4364 lines
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- *603945 - EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 5; EIF2B5
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*603945</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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</li>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603945">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>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div 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=ENSG00000145191;t=ENST00000648915" 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=8893" 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=603945" 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=ENSG00000145191;t=ENST00000648915" 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_003907,XM_011513265,XM_011513266,XM_047449148" 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_003907" 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=603945" 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=04898&isoform_id=04898_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/EIF2B5" 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/806854,15488926,21750065,62087222,83267879,119598704,119598705,119598706,119598707,119598708,160359049,767927902,767927904,2217346700,2462593481,2462593483,2462593485" 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/Q13144" 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=8893" 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=ENSG00000145191;t=ENST00000648915" 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=EIF2B5" 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=EIF2B5" 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+8893" 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/EIF2B5" 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:8893" 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/8893" 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=chr3&hgg_gene=ENST00000648915.2&hgg_start=184135358&hgg_end=184145311&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/genes/HGNC:3261" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/eif2b5" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603945[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603945[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/ENSG00000145191" 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.gwascentral.org/search?q=EIF2B5" 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=EIF2B5" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=EIF2B5&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/PA27692" 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:3261" 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/FBgn0023512.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:2446176" 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/EIF2B5#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:2446176" 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/8893/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=8893" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00008428;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-5364" 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:8893" 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=EIF2B5&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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603945
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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 2B, SUBUNIT 5; EIF2B5
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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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EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, EPSILON<br />
|
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EIF2B-EPSILON
|
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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">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=EIF2B5" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">EIF2B5</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/3/908?start=-3&limit=10&highlight=908">3q27.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:184135358-184145311&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'})">3:184,135,358-184,145,311</a> </span>
|
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</em>
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</strong>
|
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
|
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<br />
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
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Location
|
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
|
<a href="/geneMap/3/908?start=-3&limit=10&highlight=908">
|
|
3q27.1
|
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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">
|
|
Leukoencephalopathy with vanishing white matter 5, with or without ovarian failure
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620315"> 620315 </a>
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<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>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/603945" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603945" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="text" class="mim-anchor"></a>
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<h4>
|
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|
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<span class="mim-font">
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<p>The EIF2B5 gene encodes a subunit of eIF2B, a heteropentameric guanine nucleotide exchange factor necessary for the proper function of the translation initiation factor eIF2 (see <a href="/entry/603907">603907</a>). EIF2B catalyzes the exchange of GDP for GTP (summary by <a href="#1" class="mim-tip-reference" title="Asuru, A. I., Mellor, H., Thomas, N. S. B., Yu, L., Chen, J.-J., Crosby, J. S., Hartson, S. D., Kimball, S. R., Jefferson, L. S., Matts, R. L. <strong>Cloning and characterization of cDNAs encoding the epsilon-subunit of eukaryotic initiation factor-2B from rabbit and human.</strong> Biochim. Biophys. Acta 1307: 309-317, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8688466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8688466</a>] [<a href="https://doi.org/10.1016/0167-4781(96)00054-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8688466">Asuru et al., 1996</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8688466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#1" class="mim-tip-reference" title="Asuru, A. I., Mellor, H., Thomas, N. S. B., Yu, L., Chen, J.-J., Crosby, J. S., Hartson, S. D., Kimball, S. R., Jefferson, L. S., Matts, R. L. <strong>Cloning and characterization of cDNAs encoding the epsilon-subunit of eukaryotic initiation factor-2B from rabbit and human.</strong> Biochim. Biophys. Acta 1307: 309-317, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8688466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8688466</a>] [<a href="https://doi.org/10.1016/0167-4781(96)00054-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8688466">Asuru et al. (1996)</a> isolated a rabbit reticulocyte cDNA encoding the epsilon subunit of eIF2B. The predicted 721-amino acid protein migrates at approximately 84 kD by SDS-PAGE. The authors stated that the N-terminal region of eIF2B-epsilon contains a putative nucleotide-binding domain that may be directly involved in nucleotide exchange. By screening a human histiocytic lymphoma cell line library with the rabbit cDNA, <a href="#1" class="mim-tip-reference" title="Asuru, A. I., Mellor, H., Thomas, N. S. B., Yu, L., Chen, J.-J., Crosby, J. S., Hartson, S. D., Kimball, S. R., Jefferson, L. S., Matts, R. L. <strong>Cloning and characterization of cDNAs encoding the epsilon-subunit of eukaryotic initiation factor-2B from rabbit and human.</strong> Biochim. Biophys. Acta 1307: 309-317, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8688466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8688466</a>] [<a href="https://doi.org/10.1016/0167-4781(96)00054-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8688466">Asuru et al. (1996)</a> identified a partial cDNA encoding human eIF2B-epsilon. The deduced partial human protein contains 641 amino acids and is 90% identical to rabbit eIF2B-epsilon. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8688466" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong> Nature Genet. 29: 383-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>] [<a href="https://doi.org/10.1038/ng764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704758">Leegwater et al. (2001)</a> determined that the EIF2B5 gene contains 16 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#9" class="mim-tip-reference" title="Gross, M. B. <strong>Personal Communication.</strong> Baltimore, Md. 5/28/2015."None>Gross (2015)</a> mapped the EIF2B5 gene to chromosome 3q27.1 based on an alignment of the EIF2B5 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC013590" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC013590</a>) with the genomic sequence (GRCh38).</p>
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<p><a href="#7" class="mim-tip-reference" title="Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. <strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong> Europ. J. Hum. Genet. 12: 561-566, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054402">Fogli et al. (2004)</a> measured the guanine nucleotide exchange factor (GEF) activity of EIF2B in transformed lymphocytes from 30 patients with leukoencephalopathies (<a href="/entry/603896">603896</a>) with homozygous or compound heterozygous mutations in EIF2B2 (<a href="/entry/606454">606454</a>), EIF2B3 (<a href="/entry/606273">606273</a>), EIF2B4 (<a href="/entry/606687">606687</a>), and EIF2B5 compared to 10 unaffected heterozygotes and 22 controls with no EIF2B mutation. A significant decrease of 20 to 70% in GEF activity was observed in all mutated cells, and the extent of the decrease correlated with age at onset of disease. <a href="#7" class="mim-tip-reference" title="Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O. <strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong> Europ. J. Hum. Genet. 12: 561-566, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201189" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15054402">Fogli et al. (2004)</a> suggested that a deficiency in GEF activity underlies the encephalopathy in EIF2B-related disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054402" 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 cell cultures from the brain of an individual with VWM who had compound heterozygosity for mutations in EIF2B5 (T91A, <a href="#0001">603945.0001</a> and W628R, <a href="#0002">603945.0002</a>), <a href="#3" class="mim-tip-reference" title="Dietrich, J., Lacagnina, M., Gass, D., Richfield, E., Mayer-Proschel, M., Noble, M., Torres, C., Proschel, C. <strong>EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy.</strong> Nature Med. 11: 277-283, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15723074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15723074</a>] [<a href="https://doi.org/10.1038/nm1195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15723074">Dietrich et al. (2005)</a> observed prompt development of normal-appearing oligodendrocytes despite the extensive demyelination seen in the patient. However, few glial fibrillary acidic protein (GFAP; <a href="/entry/137780">137780</a>)-expressing astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP-expressing astrocytes, and RNA-interference targeting of EIF2B5 severely compromised the induction of GFAP-expressing cells from normal human glial progenitors. <a href="#3" class="mim-tip-reference" title="Dietrich, J., Lacagnina, M., Gass, D., Richfield, E., Mayer-Proschel, M., Noble, M., Torres, C., Proschel, C. <strong>EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy.</strong> Nature Med. 11: 277-283, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15723074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15723074</a>] [<a href="https://doi.org/10.1038/nm1195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15723074">Dietrich et al. (2005)</a> suggested that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15723074" 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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Integrated stress response inhibitor (ISRIB) is a drug-like eIF2B activator that reverses the effects of eIF2 phosphorylation. In rodents, it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, <a href="#15" class="mim-tip-reference" title="Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., Renslo, A. R., Frost, A., Walter, P. <strong>Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.</strong> Science 359: eaaq0939, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29599213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29599213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29599213[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.aaq0939" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29599213">Tsai et al. (2018)</a> solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryoelectron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of 2 identical tetrameric subcomplexes involving EIF2B-beta (EIF2B2), -gamma (EIF2B3), -delta (EIF2B4), and -epsilon (EIF2B5), and ISRIB promoted this step by cross-bridging a central symmetry interface. <a href="#15" class="mim-tip-reference" title="Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., Renslo, A. R., Frost, A., Walter, P. <strong>Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.