3226 lines
226 KiB
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3226 lines
226 KiB
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Entry
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- *605600 - IMPORTIN 8; IPO8
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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">*605600</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/605600">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000133704;t=ENST00000256079" 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=10526" 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=605600" 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=ENSG00000133704;t=ENST00000256079" 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_001190995,NM_006390,XM_017018691,XM_017018692,XM_017018693" 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_006390" 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=605600" 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=09282&isoform_id=09282_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/IPO8" 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/2337918,53759103,62088784,119617013,221043964,229462885,300360505,1034577590,1034577592,1034577594,2462529319,2462529321,2462529323,2462529325" 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/O15397" 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=10526" 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=ENSG00000133704;t=ENST00000256079" 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=IPO8" 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=IPO8" 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+10526" 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/IPO8" 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:10526" 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/10526" 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=chr12&hgg_gene=ENST00000256079.9&hgg_start=30628988&hgg_end=30695869&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://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=605600[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=605600[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/ENSG00000133704" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=IPO8" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=IPO8" 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=IPO8" 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=IPO8&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/PA34214" 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:9853" 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/FBgn0026252.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:2444611" 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/IPO8#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:2444611" 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/10526/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=10526" 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://zfin.org/ZDB-GENE-060503-3" 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">
|
|
<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">
|
|
<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
|
<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
|
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|
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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:10526" 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=IPO8&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>
|
|
605600
|
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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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IMPORTIN 8; IPO8
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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">
|
|
<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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
IMP8<br />
|
|
RAN-BINDING PROTEIN 8; RANBP8
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=IPO8" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">IPO8</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">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/12/266?start=-3&limit=10&highlight=266">12p11.21</a>
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|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:30628988-30695869&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'})">12:30,628,988-30,695,869</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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|
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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">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
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Location
|
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</th>
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<th>
|
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Phenotype
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</th>
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<th>
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|
Phenotype <br /> MIM number
|
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</th>
|
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<th>
|
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Inheritance
|
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</th>
|
|
<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>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/266?start=-3&limit=10&highlight=266">
|
|
12p11.21
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
VISS syndrome
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/619472"> 619472 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<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>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
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</span>
|
|
</td>
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</tr>
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</tbody>
|
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/605600" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/605600" 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>
|
|
|
|
<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
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<div>
|
|
<a id="cloning" class="mim-anchor"></a>
|
|
<h4 href="#mimCloningFold" id="mimCloningToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimCloningToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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|
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<div id="mimCloningFold" class="collapse in mimTextToggleFold">
|
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<span class="mim-text-font">
