3665 lines
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- *609213 - SEC61 TRANSLOCON, ALPHA-1 SUBUNIT; SEC61A1
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- OMIM
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</form>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*609213</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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<li role="presentation">
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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="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/609213">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000058262;t=ENST00000243253" 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=29927" 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=609213" 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=ENSG00000058262;t=ENST00000243253" 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_001400328,NM_001400329,NM_013336" 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_013336" 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=609213" 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=15316&isoform_id=15316_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/SEC61A1" 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/4689112,5106795,7019415,13517989,21732464,22760658,22760694,22761050,45503868,48429109,57997153,119599730,119599731,119599732,119599733,193786070,193786535,193786540,193786541,193786543,193786666,194386726,2181862444,2181862496" 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/P61619" 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=29927" 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=ENSG00000058262;t=ENST00000243253" 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=SEC61A1" 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=SEC61A1" 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+29927" 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/SEC61A1" 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:29927" 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/29927" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr3&hgg_gene=ENST00000243253.8&hgg_start=128051641&hgg_end=128071683&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:18276" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=609213[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=609213[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/ENSG00000058262" 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=SEC61A1" 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=SEC61A1" 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=SEC61A1" 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=SEC61A1&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/PA134901772" 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:18276" 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/FBgn0086357.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:1858417" 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/SEC61A1#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:1858417" 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/29927/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=29927" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00013311;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-020418-2" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:29927" 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=SEC61A1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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609213
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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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SEC61 TRANSLOCON, ALPHA-1 SUBUNIT; SEC61A1
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SEC61 COMPLEX, ALPHA-1 SUBUNIT<br />
|
|
SEC61A<br />
|
|
SEC61, S. CEREVISIAE, HOMOLOG OF; SEC61
|
|
</span>
|
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</h4>
|
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</div>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SEC61A1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SEC61A1</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>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/3/647?start=-3&limit=10&highlight=647">3q21.3</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr3:128051641-128071683&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">3:128,051,641-128,071,683</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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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
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</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=620674,620670,617056" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/3/647?start=-3&limit=10&highlight=647">
|
|
3q21.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Neutropenia, severe congenital, 11, autosomal dominant
|
|
|
|
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620674"> 620674 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Immunodeficiency, common variable, 15
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/620670"> 620670 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Tubulointerstitial kidney disease, autosomal dominant, 5
|
|
|
|
</span>
|
|
</td>
|
|
<td>
