McNaughton, K., Cavener, D. R.
|
|
<strong>The PERK eukaryotic initiation factor 2-alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas.</strong>
|
|
Molec. Cell. Biol. 22: 3864-3874, 2002.
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[PubMed: 11997520]
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[Full Text: https://doi.org/10.1128/MCB.22.11.3864-3874.2002]
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</p>
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</li>
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</ol>
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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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<div class="row">
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<div class="col-lg-1 col-md-1 col-sm-2 col-xs-2">
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<span class="text-nowrap mim-text-font">
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Contributors:
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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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Matthew B. Gross - updated : 02/17/2016<br>Patricia A. Hartz - updated : 1/17/2008<br>Ada Hamosh - updated : 11/26/2007<br>Marla J. F. O'Neill - updated : 9/8/2006<br>Patricia A. Hartz - updated : 8/5/2005<br>Ada Hamosh - updated : 3/8/2005<br>Patricia A. Hartz - updated : 9/23/2004<br>Victor A. McKusick - updated : 12/29/2003<br>Stylianos E. Antonarakis - updated : 7/3/2001<br>Victor A. McKusick - updated : 7/31/2000<br>Stylianos E. Antonarakis - updated : 6/21/2000<br>Carol A. Bocchini - updated : 12/15/1999
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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>
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<br />
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</div>
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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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Rebekah S. Rasooly : 7/20/1999
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<span class="text-nowrap mim-text-font">
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Edit History:
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<span class="mim-text-font">
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carol : 10/05/2017<br>mgross : 02/17/2016<br>carol : 2/16/2016<br>carol : 9/17/2012<br>mgross : 11/9/2010<br>mgross : 10/18/2010<br>mgross : 2/5/2008<br>terry : 1/17/2008<br>terry : 1/17/2008<br>alopez : 11/28/2007<br>terry : 11/26/2007<br>mgross : 5/21/2007<br>wwang : 9/12/2006<br>terry : 9/8/2006<br>mgross : 8/9/2005<br>terry : 8/5/2005<br>alopez : 3/8/2005<br>mgross : 9/23/2004<br>tkritzer : 1/2/2004<br>terry : 12/29/2003<br>cwells : 11/10/2003<br>mgross : 7/3/2001<br>mgross : 7/3/2001<br>mcapotos : 3/12/2001<br>alopez : 7/31/2000<br>terry : 7/31/2000<br>mgross : 6/21/2000<br>carol : 12/15/1999<br>carol : 12/15/1999<br>alopez : 7/20/1999
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OMIM<sup>®</sup> and Online Mendelian Inheritance in Man<sup>®</sup> are registered trademarks of the Johns Hopkins University.
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