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<p>RAN (<a href="/entry/601179">601179</a>) is a Ras-related small GTP-binding protein that plays a key role in nuclear localization signal (NLS)-dependent protein import. By searching EST databases for sequences homologous to the Xenopus Ran-binding protein RanBP7 (<a href="/entry/605586">605586</a>), <a href="#2" class="mim-tip-reference" title="Gorlich, D., Dabrowski, M., Bischoff, F. R., Kutay, U., Bork, P., Hartmann, E., Prehn, S., Izaurralde, E. <strong>A novel class of RanGTP binding proteins.</strong> J. Cell Biol. 138: 65-80, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9214382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9214382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9214382[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/10.1083/jcb.138.1.65" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9214382">Gorlich et al. (1997)</a> identified a Ran-binding protein that they designated RANBP8 and cloned the cDNA from a HeLa cDNA library. Human RANBP8 and Xenopus RanBP7 share 61% amino acid identity. They both belong to a Ran-binding protein superfamily whose members share with importin-beta (<a href="/entry/602738">602738</a>) an N-terminal sequence motif that appears to account for RanGTP binding. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9214382" 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="Weinmann, L., Hock, J., Ivacevic, T., Ohrt, T., Mutze, J., Schwille, P., Kremmer, E., Benes, V., Urlaub, H., Meister, G. <strong>Importin 8 is a gene silencing factor that targets Argonaute proteins to distinct mRNAs.</strong> Cell 136: 496-507, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19167051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19167051</a>] [<a href="https://doi.org/10.1016/j.cell.2008.12.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19167051">Weinmann et al. (2009)</a> found that epitope-tagged IPO8 localized to the nucleus and to cytoplasmic RNA processing bodies (P bodies) and stress granules in transfected human embryonic kidney cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19167051" 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="Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others. <strong>Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.</strong> Am. J. Hum. Genet. 108: 1126-1137, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010604</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010604">Ziegler et al. (2021)</a> stated that the IPO8 gene encodes a 1,037-amino acid protein with an N-terminal beta-importin domain (amino acids 22-102) and a CSE1-like domain (amino acids 202-441) containing a RanGTPase-binding motif characteristic of beta-importins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010604" 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="#6" class="mim-tip-reference" title="Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others. <strong>Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.</strong> Am. J. Hum. Genet. 108: 1126-1137, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010604</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010604">Ziegler et al. (2021)</a> stated that the IPO8 gene contains 25 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010604" 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="#3" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 08/05/2021."None>Stumpf (2021)</a> mapped the IPO8 gene to chromosome 12p11.21 based on an alignment of the IPO8 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC167853" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC167853</a>) with the genomic sequence (GRCh38).</p>
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<p>By fluorescence labeling in Xenopus, <a href="#2" class="mim-tip-reference" title="Gorlich, D., Dabrowski, M., Bischoff, F. R., Kutay, U., Bork, P., Hartmann, E., Prehn, S., Izaurralde, E. <strong>A novel class of RanGTP binding proteins.</strong> J. Cell Biol. 138: 65-80, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9214382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9214382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9214382[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/10.1083/jcb.138.1.65" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9214382">Gorlich et al. (1997)</a> showed that RanBP8 bound to the nuclear pore complex. Like importin-beta and RanBP7, RanBP8 formed a trimeric complex with RanGTP (<a href="/entry/602362">602362</a>) and RANBP1 (<a href="/entry/601180">601180</a>) and inhibited the GAP stimulation of the Ran GTPase. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9214382" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using protein pull-down assays and immunoprecipitation analysis, <a href="#5" class="mim-tip-reference" title="Weinmann, L., Hock, J., Ivacevic, T., Ohrt, T., Mutze, J., Schwille, P., Kremmer, E., Benes, V., Urlaub, H., Meister, G. <strong>Importin 8 is a gene silencing factor that targets Argonaute proteins to distinct mRNAs.</strong> Cell 136: 496-507, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19167051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19167051</a>] [<a href="https://doi.org/10.1016/j.cell.2008.12.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19167051">Weinmann et al. (2009)</a> found that IPO8 interacted in an RAN-dependent manner with argonaute (AGO) proteins, which are involved in microRNA (miRNA) processing and function. Knockdown of IMP8 in HeLa or HEK293 cells resulted in redistribution of AGO2 (EIF2C2; <a href="/entry/606229">606229</a>) from the nucleus to the cytoplasm. IPO8 was required for AGO2 binding to a large set of target mRNAs, and knockdown of IPO8 led to a moderate increase of target mRNAs. Knockdown of IPO8 had no effect on AGO stability, miRNA biogenesis, or miRNA loading onto AGO proteins. <a href="#5" class="mim-tip-reference" title="Weinmann, L., Hock, J., Ivacevic, T., Ohrt, T., Mutze, J., Schwille, P., Kremmer, E., Benes, V., Urlaub, H., Meister, G. <strong>Importin 8 is a gene silencing factor that targets Argonaute proteins to distinct mRNAs.</strong> Cell 136: 496-507, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19167051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19167051</a>] [<a href="https://doi.org/10.1016/j.cell.2008.12.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19167051">Weinmann et al. (2009)</a> concluded that IPO8 is required for miRNA-guided gene silencing and affects nuclear localization of AGO proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19167051" 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 6 unrelated probands with early-onset vascular aneurysm, skeletal anomalies, and skin and joint laxity (VISS syndrome; <a href="/entry/619472">619472</a>), <a href="#4" class="mim-tip-reference" title="Van Gucht, I., Meester, J. A. N., Bento, J. R., Bastiaansen, M., Bastianen, J., Luyckx, I., Van Den Heuvel, L., Neutel, C. H. G., Guns, P.-J., Vermont, M., Fransen, E., Perik, M. H. A. M., and 36 others. <strong>A human importin-beta-related disorder: syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.</strong> Am. J. Hum. Genet. 