</strong> Science 359: eaaq0939, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29599213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29599213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29599213[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.aaq0939" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29599213">Tsai et al. (2018)</a> concluded that thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29599213" 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>Individuals with leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>) initially develop normally or close to normally. Neurologic deterioration usually begins in late infancy or early childhood, but juvenile- and adult-onset cases have been described. Mild and severe cases have been observed, even within families. The neurologic signs include progressive cerebellar ataxia, spasticity, inconstant optic atrophy, and relatively preserved mental abilities. Disease is chronic-progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Head trauma leads only to motor deterioration, whereas infections with fever may end in coma. Death occurs after a variable period of several years to a few decades, usually following an episode of fever and coma. MRI is diagnostic and shows a diffuse abnormality of the cerebral white matter beginning in the presymptomatic stage. Both MRI and magnetic resonance spectroscopy indicate that, with time, an increasing amount of the abnormal white matter vanishes and is replaced by cerebrospinal fluid. The mode of inheritance is autosomal recessive. <a href="#10" class="mim-tip-reference" title="Leegwater, P. A. J., Konst, A. A. M., Kuyt, B., Sandkuijl, L. A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>The gene for leukoencephalopathy with vanishing white matter is located on chromosome 3q27.</strong> Am. J. Hum. Genet. 65: 728-734, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441579</a>] [<a href="https://doi.org/10.1086/302548" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10441579">Leegwater et al. (1999)</a> mapped the disorder to 3q27 and <a href="#11" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong> Nature Genet. 29: 383-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>] [<a href="https://doi.org/10.1038/ng764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704758">Leegwater et al. (2001)</a> narrowed the location to a region containing a total of 25 genes and STSs. One of these genes, EIF2B5, was found to contain 16 different mutations in 29 patients from 23 families (e.g., <a href="#0001">603945.0001</a>-<a href="#0005">603945.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11704758+10441579" 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>Cree leukoencephalopathy (CLE) is a rapidly fatal infantile autosomal recessive leukodystrophy observed in the indigenous Cree and Chippewayan populations in northern Quebec and Manitoba. <a href="#8" class="mim-tip-reference" title="Fogli, A., Wong, K., Eymard-Pierre, E., Wenger, J., Bouffard, J.-P., Goldin, E., Black, D. N., Boespflug-Tanguy, O., Schiffmann, R. <strong>Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus.</strong> Ann. Neurol. 52: 506-510, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12325082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12325082</a>] [<a href="https://doi.org/10.1002/ana.10339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12325082">Fogli et al. (2002)</a> found the typical foamy cells with the oligodendroglial phenotype described in CACH/VWM in the brains of individuals with CLE. They studied the EIF2B5 gene in 3 patients of 2 Cree families and identified a homozygous missense mutation (R195H; <a href="#0005">603945.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12325082" 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 sibs with a severe acute fatal infantile form of leukoencephalopathy with vanishing white matter, <a href="#4" class="mim-tip-reference" title="Fogli, A., Dionisi-Vici, C., Deodato, F., Bartuli, A., Boespflug-Tanguy, O., Bertini, E. <strong>A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation.</strong> Neurology 59: 1966-1968, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499492</a>] [<a href="https://doi.org/10.1212/01.wnl.0000041666.76863.47" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12499492">Fogli et al. (2002)</a> identified a homozygous missense mutation in the EIF2B5 gene (L309V; <a href="#0006">603945.0006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499492" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. <strong>Ovarian failure related to eukaryotic initiation factor 2B mutations.</strong> Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707859</a>] [<a href="https://doi.org/10.1086/375404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707859">Fogli et al. (2003)</a> identified mutations in the EIF2B2, EIF2B4 (<a href="/entry/606687">606687</a>), and EIF2B5 genes (e.g., R195C; <a href="#0007">603945.0007</a>) in patients with VWM with ovarian failure, which they referred to as ovarioleukodystrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a Japanese woman with adult-onset VWM5, <a href="#13" class="mim-tip-reference" title="Ohtake, H., Shimohata, T., Terajima, K., Kimura, T., Jo, R., Kaseda, R., Iizuka, O., Takano, M., Akaiwa, Y., Goto, H., Kobayashi, H., Sugai, T., Muratake, T., Hosoki, T., Shioiri, T., Okamoto, K., Onodera, O., Tanaka, K., Someya, T., Nakada, T., Tsuji, S. <strong>Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5.</strong> Neurology 62: 1601-1603, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15136690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15136690</a>] [<a href="https://doi.org/10.1212/01.wnl.0000123117.11264.0e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15136690">Ohtake et al. (2004)</a> identified homozygosity for a missense mutation in the EIF2B5 gene (T182M; <a href="#0008">603945.0008</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15136690" 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="#14" class="mim-tip-reference" title="Passemard, S., Gelot, A., Fogli, A., N'Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D. <strong>Progressive megalencephaly due to specific EIF2B-epsilon mutations in two unrelated families.</strong> Neurology 69: 400-402, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646634</a>] [<a href="https://doi.org/10.1212/01.wnl.0000266388.02772.f8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646634">Passemard et al. (2007)</a> reported 4 patients from 2 unrelated families with early-onset VWM disease due to compound heterozygous mutations in the EIF2B5 gene (<a href="#0009">603945.0009</a>-<a href="#0011">603945.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646634" 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>Three novel missense mutations in the EIF2B5 gene were identified by <a href="#17" class="mim-tip-reference" title="van der Knaap, M. S., van Berkel, C. G. M., Herms, J., van Coster, R., Baethmann, M., Naidu, S., Boltshauser, E., Willemsen, M. A. A. P., Plecko, B., Hoffmann, G. F., Proud, C. G., Scheper, G. C., Pronk, J. C. <strong>eIF2B-related disorders: antenatal onset and involvement of multiple organs.</strong> Am. J. Hum. Genet. 73: 1199-1207, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14566705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14566705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14566705[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/10.1086/379524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14566705">van der Knaap et al. (2003)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14566705" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Fogli, A., Schiffmann, R., Bertini, E., Ughetto, S., Combes, P., Eymard- Pierre, E., Kaneski, C. R., Pineda, M., Troncoso, M., Uziel, G., Surtees, R., Pugin, D., Chaunu, M.-P., Rodriguez, D., Boespflug-Tanguy, O. <strong>The effect of genotype on the natural history of eIF2B-related leukodystrophies.</strong> Neurology 62: 1509-1517, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15136673/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15136673</a>] [<a href="https://doi.org/10.1212/01.wnl.0000123259.67815.db" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15136673">Fogli et al. (2004)</a> found that 42 of 68 (62%) VWM families had mutations in the EIF2B5 gene; 71% of those had the R113H mutation (<a href="#0004">603945.0004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15136673" 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 6 of 11 unrelated Chinese patients with VWM disease, <a href="#19" class="mim-tip-reference" title="Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y. <strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong> J. Hum. Genet. 54: 74-77, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158808</a>] [<a href="https://doi.org/10.1038/jhg.2008.10" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19158808">Wu et al. (2009)</a> identified homozygous or compound heterozygous mutations in the EIF2B5 gene, including 3 novel missense mutations and a deletion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158808" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 53-year-old Japanese man with adult-onset VWM, <a href="#12" class="mim-tip-reference" title="Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S. <strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong> Neurogenetics 12: 259-261, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>] [<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21484434">Matsukawa et al. (2011)</a> identified a homozygous missense mutation in the EIF2B5 gene (D270H; <a href="#0012">603945.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In addition to mutations in the EIF2B5 gene, <a href="#11" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong> Nature Genet. 29: 383-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>] [<a href="https://doi.org/10.1038/ng764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704758">Leegwater et al. (2001)</a> found mutations in the gene encoding the beta subunit of eIF2B (EIF2B2; <a href="/entry/606454">606454</a>) in 4 other patients. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, <a href="#11" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong> Nature Genet. 29: 383-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>] [<a href="https://doi.org/10.1038/ng764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704758">Leegwater et al. (2001)</a> suggested that this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors had not theretofore been implicated in disease. Mutations in a gene for a modulator of eIF2-eIF2B activity, EIF2AK3 (<a href="/entry/604032">604032</a>), cause Wolcott-Rallison syndrome (<a href="/entry/226980">226980</a>). This syndrome is characterized by the malfunctioning of multiple organs and tissues. EIF2AK3 encodes a kinase that specifically phosphorylates the alpha-subunit of eIF2, which suggests that the syndrome is caused by a failure to downregulate translation under stress conditions that would normally enhance eIF2AK3 activity. EIF2AK3 is probably not essential for survival, as patients homozygous for nonsense mutations at this locus have been identified. In VWM only the brain is affected. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#18" class="mim-tip-reference" title="van der Lei, H. D. W., van Berkel, C. G. M., van Wieringen, W. N., Brenner, C., Feigenbaum, A., Mercimek-Mahmutoglu, S., Philippart, M., Tatli, B., Wassmer, E., Scheper, G. C., van der Knaap, M. S. <strong>Genotype-phenotype correlation in vanishing white matter disease.</strong> Neurology 75: 1555-1559, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20975056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20975056</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181f962ae" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20975056">Van der Lei et al. (2010)</a> identified mutations in the EIF2B5 gene in 126 (68%) of 184 patients from a large database of patients with leukoencephalopathy with VWM disease. A subset of these patients were chosen for study, including 23 with a homozygous R113H mutation (<a href="#0004">603945.0004</a>), 49 who had R113H in the compound heterozygous state, 8 with a homozygous T91A mutation (<a href="#0001">603945.0001</a>), 9 with R113H/R339any, and 7 with T91A/R339any. Patients homozygous for R113H had a milder disease than patients who were compound heterozygous for R113H and patients homozygous for T91A. Patients with R113H/R339any had a milder phenotype than patients with T91A/R339any. Finally, females tended to have a milder disease than males. <a href="#18" class="mim-tip-reference" title="van der Lei, H. D. W., van Berkel, C. G. M., van Wieringen, W. N., Brenner, C., Feigenbaum, A., Mercimek-Mahmutoglu, S., Philippart, M., Tatli, B., Wassmer, E., Scheper, G. C., van der Knaap, M. S. <strong>Genotype-phenotype correlation in vanishing white matter disease.</strong> Neurology 75: 1555-1559, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20975056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20975056</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3181f962ae" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20975056">Van der Lei et al. (2010)</a> concluded that the clinical phenotype in VWM is influenced by the combination of both mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20975056" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 53-year-old Japanese man with adult-onset VWM, <a href="#12" class="mim-tip-reference" title="Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S. <strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong> Neurogenetics 12: 259-261, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>] [<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21484434">Matsukawa et al. (2011)</a> identified a homozygous missense mutation in the EIF2B5 gene (D270H; <a href="#0012">603945.0012</a>). In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B5 was significantly decreased (30% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" 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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<strong>12 Selected Examples</a>):</strong>
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<a href="/allelicVariants/603945" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=603945[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"><span class="text-primary">●</span> rs28939717 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28939717;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/rs28939717?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=rs28939717" 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=rs28939717" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 12 individuals with leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>) from 9 families who shared a haplotype designated 'EN' because a large number of their ancestors lived in a rural region in the eastern part of the Netherlands, <a href="#11" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong> Nature Genet. 29: 383-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>] [<a href="https://doi.org/10.1038/ng764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704758">Leegwater et al. (2001)</a> found homozygosity for a 271A-G transition in exon 2 of the EIF2B5 gene, resulting in an amino acid change of threonine to alanine at codon 91 (T91A). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704758" 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">rs28937596 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28937596;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=rs28937596" 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=rs28937596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>), <a href="#11" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong> Nature Genet. 29: 383-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>] [<a href="https://doi.org/10.1038/ng764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704758">Leegwater et al. (2001)</a> found an c.1882T-C transition in exon 14 of the EIF2B5 gene, resulting in a trp628-to-arg (W628R) amino acid substitution. The exon 14 mutation was in compound heterozygous state with the T91A mutation (<a href="#0001">603945.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704758" 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>.0003 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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">rs113994074 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994074;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=rs113994074" 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=rs113994074" 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 patients with leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>), <a href="#11" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong> Nature Genet. 29: 383-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>] [<a href="https://doi.org/10.1038/ng764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704758">Leegwater et al. (2001)</a> found compound heterozygosity for a gly386-to-val (G386V) mutation and an arg113-to-his mutation (R113H; <a href="#0004">603945.0004</a>) in the EIF2B5 gene. The G386V amino acid substitution was the result of a c.1157G-T transversion that affected the first nucleotide in exon 8 and may have disturbed splicing. The R113H substitution results from a 338G-A transition in the EIF2B5 gene. <a href="#11" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong> Nature Genet. 29: 383-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>] [<a href="https://doi.org/10.1038/ng764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704758">Leegwater et al. (2001)</a> identified the R113H mutation in 12 families with VWM, with a total allelic frequency of approximately 20% in the group of affected individuals that they investigated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113994049 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994049;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/rs113994049?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=rs113994049" 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=rs113994049" 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=RCV000006308 OR RCV000254893 OR RCV001420331 OR RCV003221411 OR RCV004018575 OR RCV004755715" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006308, RCV000254893, RCV001420331, RCV003221411, RCV004018575, RCV004755715" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006308...</a>
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<p>For discussion of the arg113-to-his (R113H) mutation in the EIF2B5 gene that was found in compound heterozygous state in patients with leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>) by <a href="#11" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong> Nature Genet. 29: 383-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>] [<a href="https://doi.org/10.1038/ng764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704758">Leegwater et al. (2001)</a>, see <a href="#0003">603945.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704758" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a woman with adult onset of VWM diagnosed at the age of 27 years, <a href="#2" class="mim-tip-reference" title="Biancheri, R., Rossi, A., Di Rocco, M., Filocamo, M., Pronk, J. C., van der Knaap, M. S., Tortori-Donati, P. <strong>Leukoencephalopathy with vanishing white matter: an adult onset case.</strong> Neurology 61: 1818-1819, 2003. Note: Erratum: Neurology 62: 1242 only, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14694060/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14694060</a>] [<a href="https://doi.org/10.1212/01.wnl.0000098994.35677.3c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14694060">Biancheri et al. (2003)</a> identified homozygosity for the R113H mutation, which they originally incorrectly reported as R118H. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14694060" 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 3 of 6 families with VWM and ovarian failure, which the authors designated 'ovarioleukodystrophy,' <a href="#5" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. <strong>Ovarian failure related to eukaryotic initiation factor 2B mutations.</strong> Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707859</a>] [<a href="https://doi.org/10.1086/375404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707859">Fogli et al. (2003)</a> identified the R113H mutation. Patients from these families had the mildest form of the disease. <a href="#5" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. <strong>Ovarian failure related to eukaryotic initiation factor 2B mutations.</strong> Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707859</a>] [<a href="https://doi.org/10.1086/375404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707859">Fogli et al. (2003)</a> stated that the R113H mutation had been found in 22% of chromosomes of 41 patients with VWM (<a href="#11" class="mim-tip-reference" title="Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S. <strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong> Nature Genet. 29: 383-388, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>] [<a href="https://doi.org/10.1038/ng764" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11704758">Leegwater et al., 2001</a>). Because R113 is not conserved among species, and because H is found at this position in rat and mouse, they suggested that the homozygous R113H mutation in humans may not strongly affect EIF2B5 function. One patient studied by <a href="#5" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. <strong>Ovarian failure related to eukaryotic initiation factor 2B mutations.</strong> Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707859</a>] [<a href="https://doi.org/10.1086/375404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707859">Fogli et al. (2003)</a>, who had early secondary amenorrhea, was a compound heterozygote for the R113H mutation and an arg195-to-cys mutation (R195C; <a href="#0007">603945.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11704758+12707859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="van der Knaap, M. S, Leegwater, P. A. J., van Berkel, C. G. M., Brenner, C., Storey, E., Di Rocco, M., Salvi, F., Pronk, J. C. <strong>Arg113his mutation in eIF2B-epsilon as cause of leukoencephalopathy in adults.</strong> Neurology 62: 1598-1600, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15136689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15136689</a>] [<a href="https://doi.org/10.1212/01.wnl.0000123118.86746.fc" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15136689">Van der Knaap et al. (2004)</a> identified 6 individuals who were homozygous for the R113H mutation; 2 of them were sibs. Five of the 6 had an unusually mild form of VWM, 4 with a late-adolescent or adult onset, and 1 with childhood onset. One individual was asymptomatic at age 30 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15136689" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113994054 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994054;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/rs113994054?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=rs113994054" 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=rs113994054" 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=RCV000006310 OR RCV001064868 OR RCV003221412" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006310, RCV001064868, RCV003221412" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006310...</a>
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<p><a href="#8" class="mim-tip-reference" title="Fogli, A., Wong, K., Eymard-Pierre, E., Wenger, J., Bouffard, J.-P., Goldin, E., Black, D. N., Boespflug-Tanguy, O., Schiffmann, R. <strong>Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus.</strong> Ann. Neurol. 52: 506-510, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12325082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12325082</a>] [<a href="https://doi.org/10.1002/ana.10339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12325082">Fogli et al. (2002)</a> studied the EIF2B5 gene in 3 patients of 2 Cree families with Cree leukoencephalopathy (VWM5; <a href="/entry/620315">620315</a>) and identified a homozygous G-to-A transition at nucleotide 584, resulting in an arg195-to-his (R195H) substitution. They reported an unpublished observation of the same R195H mutation in a CACH/VWM family from the Highlands in Scotland. The northern Quebec Cree first encountered Europeans in the early 1700s; these were Scottish fur traders from the Hudson Bay Trading Company. <a href="#8" class="mim-tip-reference" title="Fogli, A., Wong, K., Eymard-Pierre, E., Wenger, J., Bouffard, J.-P., Goldin, E., Black, D. N., Boespflug-Tanguy, O., Schiffmann, R. <strong>Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus.</strong> Ann. Neurol. 52: 506-510, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12325082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12325082</a>] [<a href="https://doi.org/10.1002/ana.10339" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12325082">Fogli et al. (2002)</a> stated that the probands from the 2 Cree families in their report could trace their paternal ancestry to 3 English Hudson Bay Company employees around 1770. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12325082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs113994061 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994061;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/rs113994061?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=rs113994061" 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=rs113994061" 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=RCV000006311 OR RCV003221413" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006311, RCV003221413" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006311...</a>