108: 1115-1125, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010605</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010605">Van Gucht et al. (2021)</a> identified homozygosity or compound heterozygosity for truncating mutations in the IPO8 gene (see, e.g., <a href="#0001">605600.0001</a>-<a href="#0004">605600.0004</a>) that segregated with disease in the respective families and were not found in the gnomAD database or were present at very low minor allele frequency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 12 patients from 9 families with VISS syndrome, <a href="#6" class="mim-tip-reference" title="Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others. <strong>Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.</strong> Am. J. Hum. Genet. 108: 1126-1137, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010604</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010604">Ziegler et al. (2021)</a> reported biallelic missense or truncating mutations in the IPO8 gene (see, e.g., <a href="#0002">605600.0002</a> and <a href="#0005">605600.0005</a>-<a href="#0006">605600.0006</a>) that segregated with disease and were not found in the gnomAD database or were present at very low minor allele frequency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By combining exome/genome sequencing with data repository analysis, <a href="#1" class="mim-tip-reference" title="Bertoli-Avella, A. M., Kandaswamy, K. K., Khan, S., Ordonez-Herrera, N., Tripolszki, K., Beetz, C., Rocha, M. E., Urzi, A., Hotakainen, R., Leubauer, A., Al-Ali, R., Karageorgou, V., and 25 others. <strong>Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders.</strong> Genet. Med. 23: 1551-1568, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33875846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33875846</a>] [<a href="https://doi.org/10.1038/s41436-021-01159-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33875846">Bertoli-Avella et al. (2021)</a> identified 9 unrelated patients with VISS syndrome and mutations in the IPO8 gene (see, e.g., <a href="#0001">605600.0001</a> and <a href="#0007">605600.0007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33875846" 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="#4" class="mim-tip-reference" title="Van Gucht, I., Meester, J. A. N., Bento, J. R., Bastiaansen, M., Bastianen, J., Luyckx, I., Van Den Heuvel, L., Neutel, C. H. G., Guns, P.-J., Vermont, M., Fransen, E., Perik, M. H. A. M., and 36 others. <strong>A human importin-beta-related disorder: syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.</strong> Am. J. Hum. Genet. 108: 1115-1125, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010605</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010605">Van Gucht et al. (2021)</a> studied Ipo8 -/- mice by serial transthoracic echocardiography from age 4 weeks to 32 weeks and observed statistically significant dilatation of the aortic root and the distal ascending aorta in mutant mice compared to controls, with aneurysms of the distal ascending aorta visible at the age of 8 to 12 weeks. Aortic root enlargement was present in both mutant males and females, but ascending aortic aneurysm was very pronounced and statistically significant only in mutant males. Animals were kept alive until 48 weeks of age, during which time 3 homozygous mutant males died from aortic rupture, whereas no rupture-related mortality was observed in homozygous mutant females or wildtype mice. Compliance assays suggested augmented passive stiffness of the ascending aorta in male Ipo8-null mice throughout life. Immunohistologic investigation of mutant aortic walls revealed elastic fiber disorganization and fragmentation along with a signature of increased TGF-beta (<a href="/entry/190180">190180</a>) signaling, as evidenced by nuclear phosphorylated Smad2 (<a href="/entry/601366">601366</a>) accumulation. RT-qPCR assays of the aortic wall in mutant males demonstrated decreased Smad6 (<a href="/entry/602931">602931</a>)/7 (<a href="/entry/602932">602932</a>) and increased Mmp2 (<a href="/entry/120360">120360</a>) and Ccn2 (<a href="/entry/121009">121009</a>) expression, supporting a role for dysregulation of the TGF-beta signaling pathway in development of thoracic aortic aneurysms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010605" 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="Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others. <strong>Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.</strong> Am. J. Hum. Genet. 108: 1126-1137, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010604</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010604">Ziegler et al. (2021)</a> generated ipo8 -/- zebrafish and observed embryos that were ovoid rather than round, with a tail bud that failed to extend around the yolk, resulting in elongated pear-shaped embryos. These morphologic changes correlated with an increased death rate. As development proceeded, a range of tail elongation defects became apparent, and by 3 days postfertilization (dpf), most embryos developed cardiac edema. Analysis of heart and vessel morphology at 2 dpf revealed severe defects in heart chamber formation, with atrial and ventricular chambers being less or not delimited in ipo8 -/- mutants. The mutants also exhibited arteriovenous malformations in the head as well as abnormal arteriovenious connections in the dorsal midline junction, and poorly differentiated central arteries that appeared irregular, thin, and poorly lumenized. By 3 dpf, in addition to heart edema, there were blood vessel patterning abnormalities that resulted in absent or abnormal blood flow in the tail region. <a href="#6" class="mim-tip-reference" title="Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others. <strong>Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.</strong> Am. J. Hum. Genet. 108: 1126-1137, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010604</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010604">Ziegler et al. (2021)</a> noted that early dorsoventral patterning defects are a telltale sign of altered TGFB/BMP (see <a href="/entry/112264">112264</a>) signaling, and they detected significantly reduced nuclear localization of phosphorylated Smad1 (<a href="/entry/601595">601595</a>)/5 (<a href="/entry/603110">603110</a>)/9 (<a href="/entry/603295">603295</a>). Pathway enrichment analysis revealed that genes differentially regulated upon ipo8 depletion encode multiple components of the TGFB/BMP pathway as well as genes involved in angiotensin (see <a href="/entry/106150">106150</a>)/angiogenesis pathways. Expression of smad7, a direct transcriptional target of the TGFB/BMP pathway, was strongly decreased in ipo8 -/- embryos compared to wildtype at 13 and 24 hpf. The authors concluded that importin-8 plays a critical role during the early stage of development by controlling phosphorylated Smad nuclear translocation and downstream TGFB/BMP-dependent transcription, and that the model supports a causative role for IPO8 deficiency in the vascular and skeletal defects observed in affected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=605600[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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<p>In 2 Saudi-Arabian brothers (family 4), ages 6 years and 10 years, with VISS syndrome (VISS; <a href="/entry/619472">619472</a>), <a href="#4" class="mim-tip-reference" title="Van Gucht, I., Meester, J. A. N., Bento, J. R., Bastiaansen, M., Bastianen, J., Luyckx, I., Van Den Heuvel, L., Neutel, C. H. G., Guns, P.