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<p>In 2 sibs with a severe acute fatal infantile form of leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>), <a href="#4" class="mim-tip-reference" title="Fogli, A., Dionisi-Vici, C., Deodato, F., Bartuli, A., Boespflug-Tanguy, O., Bertini, E. <strong>A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation.</strong> Neurology 59: 1966-1968, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499492</a>] [<a href="https://doi.org/10.1212/01.wnl.0000041666.76863.47" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12499492">Fogli et al. (2002)</a> identified a homozygous 925G-C mutation in the EIF2B5 gene, resulting in a leu309-to-val (L309V) substitution. The unaffected parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499492" 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">rs113994055 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994055;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=rs113994055" 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=rs113994055" 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=RCV002512827 OR RCV003221414" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002512827, RCV003221414" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002512827...</a>
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<p>In a patient with VWM and ovarian failure (VWM5; <a href="/entry/620315">620315</a>) with early-onset secondary amenorrhea, <a href="#5" class="mim-tip-reference" title="Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O. <strong>Ovarian failure related to eukaryotic initiation factor 2B mutations.</strong> Am. J. Hum. Genet. 72: 1544-1550, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707859</a>] [<a href="https://doi.org/10.1086/375404" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12707859">Fogli et al. (2003)</a> found compound heterozygosity for the arg113-to-his mutation (R113H; <a href="#0004">603945.0004</a>) and an arg195-to-cys (R195C) mutation in the EIF2B5 gene. The R195C mutation resulted from a C-to-T transition at nucleotide 583. The authors noted that the R195C mutation involved the same codon as that mutated in Cree leukoencephalopathy, which is caused by homozygosity for arg195 to his (R195H; <a href="#0005">603945.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707859" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5, ADULT-ONSET</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> rs113994053 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994053;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/rs113994053?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=rs113994053" 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=rs113994053" 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=RCV000416181 OR RCV003221415 OR RCV003485519" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000416181, RCV003221415, RCV003485519" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000416181...</a>
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<p>In a Japanese woman, born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>), <a href="#13" class="mim-tip-reference" title="Ohtake, H., Shimohata, T., Terajima, K., Kimura, T., Jo, R., Kaseda, R., Iizuka, O., Takano, M., Akaiwa, Y., Goto, H., Kobayashi, H., Sugai, T., Muratake, T., Hosoki, T., Shioiri, T., Okamoto, K., Onodera, O., Tanaka, K., Someya, T., Nakada, T., Tsuji, S. <strong>Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5.</strong> Neurology 62: 1601-1603, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15136690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15136690</a>] [<a href="https://doi.org/10.1212/01.wnl.0000123117.11264.0e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15136690">Ohtake et al. (2004)</a> identified a homozygous 545C-T transition in exon 4 of the EIF2B5 gene, resulting in a thr182-to-met (T182M) substitution. The patient presented with presenile dementia and psychiatric symptoms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15136690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0009 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</strong>
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EIF2B5, ARG315HIS
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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> rs113994064 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994064;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/rs113994064?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=rs113994064" 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=rs113994064" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006314 OR RCV001070077 OR RCV003221416" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006314, RCV001070077, RCV003221416" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006314...</a>
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<p>In 4 patients from 2 unrelated families with early-onset leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>), <a href="#14" class="mim-tip-reference" title="Passemard, S., Gelot, A., Fogli, A., N'Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D. <strong>Progressive megalencephaly due to specific EIF2B-epsilon mutations in two unrelated families.</strong> Neurology 69: 400-402, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646634</a>] [<a href="https://doi.org/10.1212/01.wnl.0000266388.02772.f8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646634">Passemard et al. (2007)</a> identified compound heterozygosity for mutations in the EIF2B5 gene. In a brother and sister, they identified a 944G-A transition resulting in an arg315-to-his (R315H) substitution and a 166T-G transversion resulting in a phe56-to-val (F56V; <a href="#0010">603945.0010</a>) substitution. In 2 sisters, they identified the R315H mutation and a 167T-G transversion resulting in a phe56-to-cys (F56C; <a href="#0011">603945.0011</a>) substitution. In the first family, the 2 sibs had acute neurologic deterioration in infancy following viral infections. Brain MRIs showed severe white matter abnormalities and complete disappearance of hemispheric white matter, respectively. Both developed progressive severe macrocephaly after age 3 years. In the second family, 1 sister who survived beyond age 3 years developed macrocephaly. <a href="#14" class="mim-tip-reference" title="Passemard, S., Gelot, A., Fogli, A., N'Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D. <strong>Progressive megalencephaly due to specific EIF2B-epsilon mutations in two unrelated families.</strong> Neurology 69: 400-402, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646634</a>] [<a href="https://doi.org/10.1212/01.wnl.0000266388.02772.f8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646634">Passemard et al. (2007)</a> suggested that altered brain water balance may result in swelling of the disease white matter and macrocephaly in some patients with VWM disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</strong>
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</h4>
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EIF2B5, PHE56VAL
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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> rs113994043 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs113994043;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/rs113994043?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=rs113994043" 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=rs113994043" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001851695 OR RCV003221417 OR RCV004700193" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001851695, RCV003221417, RCV004700193" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001851695...</a>
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<span class="mim-text-font">
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<p>For discussion of the phe56-to-val (F56V) mutation in the EIF2B5 gene that was found in compound heterozygous state in patients with leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>) by <a href="#14" class="mim-tip-reference" title="Passemard, S., Gelot, A., Fogli, A., N'Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D. <strong>Progressive megalencephaly due to specific EIF2B-epsilon mutations in two unrelated families.</strong> Neurology 69: 400-402, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646634</a>] [<a href="https://doi.org/10.1212/01.wnl.0000266388.02772.f8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646634">Passemard et al. (2007)</a>, see <a href="#0009">603945.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</strong>
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EIF2B5, PHE56CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908541 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908541;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=rs121908541" 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=rs121908541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003221418" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003221418" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003221418</a>
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<p>For discussion of the phe56-to-cys (F56C) mutation in the EIF2B5 gene that was found in compound heterozygous state in patients with leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>) by <a href="#14" class="mim-tip-reference" title="Passemard, S., Gelot, A., Fogli, A., N'Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D. <strong>Progressive megalencephaly due to specific EIF2B-epsilon mutations in two unrelated families.</strong> Neurology 69: 400-402, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646634</a>] [<a href="https://doi.org/10.1212/01.wnl.0000266388.02772.f8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17646634">Passemard et al. (2007)</a>, see <a href="#0009">603945.0009</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646634" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5, ADULT-ONSET</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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EIF2B5, ASP270HIS
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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> rs397514646 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397514646;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/rs397514646?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=rs397514646" 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=rs397514646" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003221419" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003221419" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003221419</a>
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<span class="mim-text-font">
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<p>In a 53-year-old Japanese man, born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter (VWM5; <a href="/entry/620315">620315</a>), <a href="#12" class="mim-tip-reference" title="Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S. <strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong> Neurogenetics 12: 259-261, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>] [<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21484434">Matsukawa et al. (2011)</a> identified a homozygous 808G-C transversion in the EIF2B5 gene, resulting in an asp270-to-his (D270H) substitution. The mutation was not found in 96 Japanese control individuals. The patient developed progressive gait unsteadiness and miscalculation at age 50. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B5 was significantly decreased (30% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[<a href="https://doi.org/10.1212/01.wnl.0000098994.35677.3c" target="_blank">Full Text</a>]
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Dietrich, J., Lacagnina, M., Gass, D., Richfield, E., Mayer-Proschel, M., Noble, M., Torres, C., Proschel, C.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15723074/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15723074</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15723074" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12499492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12499492</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12499492" 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/10.1212/01.wnl.0000041666.76863.47" target="_blank">Full Text</a>]
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Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12707859/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12707859</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12707859" 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/10.1212/01.wnl.0000123259.67815.db" target="_blank">Full Text</a>]
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Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15054402/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15054402</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15054402" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.ejhg.5201189" target="_blank">Full Text</a>]
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Fogli, A., Wong, K., Eymard-Pierre, E., Wenger, J., Bouffard, J.-P., Goldin, E., Black, D. N., Boespflug-Tanguy, O., Schiffmann, R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12325082/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12325082</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12325082" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.10339" target="_blank">Full Text</a>]
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Leegwater, P. A. J., Konst, A. A. M., Kuyt, B., Sandkuijl, L. A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10441579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10441579</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10441579" 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/10.1086/302548" target="_blank">Full Text</a>]
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Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S.
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<strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11704758/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11704758</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11704758" 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/ng764" target="_blank">Full Text</a>]
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<a id="Matsukawa2011" class="mim-anchor"></a>
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Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S.
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<strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong>
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Neurogenetics 12: 259-261, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21484434/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21484434</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21484434" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-011-0284-7" target="_blank">Full Text</a>]
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Ohtake, H., Shimohata, T., Terajima, K., Kimura, T., Jo, R., Kaseda, R., Iizuka, O., Takano, M., Akaiwa, Y., Goto, H., Kobayashi, H., Sugai, T., Muratake, T., Hosoki, T., Shioiri, T., Okamoto, K., Onodera, O., Tanaka, K., Someya, T., Nakada, T., Tsuji, S.
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<strong>Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5.</strong>
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Neurology 62: 1601-1603, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15136690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15136690</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15136690" 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/10.1212/01.wnl.0000123117.11264.0e" target="_blank">Full Text</a>]
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Passemard, S., Gelot, A., Fogli, A., N'Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D.
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<strong>Progressive megalencephaly due to specific EIF2B-epsilon mutations in two unrelated families.</strong>
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Neurology 69: 400-402, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17646634/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17646634</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17646634" 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/10.1212/01.wnl.0000266388.02772.f8" target="_blank">Full Text</a>]
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<a id="Tsai2018" class="mim-anchor"></a>
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Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., Renslo, A. R., Frost, A., Walter, P.
|
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<strong>Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.</strong>
|
|
Science 359: eaaq0939, 2018. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29599213/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29599213</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29599213[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=29599213" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.aaq0939" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="van der Knaap2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van der Knaap, M. S, Leegwater, P. A. J., van Berkel, C. G. M., Brenner, C., Storey, E., Di Rocco, M., Salvi, F., Pronk, J. C.
|
|
<strong>Arg113his mutation in eIF2B-epsilon as cause of leukoencephalopathy in adults.</strong>
|
|
Neurology 62: 1598-1600, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15136689/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15136689</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15136689" 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/10.1212/01.wnl.0000123118.86746.fc" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="van der Knaap2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van der Knaap, M. S., van Berkel, C. G. M., Herms, J., van Coster, R., Baethmann, M., Naidu, S., Boltshauser, E., Willemsen, M. A. A. P., Plecko, B., Hoffmann, G. F., Proud, C. G., Scheper, G. C., Pronk, J. C.
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<strong>eIF2B-related disorders: antenatal onset and involvement of multiple organs.</strong>
|
|
Am. J. Hum. Genet. 73: 1199-1207, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14566705/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14566705</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=14566705[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=14566705" 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/10.1086/379524" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="van der Lei2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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van der Lei, H. D. W., van Berkel, C. G. M., van Wieringen, W. N., Brenner, C., Feigenbaum, A., Mercimek-Mahmutoglu, S., Philippart, M., Tatli, B., Wassmer, E., Scheper, G. C., van der Knaap, M. S.
|
|
<strong>Genotype-phenotype correlation in vanishing white matter disease.</strong>
|
|
Neurology 75: 1555-1559, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20975056/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20975056</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20975056" 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/10.1212/WNL.0b013e3181f962ae" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Wu2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y.
|
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<strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong>
|
|
J. Hum. Genet. 54: 74-77, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19158808/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19158808</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19158808" 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/jhg.2008.10" target="_blank">Full Text</a>]
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</p>
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</div>
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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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<a id="contributors" 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="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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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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Ada Hamosh - updated : 07/23/2018
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
|
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
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Matthew B. Gross - updated : 5/28/2015<br>Cassandra L. Kniffin - updated : 2/13/2013<br>Cassandra L. Kniffin - updated : 11/13/2012<br>Cassandra L. Kniffin - updated : 6/26/2009<br>Cassandra L. Kniffin - updated : 12/4/2007<br>Marla J. F. O'Neill - updated : 3/28/2005<br>Marla J. F. O'Neill - updated : 2/8/2005<br>Cassandra L. Kniffin - updated : 1/31/2005<br>Cassandra L. Kniffin - updated : 2/3/2004<br>Victor A. McKusick - updated : 12/12/2003<br>Victor A. McKusick - updated : 5/23/2003<br>Cassandra L. Kniffin - updated : 2/13/2003<br>Victor A. McKusick - updated : 11/19/2002<br>Paul J. Converse - updated : 2/19/2002<br>Victor A. McKusick - updated : 11/12/2001
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Rebekah S. Rasooly : 6/29/1999
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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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<a id="editHistory" 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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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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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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alopez : 04/17/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 03/17/2021<br>alopez : 07/23/2018<br>carol : 09/27/2016<br>carol : 06/24/2016<br>alopez : 7/15/2015<br>mcolton : 7/13/2015<br>mgross : 5/28/2015<br>carol : 3/4/2013<br>ckniffin : 2/13/2013<br>carol : 11/28/2012<br>alopez : 11/20/2012<br>terry : 11/15/2012<br>ckniffin : 11/13/2012<br>wwang : 6/26/2009<br>ckniffin : 6/26/2009<br>wwang : 12/11/2007<br>ckniffin : 12/4/2007<br>wwang : 3/29/2005<br>wwang : 3/28/2005<br>wwang : 2/11/2005<br>terry : 2/8/2005<br>tkritzer : 2/4/2005<br>ckniffin : 1/31/2005<br>tkritzer : 2/24/2004<br>ckniffin : 2/3/2004<br>cwells : 12/18/2003<br>terry : 12/12/2003<br>mgross : 5/29/2003<br>mgross : 5/29/2003<br>terry : 5/23/2003<br>carol : 3/17/2003<br>terry : 3/14/2003<br>carol : 2/24/2003<br>ckniffin : 2/13/2003<br>mgross : 11/20/2002<br>terry : 11/19/2002<br>alopez : 11/12/2002<br>terry : 11/11/2002<br>mgross : 2/19/2002<br>alopez : 11/20/2001<br>alopez : 11/13/2001<br>terry : 11/12/2001<br>mgross : 6/30/1999<br>mgross : 6/29/1999
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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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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 603945
|
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</span>
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</h3>
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</div>
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<div>
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<h3>
|
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<span class="mim-font">
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EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, SUBUNIT 5; EIF2B5
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</span>
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</h3>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</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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EUKARYOTIC TRANSLATION INITIATION FACTOR 2B, EPSILON<br />
|
|
EIF2B-EPSILON
|
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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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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: EIF2B5</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>
|
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<em>
|
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Cytogenetic location: 3q27.1
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|
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Genomic coordinates <span class="small">(GRCh38)</span> : 3:184,135,358-184,145,311 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
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Location
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</th>
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<th>
|
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Phenotype
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</th>
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<th>
|
|
Phenotype <br /> MIM number
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
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">
|
|
<span class="mim-font">
|
|
3q27.1
|
|
</span>
|
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</td>
|
|
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<td>
|
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<span class="mim-font">
|
|
Leukoencephalopathy with vanishing white matter 5, with or without ovarian failure
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
620315
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
|
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
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</h4>
|
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Description</strong>
|
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>The EIF2B5 gene encodes a subunit of eIF2B, a heteropentameric guanine nucleotide exchange factor necessary for the proper function of the translation initiation factor eIF2 (see 603907). EIF2B catalyzes the exchange of GDP for GTP (summary by Asuru et al., 1996). </p>
|
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</span>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<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">
|
|
<p>Asuru et al. (1996) isolated a rabbit reticulocyte cDNA encoding the epsilon subunit of eIF2B. The predicted 721-amino acid protein migrates at approximately 84 kD by SDS-PAGE. The authors stated that the N-terminal region of eIF2B-epsilon contains a putative nucleotide-binding domain that may be directly involved in nucleotide exchange. By screening a human histiocytic lymphoma cell line library with the rabbit cDNA, Asuru et al. (1996) identified a partial cDNA encoding human eIF2B-epsilon. The deduced partial human protein contains 641 amino acids and is 90% identical to rabbit eIF2B-epsilon. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Structure</strong>