-J., Vermont, M., Fransen, E., Perik, M. H. A. M., and 36 others. <strong>A human importin-beta-related disorder: syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.</strong> Am. J. Hum. Genet. 108: 1115-1125, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010605</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010605">Van Gucht et al. (2021)</a> identified homozygosity for a c.776G-A transition (c.776G-A, NM_006390.3) in the IPO8 gene, resulting in a trp259-to-ter (W259X) substitution. Their unaffected consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010605" 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 unrelated patients (patients 8, 9, and 12) with VISS syndrome, <a href="#1" class="mim-tip-reference" title="Bertoli-Avella, A. M., Kandaswamy, K. K., Khan, S., Ordonez-Herrera, N., Tripolszki, K., Beetz, C., Rocha, M. E., Urzi, A., Hotakainen, R., Leubauer, A., Al-Ali, R., Karageorgou, V., and 25 others. <strong>Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders.</strong> Genet. Med. 23: 1551-1568, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33875846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33875846</a>] [<a href="https://doi.org/10.1038/s41436-021-01159-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33875846">Bertoli-Avella et al. (2021)</a> identified homozygosity for the W259X mutation in the IPO8 gene. Familial segregation was not reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33875846" 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 a 19-year-old man (family 6) with VISS syndrome (VISS; <a href="/entry/619472">619472</a>), <a href="#4" class="mim-tip-reference" title="Van Gucht, I., Meester, J. A. N., Bento, J. R., Bastiaansen, M., Bastianen, J., Luyckx, I., Van Den Heuvel, L., Neutel, C. H. G., Guns, P.-J., Vermont, M., Fransen, E., Perik, M. H. A. M., and 36 others. <strong>A human importin-beta-related disorder: syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.</strong> Am. J. Hum. Genet. 108: 1115-1125, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010605</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010605">Van Gucht et al. (2021)</a> identified homozygosity for a splicing mutation (c.2900-1G-A, NM_006390.3) in the IPO8 gene, predicted to result in a deletion/insertion (Thr967_Glu1006delinsLys). His unaffected first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010605" 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 33-year-old Australian woman (family 7, patient I-10) with VISS syndrome, <a href="#6" class="mim-tip-reference" title="Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others. <strong>Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.</strong> Am. J. Hum. Genet. 108: 1126-1137, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010604</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010604">Ziegler et al. (2021)</a> identified compound heterozygosity for the c.2900-1G-A splicing mutation in intron 23 of the IPO8 gene, and a 1-bp deletion (c.2279delT; <a href="#0005">605600.0005</a>), causing a frameshift predicted to result in a premature termination codon (Leu760ProfsTer10) in the IPO8 gene. Her unaffected parents were each heterozygous for 1 of the mutations. The 1-bp deletion was present at very low frequency in the gnomAD database (1.06 x 10(-5), no homozygotes). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In an 8-year-old girl (family 3) with VISS syndrome (VISS; <a href="/entry/619472">619472</a>), <a href="#4" class="mim-tip-reference" title="Van Gucht, I., Meester, J. A. N., Bento, J. R., Bastiaansen, M., Bastianen, J., Luyckx, I., Van Den Heuvel, L., Neutel, C. H. G., Guns, P.-J., Vermont, M., Fransen, E., Perik, M. H. A. M., and 36 others. <strong>A human importin-beta-related disorder: syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.</strong> Am. J. Hum. Genet. 108: 1115-1125, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010605</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010605">Van Gucht et al. (2021)</a> identified compound heterozygosity for a splicing mutation (c.1428+5G-A, NM_006390.3) in intron 12 of the IPO8 gene, causing skipping of exon 13 and a predicted in-frame deletion of 30 amino acids (Lys447_Arg476del), and a 5-bp deletion (c.2597_2601delTTTTC; <a href="#0004">605600.0004</a>), causing a frameshift predicted to result in an premature termination codon (Leu866ProfsTer12). Her unaffected parents were each heterozygous for 1 of the mutations. The splicing mutation was not found in the gnomAD database, whereas the 5-bp deletion was present at very low minor allele frequency (1 of 250,920 alleles). Analysis of cDNA from puromycin-treated and untreated patient fibroblasts indicated that the 5-bp mutation results in nonsense-mediated decay; Sanger sequencing of the RT-PCR produced from blood-derived cDNA confirmed in-frame skipping of exon 13 with the splicing mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010605" 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">rs1565492786 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565492786;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=rs1565492786" 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=rs1565492786" 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=RCV001507275 OR RCV001553798" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001507275, RCV001553798" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001507275...</a>
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<p>For discussion of the 5-bp deletion (c.2597_2601delTTTTC, NM_006390.3) in the IPO8 gene that was found in compound heterozygous state in an 8-year-old girl (family 3) with VISS syndrome (VISS; <a href="/entry/619472">619472</a>) by <a href="#4" class="mim-tip-reference" title="Van Gucht, I., Meester, J. A. N., Bento, J. R., Bastiaansen, M., Bastianen, J., Luyckx, I., Van Den Heuvel, L., Neutel, C. H. G., Guns, P.-J., Vermont, M., Fransen, E., Perik, M. H. A. M., and 36 others. <strong>A human importin-beta-related disorder: syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.</strong> Am. J. Hum. Genet. 108: 1115-1125, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010605</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.019" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010605">Van Gucht et al. (2021)</a>, see <a href="#0003">605600.0003</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010605" 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> rs775937664 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs775937664;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/rs775937664?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=rs775937664" 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=rs775937664" 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=RCV001553799 OR RCV001731205" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001553799, RCV001731205" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001553799...</a>