|
|
</span>
|
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</h4>
|
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</div>
|
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<span class="mim-text-font">
|
|
<p>Leegwater et al. (2001) determined that the EIF2B5 gene contains 16 exons. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Gross (2015) mapped the EIF2B5 gene to chromosome 3q27.1 based on an alignment of the EIF2B5 sequence (GenBank BC013590) with the genomic sequence (GRCh38).</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
|
|
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<span class="mim-text-font">
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<p>Fogli et al. (2004) measured the guanine nucleotide exchange factor (GEF) activity of EIF2B in transformed lymphocytes from 30 patients with leukoencephalopathies (603896) with homozygous or compound heterozygous mutations in EIF2B2 (606454), EIF2B3 (606273), EIF2B4 (606687), and EIF2B5 compared to 10 unaffected heterozygotes and 22 controls with no EIF2B mutation. A significant decrease of 20 to 70% in GEF activity was observed in all mutated cells, and the extent of the decrease correlated with age at onset of disease. Fogli et al. (2004) suggested that a deficiency in GEF activity underlies the encephalopathy in EIF2B-related disease. </p><p>In cell cultures from the brain of an individual with VWM who had compound heterozygosity for mutations in EIF2B5 (T91A, 603945.0001 and W628R, 603945.0002), Dietrich et al. (2005) observed prompt development of normal-appearing oligodendrocytes despite the extensive demyelination seen in the patient. However, few glial fibrillary acidic protein (GFAP; 137780)-expressing astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP-expressing astrocytes, and RNA-interference targeting of EIF2B5 severely compromised the induction of GFAP-expressing cells from normal human glial progenitors. Dietrich et al. (2005) suggested that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Integrated stress response inhibitor (ISRIB) is a drug-like eIF2B activator that reverses the effects of eIF2 phosphorylation. In rodents, it enhances cognition and corrects cognitive deficits after brain injury. To determine its mechanism of action, Tsai et al. (2018) solved an atomic-resolution structure of ISRIB bound in a deep cleft within decameric human eIF2B by cryoelectron microscopy. Formation of fully active, decameric eIF2B holoenzyme depended on the assembly of 2 identical tetrameric subcomplexes involving EIF2B-beta (EIF2B2), -gamma (EIF2B3), -delta (EIF2B4), and -epsilon (EIF2B5), and ISRIB promoted this step by cross-bridging a central symmetry interface. Tsai et al. (2018) concluded that thus, regulation of eIF2B assembly emerges as a rheostat for eIF2B activity that tunes translation during the ISR and that can be further modulated by ISRIB. </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>Individuals with leukoencephalopathy with vanishing white matter (VWM5; 620315) initially develop normally or close to normally. Neurologic deterioration usually begins in late infancy or early childhood, but juvenile- and adult-onset cases have been described. Mild and severe cases have been observed, even within families. The neurologic signs include progressive cerebellar ataxia, spasticity, inconstant optic atrophy, and relatively preserved mental abilities. Disease is chronic-progressive with, in most individuals, additional episodes of rapid deterioration following febrile infections or minor head trauma. Head trauma leads only to motor deterioration, whereas infections with fever may end in coma. Death occurs after a variable period of several years to a few decades, usually following an episode of fever and coma. MRI is diagnostic and shows a diffuse abnormality of the cerebral white matter beginning in the presymptomatic stage. Both MRI and magnetic resonance spectroscopy indicate that, with time, an increasing amount of the abnormal white matter vanishes and is replaced by cerebrospinal fluid. The mode of inheritance is autosomal recessive. Leegwater et al. (1999) mapped the disorder to 3q27 and Leegwater et al. (2001) narrowed the location to a region containing a total of 25 genes and STSs. One of these genes, EIF2B5, was found to contain 16 different mutations in 29 patients from 23 families (e.g., 603945.0001-603945.0005). </p><p>Cree leukoencephalopathy (CLE) is a rapidly fatal infantile autosomal recessive leukodystrophy observed in the indigenous Cree and Chippewayan populations in northern Quebec and Manitoba. Fogli et al. (2002) found the typical foamy cells with the oligodendroglial phenotype described in CACH/VWM in the brains of individuals with CLE. They studied the EIF2B5 gene in 3 patients of 2 Cree families and identified a homozygous missense mutation (R195H; 603945.0005). </p><p>In 2 sibs with a severe acute fatal infantile form of leukoencephalopathy with vanishing white matter, Fogli et al. (2002) identified a homozygous missense mutation in the EIF2B5 gene (L309V; 603945.0006). </p><p>Fogli et al. (2003) identified mutations in the EIF2B2, EIF2B4 (606687), and EIF2B5 genes (e.g., R195C; 603945.0007) in patients with VWM with ovarian failure, which they referred to as ovarioleukodystrophy. </p><p>In a Japanese woman with adult-onset VWM5, Ohtake et al. (2004) identified homozygosity for a missense mutation in the EIF2B5 gene (T182M; 603945.0008). </p><p>Passemard et al. (2007) reported 4 patients from 2 unrelated families with early-onset VWM disease due to compound heterozygous mutations in the EIF2B5 gene (603945.0009-603945.0011). </p><p>Three novel missense mutations in the EIF2B5 gene were identified by van der Knaap et al. (2003). </p><p>Fogli et al. (2004) found that 42 of 68 (62%) VWM families had mutations in the EIF2B5 gene; 71% of those had the R113H mutation (603945.0004). </p><p>In 6 of 11 unrelated Chinese patients with VWM disease, Wu et al. (2009) identified homozygous or compound heterozygous mutations in the EIF2B5 gene, including 3 novel missense mutations and a deletion. </p><p>In a 53-year-old Japanese man with adult-onset VWM, Matsukawa et al. (2011) identified a homozygous missense mutation in the EIF2B5 gene (D270H; 603945.0012). </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>Pathogenesis</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 addition to mutations in the EIF2B5 gene, Leegwater et al. (2001) found mutations in the gene encoding the beta subunit of eIF2B (EIF2B2; 606454) in 4 other patients. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, Leegwater et al. (2001) suggested that this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors had not theretofore been implicated in disease. Mutations in a gene for a modulator of eIF2-eIF2B activity, EIF2AK3 (604032), cause Wolcott-Rallison syndrome (226980). This syndrome is characterized by the malfunctioning of multiple organs and tissues. EIF2AK3 encodes a kinase that specifically phosphorylates the alpha-subunit of eIF2, which suggests that the syndrome is caused by a failure to downregulate translation under stress conditions that would normally enhance eIF2AK3 activity. EIF2AK3 is probably not essential for survival, as patients homozygous for nonsense mutations at this locus have been identified. In VWM only the brain is affected. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Van der Lei et al. (2010) identified mutations in the EIF2B5 gene in 126 (68%) of 184 patients from a large database of patients with leukoencephalopathy with VWM disease. A subset of these patients were chosen for study, including 23 with a homozygous R113H mutation (603945.0004), 49 who had R113H in the compound heterozygous state, 8 with a homozygous T91A mutation (603945.0001), 9 with R113H/R339any, and 7 with T91A/R339any. Patients homozygous for R113H had a milder disease than patients who were compound heterozygous for R113H and patients homozygous for T91A. Patients with R113H/R339any had a milder phenotype than patients with T91A/R339any. Finally, females tended to have a milder disease than males. Van der Lei et al. (2010) concluded that the clinical phenotype in VWM is influenced by the combination of both mutations. </p><p>In a 53-year-old Japanese man with adult-onset VWM, Matsukawa et al. (2011) identified a homozygous missense mutation in the EIF2B5 gene (D270H; 603945.0012). In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B5 was significantly decreased (30% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset. </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>12 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 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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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EIF2B5, THR91ALA
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<br />
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SNP: rs28939717,
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gnomAD: rs28939717,
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ClinVar: RCV000006305, RCV000255738, RCV003221408
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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 12 individuals with leukoencephalopathy with vanishing white matter (VWM5; 620315) from 9 families who shared a haplotype designated 'EN' because a large number of their ancestors lived in a rural region in the eastern part of the Netherlands, Leegwater et al. (2001) found homozygosity for a 271A-G transition in exon 2 of the EIF2B5 gene, resulting in an amino acid change of threonine to alanine at codon 91 (T91A). </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0002 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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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EIF2B5, TRP628ARG
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<br />
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SNP: rs28937596,
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ClinVar: RCV003221409
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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 leukoencephalopathy with vanishing white matter (VWM5; 620315), Leegwater et al. (2001) found an c.1882T-C transition in exon 14 of the EIF2B5 gene, resulting in a trp628-to-arg (W628R) amino acid substitution. The exon 14 mutation was in compound heterozygous state with the T91A mutation (603945.0001). </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 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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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EIF2B5, GLY386VAL
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<br />
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SNP: rs113994074,
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ClinVar: RCV003221410
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 patients with leukoencephalopathy with vanishing white matter (VWM5; 620315), Leegwater et al. (2001) found compound heterozygosity for a gly386-to-val (G386V) mutation and an arg113-to-his mutation (R113H; 603945.0004) in the EIF2B5 gene. The G386V amino acid substitution was the result of a c.1157G-T transversion that affected the first nucleotide in exon 8 and may have disturbed splicing. The R113H substitution results from a 338G-A transition in the EIF2B5 gene. Leegwater et al. (2001) identified the R113H mutation in 12 families with VWM, with a total allelic frequency of approximately 20% in the group of affected individuals that they investigated. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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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EIF2B5, ARG113HIS
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<br />
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SNP: rs113994049,
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gnomAD: rs113994049,
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ClinVar: RCV000006308, RCV000254893, RCV001420331, RCV003221411, RCV004018575, RCV004755715
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the arg113-to-his (R113H) mutation in the EIF2B5 gene that was found in compound heterozygous state in patients with leukoencephalopathy with vanishing white matter (VWM5; 620315) by Leegwater et al. (2001), see 603945.0003. </p><p>In a woman with adult onset of VWM diagnosed at the age of 27 years, Biancheri et al. (2003) identified homozygosity for the R113H mutation, which they originally incorrectly reported as R118H. </p><p>In 3 of 6 families with VWM and ovarian failure, which the authors designated 'ovarioleukodystrophy,' Fogli et al. (2003) identified the R113H mutation. Patients from these families had the mildest form of the disease. Fogli et al. (2003) stated that the R113H mutation had been found in 22% of chromosomes of 41 patients with VWM (Leegwater et al., 2001). Because R113 is not conserved among species, and because H is found at this position in rat and mouse, they suggested that the homozygous R113H mutation in humans may not strongly affect EIF2B5 function. One patient studied by Fogli et al. (2003), who had early secondary amenorrhea, was a compound heterozygote for the R113H mutation and an arg195-to-cys mutation (R195C; 603945.0007). </p><p>Van der Knaap et al. (2004) identified 6 individuals who were homozygous for the R113H mutation; 2 of them were sibs. Five of the 6 had an unusually mild form of VWM, 4 with a late-adolescent or adult onset, and 1 with childhood onset. One individual was asymptomatic at age 30 years. </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>
|
|
<span class="mim-font">
|
|
<strong>.0005 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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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|
EIF2B5, ARG195HIS
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<br />
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|
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SNP: rs113994054,
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gnomAD: rs113994054,
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ClinVar: RCV000006310, RCV001064868, RCV003221412
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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>Fogli et al. (2002) studied the EIF2B5 gene in 3 patients of 2 Cree families with Cree leukoencephalopathy (VWM5; 620315) and identified a homozygous G-to-A transition at nucleotide 584, resulting in an arg195-to-his (R195H) substitution. They reported an unpublished observation of the same R195H mutation in a CACH/VWM family from the Highlands in Scotland. The northern Quebec Cree first encountered Europeans in the early 1700s; these were Scottish fur traders from the Hudson Bay Trading Company. Fogli et al. (2002) stated that the probands from the 2 Cree families in their report could trace their paternal ancestry to 3 English Hudson Bay Company employees around 1770. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0006 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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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EIF2B5, LEU309VAL
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<br />
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SNP: rs113994061,
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gnomAD: rs113994061,
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ClinVar: RCV000006311, RCV003221413
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In 2 sibs with a severe acute fatal infantile form of leukoencephalopathy with vanishing white matter (VWM5; 620315), Fogli et al. (2002) identified a homozygous 925G-C mutation in the EIF2B5 gene, resulting in a leu309-to-val (L309V) substitution. The unaffected parents were heterozygous for the mutation. </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>.0007 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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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EIF2B5, ARG195CYS
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<br />
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SNP: rs113994055,
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ClinVar: RCV002512827, RCV003221414
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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 VWM and ovarian failure (VWM5; 620315) with early-onset secondary amenorrhea, Fogli et al. (2003) found compound heterozygosity for the arg113-to-his mutation (R113H; 603945.0004) and an arg195-to-cys (R195C) mutation in the EIF2B5 gene. The R195C mutation resulted from a C-to-T transition at nucleotide 583. The authors noted that the R195C mutation involved the same codon as that mutated in Cree leukoencephalopathy, which is caused by homozygosity for arg195 to his (R195H; 603945.0005). </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>.0008 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5, ADULT-ONSET</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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EIF2B5, THR182MET
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<br />
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SNP: rs113994053,
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gnomAD: rs113994053,
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ClinVar: RCV000416181, RCV003221415, RCV003485519
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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 Japanese woman, born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter (VWM5; 620315), Ohtake et al. (2004) identified a homozygous 545C-T transition in exon 4 of the EIF2B5 gene, resulting in a thr182-to-met (T182M) substitution. The patient presented with presenile dementia and psychiatric symptoms. </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>.0009 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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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EIF2B5, ARG315HIS
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<br />
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SNP: rs113994064,
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gnomAD: rs113994064,
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ClinVar: RCV000006314, RCV001070077, RCV003221416
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 4 patients from 2 unrelated families with early-onset leukoencephalopathy with vanishing white matter (VWM5; 620315), Passemard et al. (2007) identified compound heterozygosity for mutations in the EIF2B5 gene. In a brother and sister, they identified a 944G-A transition resulting in an arg315-to-his (R315H) substitution and a 166T-G transversion resulting in a phe56-to-val (F56V; 603945.0010) substitution. In 2 sisters, they identified the R315H mutation and a 167T-G transversion resulting in a phe56-to-cys (F56C; 603945.0011) substitution. In the first family, the 2 sibs had acute neurologic deterioration in infancy following viral infections. Brain MRIs showed severe white matter abnormalities and complete disappearance of hemispheric white matter, respectively. Both developed progressive severe macrocephaly after age 3 years. In the second family, 1 sister who survived beyond age 3 years developed macrocephaly. Passemard et al. (2007) suggested that altered brain water balance may result in swelling of the disease white matter and macrocephaly in some patients with VWM disease. </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>.0010 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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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EIF2B5, PHE56VAL
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<br />
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SNP: rs113994043,
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gnomAD: rs113994043,
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|
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ClinVar: RCV001851695, RCV003221417, RCV004700193
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the phe56-to-val (F56V) mutation in the EIF2B5 gene that was found in compound heterozygous state in patients with leukoencephalopathy with vanishing white matter (VWM5; 620315) by Passemard et al. (2007), see 603945.0009. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0011 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5</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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EIF2B5, PHE56CYS
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<br />
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SNP: rs121908541,
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|
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ClinVar: RCV003221418
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>For discussion of the phe56-to-cys (F56C) mutation in the EIF2B5 gene that was found in compound heterozygous state in patients with leukoencephalopathy with vanishing white matter (VWM5; 620315) by Passemard et al. (2007), see 603945.0009. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 LEUKOENCEPHALOPATHY WITH VANISHING WHITE MATTER 5, ADULT-ONSET</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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EIF2B5, ASP270HIS
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<br />
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SNP: rs397514646,
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|
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gnomAD: rs397514646,
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|
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|
|
|
ClinVar: RCV003221419
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|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 53-year-old Japanese man, born of consanguineous parents, with adult-onset leukoencephalopathy with vanishing white matter (VWM5; 620315), Matsukawa et al. (2011) identified a homozygous 808G-C transversion in the EIF2B5 gene, resulting in an asp270-to-his (D270H) substitution. The mutation was not found in 96 Japanese control individuals. The patient developed progressive gait unsteadiness and miscalculation at age 50. In vitro functional expression studies showed that the GDP/GTP exchange activity of eIF2B containing mutant EIF2B5 was significantly decreased (30% decrease) compared to wildtype, although the decrease was not as much as observed in mutations associated with childhood-onset VWM. The findings suggested that mutations that result in residual eIF2B activity may be associated with a later age at disease onset. </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>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
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</h4>
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<div>
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<p />
|
|
</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">
|
|
Asuru, A. I., Mellor, H., Thomas, N. S. B., Yu, L., Chen, J.-J., Crosby, J. S., Hartson, S. D., Kimball, S. R., Jefferson, L. S., Matts, R. L.
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|
<strong>Cloning and characterization of cDNAs encoding the epsilon-subunit of eukaryotic initiation factor-2B from rabbit and human.</strong>
|
|
Biochim. Biophys. Acta 1307: 309-317, 1996.
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[PubMed: 8688466]
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[Full Text: https://doi.org/10.1016/0167-4781(96)00054-1]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Biancheri, R., Rossi, A., Di Rocco, M., Filocamo, M., Pronk, J. C., van der Knaap, M. S., Tortori-Donati, P.
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|
<strong>Leukoencephalopathy with vanishing white matter: an adult onset case.</strong>
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|
Neurology 61: 1818-1819, 2003. Note: Erratum: Neurology 62: 1242 only, 2004.
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[PubMed: 14694060]
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|
[Full Text: https://doi.org/10.1212/01.wnl.0000098994.35677.3c]
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</p>
|
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Dietrich, J., Lacagnina, M., Gass, D., Richfield, E., Mayer-Proschel, M., Noble, M., Torres, C., Proschel, C.
|
|
<strong>EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy.</strong>
|
|
Nature Med. 11: 277-283, 2005.
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|
[PubMed: 15723074]
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[Full Text: https://doi.org/10.1038/nm1195]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Fogli, A., Dionisi-Vici, C., Deodato, F., Bartuli, A., Boespflug-Tanguy, O., Bertini, E.
|
|
<strong>A severe variant of childhood ataxia with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation.</strong>
|
|
Neurology 59: 1966-1968, 2002.