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<p>For discussion of the 1-bp deletion (c.2279delT, NM_006390.3) in the IPO8 gene, causing a frameshift predicted to result in an premature termination codon (Leu760ProfsTer10), that was found in compound heterozygous state in an 8-year-old Australian girl (family 7, patient I-10) with VISS syndrome (VISS; <a href="/entry/619472">619472</a>) by <a href="#6" class="mim-tip-reference" title="Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others. <strong>Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.</strong> Am. J. Hum. Genet. 108: 1126-1137, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010604</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010604">Ziegler et al. (2021)</a>, see <a href="#0002">605600.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010604" 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> rs1234764565 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1234764565;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/rs1234764565?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=rs1234764565" 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=rs1234764565" 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=RCV001553800 OR RCV001731198" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001553800, RCV001731198" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001553800...</a>
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<p>In an Ashkenazi brother and sister (family 1, patients I-1 and I-2) with VISS syndrome (VISS; <a href="/entry/619472">619472</a>), <a href="#6" class="mim-tip-reference" title="Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others. <strong>Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.</strong> Am. J. Hum. Genet. 108: 1126-1137, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010604</a>] [<a href="https://doi.org/10.1016/j.ajhg.2021.04.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34010604">Ziegler et al. (2021)</a> identified homozygosity for a c.262G-A transition (c.262G-A, NM_006390.3) in the IPO8 gene, resulting in an asp88-to-asn (D88N) substitution at a highly conserved residue within the N-terminal domain. Their unaffected sister was heterozygous for the mutation, which was not found in the gnomAD database; DNA was unavailable from their deceased consanguineous parents. Immunoblot analysis of protein lysates from patient fibroblasts showed a striking reduction in IPO8 compared to control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010604" 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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IPO8, 5-BP DEL, NT2965+4
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs2136125267 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2136125267;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=rs2136125267" 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=rs2136125267" 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=RCV001553801" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001553801" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001553801</a>
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<p>In 2 unrelated patients (patients 7 and 11) with VISS syndrome (VISS; <a href="/entry/619472">619472</a>), <a href="#1" class="mim-tip-reference" title="Bertoli-Avella, A. M., Kandaswamy, K. K., Khan, S., Ordonez-Herrera, N., Tripolszki, K., Beetz, C., Rocha, M. E., Urzi, A., Hotakainen, R., Leubauer, A., Al-Ali, R., Karageorgou, V., and 25 others. <strong>Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders.</strong> Genet. Med. 23: 1551-1568, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33875846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33875846</a>] [<a href="https://doi.org/10.1038/s41436-021-01159-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33875846">Bertoli-Avella et al. (2021)</a> identified homozygosity for a 5-bp deletion (c.2695+4_2695+8del) in the IPO8 gene. Familial segregation and functional analysis were not reported. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33875846" 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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Bertoli-Avella, A. M., Kandaswamy, K. K., Khan, S., Ordonez-Herrera, N., Tripolszki, K., Beetz, C., Rocha, M. E., Urzi, A., Hotakainen, R., Leubauer, A., Al-Ali, R., Karageorgou, V., and 25 others.
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<strong>Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders.</strong>
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Genet. Med. 23: 1551-1568, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33875846/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33875846</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33875846" 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/s41436-021-01159-0" target="_blank">Full Text</a>]
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Gorlich, D., Dabrowski, M., Bischoff, F. R., Kutay, U., Bork, P., Hartmann, E., Prehn, S., Izaurralde, E.
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<strong>A novel class of RanGTP binding proteins.</strong>
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J. Cell Biol. 138: 65-80, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9214382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9214382</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9214382[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=9214382" 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/10.1083/jcb.138.1.65" target="_blank">Full Text</a>]
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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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Baltimore, Md. 08/05/2021.
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Van Gucht, I., Meester, J. A. N., Bento, J. R., Bastiaansen, M., Bastianen, J., Luyckx, I., Van Den Heuvel, L., Neutel, C. H. G., Guns, P.-J., Vermont, M., Fransen, E., Perik, M. H. A. M., and 36 others.
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<strong>A human importin-beta-related disorder: syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.</strong>
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Am. J. Hum. Genet. 108: 1115-1125, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010605</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2021.04.019" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
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<a id="Weinmann2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Weinmann, L., Hock, J., Ivacevic, T., Ohrt, T., Mutze, J., Schwille, P., Kremmer, E., Benes, V., Urlaub, H., Meister, G.
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<strong>Importin 8 is a gene silencing factor that targets Argonaute proteins to distinct mRNAs.</strong>
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Cell 136: 496-507, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19167051/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19167051</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19167051" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2008.12.023" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="6" class="mim-anchor"></a>
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<a id="Ziegler2021" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others.