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|
|
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|
|
[PubMed: 12499492]
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|
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|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000041666.76863.47]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Fogli, A., Rodriguez, D., Eymard-Pierre, E., Bouhour, F., Labauge, P., Meaney, B. F., Zeesman, S., Kaneski, C. R., Schiffmann, R., Boespflug-Tanguy, O.
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|
<strong>Ovarian failure related to eukaryotic initiation factor 2B mutations.</strong>
|
|
Am. J. Hum. Genet. 72: 1544-1550, 2003.
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|
[PubMed: 12707859]
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[Full Text: https://doi.org/10.1086/375404]
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Fogli, A., Schiffmann, R., Bertini, E., Ughetto, S., Combes, P., Eymard- Pierre, E., Kaneski, C. R., Pineda, M., Troncoso, M., Uziel, G., Surtees, R., Pugin, D., Chaunu, M.-P., Rodriguez, D., Boespflug-Tanguy, O.
|
|
<strong>The effect of genotype on the natural history of eIF2B-related leukodystrophies.</strong>
|
|
Neurology 62: 1509-1517, 2004.
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|
|
[PubMed: 15136673]
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|
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|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000123259.67815.db]
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|
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|
|
</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Fogli, A., Schiffmann, R., Hugendubler, L., Combes, P., Bertini, E., Rodriguez, D., Kimball, S. R., Boespflug-Tanguy, O.
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|
<strong>Decreased guanine nucleotide exchange factor activity in eIF2B-mutated patients.</strong>
|
|
Europ. J. Hum. Genet. 12: 561-566, 2004.
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|
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|
|
[PubMed: 15054402]
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[Full Text: https://doi.org/10.1038/sj.ejhg.5201189]
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|
|
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</p>
|
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</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Fogli, A., Wong, K., Eymard-Pierre, E., Wenger, J., Bouffard, J.-P., Goldin, E., Black, D. N., Boespflug-Tanguy, O., Schiffmann, R.
|
|
<strong>Cree leukoencephalopathy and CACH/VWM disease are allelic at the EIF2B5 locus.</strong>
|
|
Ann. Neurol. 52: 506-510, 2002.
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|
|
[PubMed: 12325082]
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[Full Text: https://doi.org/10.1002/ana.10339]
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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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|
Gross, M. B.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 5/28/2015.
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Leegwater, P. A. J., Konst, A. A. M., Kuyt, B., Sandkuijl, L. A., Naidu, S., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S.
|
|
<strong>The gene for leukoencephalopathy with vanishing white matter is located on chromosome 3q27.</strong>
|
|
Am. J. Hum. Genet. 65: 728-734, 1999.
|
|
|
|
|
|
[PubMed: 10441579]
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|
|
[Full Text: https://doi.org/10.1086/302548]
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|
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Leegwater, P. A. J., Vermeulen, G., Konst, A. A. M., Naidu, S., Mulders, J., Visser, A., Kersbergen, P., Mobach, D., Fonds, D., van Berkel, C. G. M., Lemmers, R. J. L. F., Frants, R. R., Oudejans, C. B. M., Schutgens, R. B. H., Pronk, J. C., van der Knaap, M. S.
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<strong>Subunits of the translation initiation factor eiF2B are mutant in leukoencephalopathy with vanishing white matter.</strong>
|
|
Nature Genet. 29: 383-388, 2001.
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|
|
[PubMed: 11704758]
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[Full Text: https://doi.org/10.1038/ng764]
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|
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Matsukawa, T., Wang, X., Liu, R., Wortham, N. C., Onuki, Y., Kubota, A., Hida, A., Kowa, H., Fukuda, Y., Ishiura, H., Mitsui, J., Takahashi, Y., Aoki, S., Takizawa, S., Shimizu, J., Goto, J., Proud, C. G., Tsuji, S.
|
|
<strong>Adult-onset leukoencephalopathies with vanishing white matter with novel missense mutations in EIF2B2, EIF2B3, and EIF2B5.</strong>
|
|
Neurogenetics 12: 259-261, 2011.
|
|
|
|
|
|
[PubMed: 21484434]
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|
|
|
[Full Text: https://doi.org/10.1007/s10048-011-0284-7]
|
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|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ohtake, H., Shimohata, T., Terajima, K., Kimura, T., Jo, R., Kaseda, R., Iizuka, O., Takano, M., Akaiwa, Y., Goto, H., Kobayashi, H., Sugai, T., Muratake, T., Hosoki, T., Shioiri, T., Okamoto, K., Onodera, O., Tanaka, K., Someya, T., Nakada, T., Tsuji, S.
|
|
<strong>Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5.</strong>
|
|
Neurology 62: 1601-1603, 2004.
|
|
|
|
|
|
[PubMed: 15136690]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000123117.11264.0e]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Passemard, S., Gelot, A., Fogli, A., N'Guyen, S., Barnerias, C., Niel, F., Doummar, D., Arbues, A.-S., Mignot, C., Billette de Villemeur, T., Ponsot, G., Boespflug-Tanguy, O., Rodriguez, D.
|
|
<strong>Progressive megalencephaly due to specific EIF2B-epsilon mutations in two unrelated families.</strong>
|
|
Neurology 69: 400-402, 2007.
|
|
|
|
|
|
[PubMed: 17646634]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000266388.02772.f8]
|
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|
|
</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Tsai, J. C., Miller-Vedam, L. E., Anand, A. A., Jaishankar, P., Nguyen, H. C., Renslo, A. R., Frost, A., Walter, P.
|
|
<strong>Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule.</strong>
|
|
Science 359: eaaq0939, 2018. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 29599213]
|
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|
|
[Full Text: https://doi.org/10.1126/science.aaq0939]
|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
van der Knaap, M. S, Leegwater, P. A. J., van Berkel, C. G. M., Brenner, C., Storey, E., Di Rocco, M., Salvi, F., Pronk, J. C.
|
|
<strong>Arg113his mutation in eIF2B-epsilon as cause of leukoencephalopathy in adults.</strong>
|
|
Neurology 62: 1598-1600, 2004.
|
|
|
|
|
|
[PubMed: 15136689]
|
|
|
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|
|
[Full Text: https://doi.org/10.1212/01.wnl.0000123118.86746.fc]
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
van der Knaap, M. S., van Berkel, C. G. M., Herms, J., van Coster, R., Baethmann, M., Naidu, S., Boltshauser, E., Willemsen, M. A. A. P., Plecko, B., Hoffmann, G. F., Proud, C. G., Scheper, G. C., Pronk, J. C.
|
|
<strong>eIF2B-related disorders: antenatal onset and involvement of multiple organs.</strong>
|
|
Am. J. Hum. Genet. 73: 1199-1207, 2003.
|
|
|
|
|
|
[PubMed: 14566705]
|
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|
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|
|
[Full Text: https://doi.org/10.1086/379524]
|
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|
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</p>
|
|
</li>
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<li>
|
|
<p class="mim-text-font">
|
|
van der Lei, H. D. W., van Berkel, C. G. M., van Wieringen, W. N., Brenner, C., Feigenbaum, A., Mercimek-Mahmutoglu, S., Philippart, M., Tatli, B., Wassmer, E., Scheper, G. C., van der Knaap, M. S.
|
|
<strong>Genotype-phenotype correlation in vanishing white matter disease.</strong>
|
|
Neurology 75: 1555-1559, 2010.
|
|
|
|
|
|
[PubMed: 20975056]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1212/WNL.0b013e3181f962ae]
|
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|
</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Wu, Y., Pan, Y., Du, L., Wang, J., Gu, Q., Gao, Z., Li, J., Leng, X., Qin, J., Wu, X., Jiang, Y.
|
|
<strong>Identification of novel EIF2B mutations in Chinese patients with vanishing white matter disease.</strong>
|
|
J. Hum. Genet. 54: 74-77, 2009.
|
|
|
|
|
|
[PubMed: 19158808]
|
|
|
|
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[Full Text: https://doi.org/10.1038/jhg.2008.10]
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Ada Hamosh - updated : 07/23/2018<br>Matthew B. Gross - updated : 5/28/2015<br>Cassandra L. Kniffin - updated : 2/13/2013<br>Cassandra L. Kniffin - updated : 11/13/2012<br>Cassandra L. Kniffin - updated : 6/26/2009<br>Cassandra L. Kniffin - updated : 12/4/2007<br>Marla J. F. O'Neill - updated : 3/28/2005<br>Marla J. F. O'Neill - updated : 2/8/2005<br>Cassandra L. Kniffin - updated : 1/31/2005<br>Cassandra L. Kniffin - updated : 2/3/2004<br>Victor A. McKusick - updated : 12/12/2003<br>Victor A. McKusick - updated : 5/23/2003<br>Cassandra L. Kniffin - updated : 2/13/2003<br>Victor A. McKusick - updated : 11/19/2002<br>Paul J. Converse - updated : 2/19/2002<br>Victor A. McKusick - updated : 11/12/2001
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Rebekah S. Rasooly : 6/29/1999
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