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<strong>Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.</strong>
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Am. J. Hum. Genet. 108: 1126-1137, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34010604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34010604</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34010604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2021.04.020" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 08/05/2021
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<span class="mim-text-font">
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Marla J. F. O'Neill - updated : 08/05/2021<br>Patricia A. Hartz - updated : 04/07/2009
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</span>
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</div>
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</div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</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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Yen-Pei C. Chang : 1/29/2001
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 08/12/2021
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<div class="row collapse" id="mimCollapseEditHistory">
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<span class="mim-text-font">
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alopez : 08/10/2021<br>alopez : 08/05/2021<br>alopez : 08/05/2021<br>mgross : 04/07/2009<br>carol : 3/13/2003<br>carol : 12/19/2001<br>carol : 2/5/2001<br>cwells : 1/30/2001<br>cwells : 1/29/2001
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<h3>
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<span class="mim-font">
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<strong>*</strong> 605600
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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IMPORTIN 8; IPO8
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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IMP8<br />
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RAN-BINDING PROTEIN 8; RANBP8
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</span>
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</h4>
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</div>
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<div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: IPO8</em></strong>
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</span>
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<strong>
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<em>
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Cytogenetic location: 12p11.21
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:30,628,988-30,695,869 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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<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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<table class="table table-bordered table-condensed small mim-table-padding">
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Location
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</th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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<tbody>
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<td rowspan="1">
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<span class="mim-font">
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12p11.21
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</td>
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<td>
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<span class="mim-font">
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VISS syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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619472
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<td>
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<span class="mim-font">
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Autosomal recessive
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>RAN (601179) is a Ras-related small GTP-binding protein that plays a key role in nuclear localization signal (NLS)-dependent protein import. By searching EST databases for sequences homologous to the Xenopus Ran-binding protein RanBP7 (605586), Gorlich et al. (1997) identified a Ran-binding protein that they designated RANBP8 and cloned the cDNA from a HeLa cDNA library. Human RANBP8 and Xenopus RanBP7 share 61% amino acid identity. They both belong to a Ran-binding protein superfamily whose members share with importin-beta (602738) an N-terminal sequence motif that appears to account for RanGTP binding. </p><p>Weinmann et al. (2009) found that epitope-tagged IPO8 localized to the nucleus and to cytoplasmic RNA processing bodies (P bodies) and stress granules in transfected human embryonic kidney cells. </p><p>Ziegler et al. (2021) stated that the IPO8 gene encodes a 1,037-amino acid protein with an N-terminal beta-importin domain (amino acids 22-102) and a CSE1-like domain (amino acids 202-441) containing a RanGTPase-binding motif characteristic of beta-importins. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Ziegler et al. (2021) stated that the IPO8 gene contains 25 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Stumpf (2021) mapped the IPO8 gene to chromosome 12p11.21 based on an alignment of the IPO8 sequence (GenBank BC167853) with the genomic sequence (GRCh38).</p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By fluorescence labeling in Xenopus, Gorlich et al. (1997) showed that RanBP8 bound to the nuclear pore complex. Like importin-beta and RanBP7, RanBP8 formed a trimeric complex with RanGTP (602362) and RANBP1 (601180) and inhibited the GAP stimulation of the Ran GTPase. </p><p>Using protein pull-down assays and immunoprecipitation analysis, Weinmann et al. (2009) found that IPO8 interacted in an RAN-dependent manner with argonaute (AGO) proteins, which are involved in microRNA (miRNA) processing and function. Knockdown of IMP8 in HeLa or HEK293 cells resulted in redistribution of AGO2 (EIF2C2; 606229) from the nucleus to the cytoplasm. IPO8 was required for AGO2 binding to a large set of target mRNAs, and knockdown of IPO8 led to a moderate increase of target mRNAs. Knockdown of IPO8 had no effect on AGO stability, miRNA biogenesis, or miRNA loading onto AGO proteins. Weinmann et al. (2009) concluded that IPO8 is required for miRNA-guided gene silencing and affects nuclear localization of AGO proteins. </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>In 6 unrelated probands with early-onset vascular aneurysm, skeletal anomalies, and skin and joint laxity (VISS syndrome; 619472), Van Gucht et al. (2021) identified homozygosity or compound heterozygosity for truncating mutations in the IPO8 gene (see, e.g., 605600.0001-605600.0004) that segregated with disease in the respective families and were not found in the gnomAD database or were present at very low minor allele frequency. </p><p>In 12 patients from 9 families with VISS syndrome, Ziegler et al. (2021) reported biallelic missense or truncating mutations in the IPO8 gene (see, e.g., 605600.0002 and 605600.0005-605600.0006) that segregated with disease and were not found in the gnomAD database or were present at very low minor allele frequency. </p><p>By combining exome/genome sequencing with data repository analysis, Bertoli-Avella et al. (2021) identified 9 unrelated patients with VISS syndrome and mutations in the IPO8 gene (see, e.g., 605600.0001 and 605600.0007). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Van Gucht et al. (2021) studied Ipo8 -/- mice by serial transthoracic echocardiography from age 4 weeks to 32 weeks and observed statistically significant dilatation of the aortic root and the distal ascending aorta in mutant mice compared to controls, with aneurysms of the distal ascending aorta visible at the age of 8 to 12 weeks. Aortic root enlargement was present in both mutant males and females, but ascending aortic aneurysm was very pronounced and statistically significant only in mutant males. Animals were kept alive until 48 weeks of age, during which time 3 homozygous mutant males died from aortic rupture, whereas no rupture-related mortality was observed in homozygous mutant females or wildtype mice. Compliance assays suggested augmented passive stiffness of the ascending aorta in male Ipo8-null mice throughout life. Immunohistologic investigation of mutant aortic walls revealed elastic fiber disorganization and fragmentation along with a signature of increased TGF-beta (190180) signaling, as evidenced by nuclear phosphorylated Smad2 (601366) accumulation. RT-qPCR assays of the aortic wall in mutant males demonstrated decreased Smad6 (602931)/7 (602932) and increased Mmp2 (120360) and Ccn2 (121009) expression, supporting a role for dysregulation of the TGF-beta signaling pathway in development of thoracic aortic aneurysms. </p><p>Ziegler et al. (2021) generated ipo8 -/- zebrafish and observed embryos that were ovoid rather than round, with a tail bud that failed to extend around the yolk, resulting in elongated pear-shaped embryos. These morphologic changes correlated with an increased death rate. As development proceeded, a range of tail elongation defects became apparent, and by 3 days postfertilization (dpf), most embryos developed cardiac edema. Analysis of heart and vessel morphology at 2 dpf revealed severe defects in heart chamber formation, with atrial and ventricular chambers being less or not delimited in ipo8 -/- mutants. The mutants also exhibited arteriovenous malformations in the head as well as abnormal arteriovenious connections in the dorsal midline junction, and poorly differentiated central arteries that appeared irregular, thin, and poorly lumenized. By 3 dpf, in addition to heart edema, there were blood vessel patterning abnormalities that resulted in absent or abnormal blood flow in the tail region. Ziegler et al. (2021) noted that early dorsoventral patterning defects are a telltale sign of altered TGFB/BMP (see 112264) signaling, and they detected significantly reduced nuclear localization of phosphorylated Smad1 (601595)/5 (603110)/9 (603295). Pathway enrichment analysis revealed that genes differentially regulated upon ipo8 depletion encode multiple components of the TGFB/BMP pathway as well as genes involved in angiotensin (see 106150)/angiogenesis pathways. Expression of smad7, a direct transcriptional target of the TGFB/BMP pathway, was strongly decreased in ipo8 -/- embryos compared to wildtype at 13 and 24 hpf. The authors concluded that importin-8 plays a critical role during the early stage of development by controlling phosphorylated Smad nuclear translocation and downstream TGFB/BMP-dependent transcription, and that the model supports a causative role for IPO8 deficiency in the vascular and skeletal defects observed in affected individuals. </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>7 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 VISS SYNDROME</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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IPO8, TRP259TER
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<br />
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SNP: rs2136163716,
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ClinVar: RCV001507276, RCV001553795
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
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<p>In 2 Saudi-Arabian brothers (family 4), ages 6 years and 10 years, with VISS syndrome (VISS; 619472), Van Gucht et al. (2021) identified homozygosity for a c.776G-A transition (c.776G-A, NM_006390.3) in the IPO8 gene, resulting in a trp259-to-ter (W259X) substitution. Their unaffected consanguineous parents were heterozygous for the mutation, which was not found in the gnomAD database. </p><p>In 3 unrelated patients (patients 8, 9, and 12) with VISS syndrome, Bertoli-Avella et al. (2021) identified homozygosity for the W259X mutation in the IPO8 gene. Familial segregation was not reported. </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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<h4>
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<span class="mim-font">
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<strong>.0002 VISS SYNDROME</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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IPO8, IVS23, G-A, -1
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<br />
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SNP: rs1243135564,
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ClinVar: RCV001507278, RCV001553796, RCV001731197, RCV002225829
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a 19-year-old man (family 6) with VISS syndrome (VISS; 619472), Van Gucht et al. (2021) identified homozygosity for a splicing mutation (c.2900-1G-A, NM_006390.3) in the IPO8 gene, predicted to result in a deletion/insertion (Thr967_Glu1006delinsLys). His unaffected first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database. </p><p>In a 33-year-old Australian woman (family 7, patient I-10) with VISS syndrome, Ziegler et al. (2021) identified compound heterozygosity for the c.2900-1G-A splicing mutation in intron 23 of the IPO8 gene, and a 1-bp deletion (c.2279delT; 605600.0005), causing a frameshift predicted to result in a premature termination codon (Leu760ProfsTer10) in the IPO8 gene. Her unaffected parents were each heterozygous for 1 of the mutations. The 1-bp deletion was present at very low frequency in the gnomAD database (1.06 x 10(-5), no homozygotes). </p>
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</span>
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<br />
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<h4>
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<span class="mim-font">
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<strong>.0003 VISS SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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IPO8, IVS12, G-A, +5
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<br />
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SNP: rs2136152576,
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ClinVar: RCV001507274, RCV001553797
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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 an 8-year-old girl (family 3) with VISS syndrome (VISS; 619472), Van Gucht et al. (2021) identified compound heterozygosity for a splicing mutation (c.1428+5G-A, NM_006390.3) in intron 12 of the IPO8 gene, causing skipping of exon 13 and a predicted in-frame deletion of 30 amino acids (Lys447_Arg476del), and a 5-bp deletion (c.2597_2601delTTTTC; 605600.0004), causing a frameshift predicted to result in an premature termination codon (Leu866ProfsTer12). Her unaffected parents were each heterozygous for 1 of the mutations. The splicing mutation was not found in the gnomAD database, whereas the 5-bp deletion was present at very low minor allele frequency (1 of 250,920 alleles). Analysis of cDNA from puromycin-treated and untreated patient fibroblasts indicated that the 5-bp mutation results in nonsense-mediated decay; Sanger sequencing of the RT-PCR produced from blood-derived cDNA confirmed in-frame skipping of exon 13 with the splicing 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>.0004 VISS SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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IPO8, 5-BP DEL, 2597TTTTC
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<br />
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SNP: rs1565492786,
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ClinVar: RCV001507275, RCV001553798
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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>For discussion of the 5-bp deletion (c.2597_2601delTTTTC, NM_006390.3) in the IPO8 gene that was found in compound heterozygous state in an 8-year-old girl (family 3) with VISS syndrome (VISS; 619472) by Van Gucht et al. (2021), see 605600.0003. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 VISS SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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IPO8, 1-BP DEL, 2279T
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<br />
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SNP: rs775937664,
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gnomAD: rs775937664,
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ClinVar: RCV001553799, RCV001731205
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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>For discussion of the 1-bp deletion (c.2279delT, NM_006390.3) in the IPO8 gene, causing a frameshift predicted to result in an premature termination codon (Leu760ProfsTer10), that was found in compound heterozygous state in an 8-year-old Australian girl (family 7, patient I-10) with VISS syndrome (VISS; 619472) by Ziegler et al. (2021), see 605600.0002. </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>.0006 VISS SYNDROME</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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IPO8, ASP88ASN
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<br />
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SNP: rs1234764565,
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gnomAD: rs1234764565,
|
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|
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ClinVar: RCV001553800, RCV001731198
|
|
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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 an Ashkenazi brother and sister (family 1, patients I-1 and I-2) with VISS syndrome (VISS; 619472), Ziegler et al. (2021) identified homozygosity for a c.262G-A transition (c.262G-A, NM_006390.3) in the IPO8 gene, resulting in an asp88-to-asn (D88N) substitution at a highly conserved residue within the N-terminal domain. Their unaffected sister was heterozygous for the mutation, which was not found in the gnomAD database; DNA was unavailable from their deceased consanguineous parents. Immunoblot analysis of protein lysates from patient fibroblasts showed a striking reduction in IPO8 compared to control. </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>.0007 VISS SYNDROME</strong>
|
|
</span>
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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IPO8, 5-BP DEL, NT2965+4
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<br />
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SNP: rs2136125267,
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ClinVar: RCV001553801
|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 unrelated patients (patients 7 and 11) with VISS syndrome (VISS; 619472), Bertoli-Avella et al. (2021) identified homozygosity for a 5-bp deletion (c.2695+4_2695+8del) in the IPO8 gene. Familial segregation and functional analysis were not reported. </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>REFERENCES</strong>
|
|
</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Bertoli-Avella, A. M., Kandaswamy, K. K., Khan, S., Ordonez-Herrera, N., Tripolszki, K., Beetz, C., Rocha, M. E., Urzi, A., Hotakainen, R., Leubauer, A., Al-Ali, R., Karageorgou, V., and 25 others.
|
|
<strong>Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders.</strong>
|
|
Genet. Med. 23: 1551-1568, 2021.
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[PubMed: 33875846]
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[Full Text: https://doi.org/10.1038/s41436-021-01159-0]
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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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Gorlich, D., Dabrowski, M., Bischoff, F. R., Kutay, U., Bork, P., Hartmann, E., Prehn, S., Izaurralde, E.
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<strong>A novel class of RanGTP binding proteins.</strong>
|
|
J. Cell Biol. 138: 65-80, 1997.
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[PubMed: 9214382]
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[Full Text: https://doi.org/10.1083/jcb.138.1.65]
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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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Stumpf, A. M.
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<strong>Personal Communication.</strong>
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|
Baltimore, Md. 08/05/2021.
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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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Van Gucht, I., Meester, J. A. N., Bento, J. R., Bastiaansen, M., Bastianen, J., Luyckx, I., Van Den Heuvel, L., Neutel, C. H. G., Guns, P.-J., Vermont, M., Fransen, E., Perik, M. H. A. M., and 36 others.
|
|
<strong>A human importin-beta-related disorder: syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.</strong>
|
|
Am. J. Hum. Genet. 108: 1115-1125, 2021.
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[PubMed: 34010605]
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[Full Text: https://doi.org/10.1016/j.ajhg.2021.04.019]
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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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Weinmann, L., Hock, J., Ivacevic, T., Ohrt, T., Mutze, J., Schwille, P., Kremmer, E., Benes, V., Urlaub, H., Meister, G.
|
|
<strong>Importin 8 is a gene silencing factor that targets Argonaute proteins to distinct mRNAs.</strong>
|
|
Cell 136: 496-507, 2009.
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[PubMed: 19167051]
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[Full Text: https://doi.org/10.1016/j.cell.2008.12.023]
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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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Ziegler, A., Duclaux-Loras, R., Revenu, C., Charbit-Henrion, F., Begue, B., Duroure, K., Grimaud, L., Guihot, A. L., Desquiret-Dumas, V., Zarhrate, M., Cagnard, N., Mas, E., and 35 others.
|
|
<strong>Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.</strong>
|
|
Am. J. Hum. Genet. 108: 1126-1137, 2021.
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[PubMed: 34010604]
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[Full Text: https://doi.org/10.1016/j.ajhg.2021.04.020]
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</p>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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Contributors:
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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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Anne M. Stumpf - updated : 08/05/2021<br>Marla J. F. O'Neill - updated : 08/05/2021<br>Patricia A. Hartz - updated : 04/07/2009
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</span>
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</div>
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Yen-Pei C. Chang : 1/29/2001
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alopez : 08/12/2021<br>alopez : 08/10/2021<br>alopez : 08/05/2021<br>alopez : 08/05/2021<br>mgross : 04/07/2009<br>carol : 3/13/2003<br>carol : 12/19/2001<br>carol : 2/5/2001<br>cwells : 1/30/2001<br>cwells : 1/29/2001
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<p>
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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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