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<p>SEC61A1 is a subunit of the heteromeric SEC61 complex, which also contains beta (SEC61B; <a href="/entry/609214">609214</a>) and gamma (SEC61G; <a href="/entry/609215">609215</a>) subunits. The SEC61 complex forms the core of the mammalian endoplasmic reticulum (ER) translocon, a transmembrane channel for the translocation of proteins across the ER membrane (<a href="#8" class="mim-tip-reference" title="Greenfield, J. J. A., High, S. <strong>The Sec61 complex is located in both the ER and the ER-Golgi intermediate compartment.</strong> J. Cell Sci. 112: 1477-1486, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10212142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10212142</a>] [<a href="https://doi.org/10.1242/jcs.112.10.1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10212142">Greenfield and High, 1999</a>). Genes encoding the SEC61 complex are involved in the unfolded protein response (UPR) in the ER. The SEC61 complex also acts as a passive calcium leakage channel between the ER and the cytoplasm (summary by <a href="#14" class="mim-tip-reference" title="Schubert, D., Klein, M.-C., Hassdenteufel, S., Caballero-Oteyza, A., Yang, L., Proietti, M., Bulashevska, A., Kemming, J., Kuhn, J., Winzer, S., Rusch, S., Fliegauf, M., and 16 others. <strong>Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).</strong> J. Allergy Clin. Immun. 141: 1427-1438, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28782633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28782633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28782633[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.06.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28782633">Schubert et al., 2018</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10212142+28782633" 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="#14" class="mim-tip-reference" title="Schubert, D., Klein, M.-C., Hassdenteufel, S., Caballero-Oteyza, A., Yang, L., Proietti, M., Bulashevska, A., Kemming, J., Kuhn, J., Winzer, S., Rusch, S., Fliegauf, M., and 16 others. <strong>Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).</strong> J. Allergy Clin. Immun. 141: 1427-1438, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28782633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28782633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28782633[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.06.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28782633">Schubert et al. (2018)</a> found that the relative abundance of SEC61A protein in plasmablasts from human peripheral blood was about 2-fold higher when compared to naive and memory B cells. This is consistent with a SEC61A1 being a target gene of XBP1 (<a href="/entry/194355">194355</a>) during plasma cell differentiation. XBP1 induces the transcription of genes encoding mediators of protein synthesis, transport, folding, and degradation, and plays a role in activation of the UPR during ER stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28782633" 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>The SEC61 complex is an essential translocation component that can associate with either ribosomes or the SEC62 (<a href="/entry/602173">602173</a>)/SEC63 (<a href="/entry/608648">608648</a>) complex to perform cotranslational or posttranslational transport, respectively (<a href="#18" class="mim-tip-reference" title="Wiertz, E. J. H. J., Tortorella, D., Bogyo, M., Yu, J., Mothes, W., Jones, T. R., Rapoport, T. A., Ploegh, H. L. <strong>Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction.</strong> Nature 384: 432-438, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8945469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8945469</a>] [<a href="https://doi.org/10.1038/384432a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8945469">Wiertz et al., 1996</a>). It was originally thought to have a role only in translocation of proteins from the cytosol into the ER. However, <a href="#18" class="mim-tip-reference" title="Wiertz, E. J. H. J., Tortorella, D., Bogyo, M., Yu, J., Mothes, W., Jones, T. R., Rapoport, T. A., Ploegh, H. L. <strong>Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction.</strong> Nature 384: 432-438, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8945469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8945469</a>] [<a href="https://doi.org/10.1038/384432a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8945469">Wiertz et al. (1996)</a>, <a href="#2" class="mim-tip-reference" title="Bebok, Z., Mazzochi, C., King, S. A., Hong, J. S., Sorscher, E. J. <strong>The mechanism underlying cystic fibrosis transmembrane conductance regulator transport from the endoplasmic reticulum to the proteasome includes Sec61-beta and a cytosolic, deglycosylated intermediary.</strong> J. Biol. Chem. 273: 29873-29878, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792704</a>] [<a href="https://doi.org/10.1074/jbc.273.45.29873" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9792704">Bebok et al. (1998)</a>, <a href="#5" class="mim-tip-reference" title="Chen, Y., Le Caherec, F., Chuck, S. L. <strong>Calnexin and other factors that alter translocation affect the rapid binding of ubiquitin to apoB in the Sec61 complex.</strong> J. Biol. Chem. 273: 11887-11894, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9565615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9565615</a>] [<a href="https://doi.org/10.1074/jbc.273.19.11887" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9565615">Chen et al. (1998)</a>, and <a href="#12" class="mim-tip-reference" title="Petaja-Repo, U. E., Hogue, M., Laperriere, A., Bhalla, S., Walker, P., Bouvier, M. <strong>Newly synthesized human delta opioid receptors retained in the endoplasmic reticulum are retrotranslocated to the cytosol, deglycosylated, ubiquitinated, and degraded by the proteasome.</strong> J. Biol. Chem. 276: 4416-4423, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11054417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11054417</a>] [<a href="https://doi.org/10.1074/jbc.M007151200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11054417">Petaja-Repo et al. (2001)</a> presented evidence suggesting that the human SEC61 complex can also function in retrograde transport of multidomain integral membrane proteins from the ER to the cytosol for proteasomal degradation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9792704+11054417+8945469+9565615" 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 immunolocalization of fluorescence-tagged canine Sec61a transfected into COS-1 cells, <a href="#8" class="mim-tip-reference" title="Greenfield, J. J. A., High, S. <strong>The Sec61 complex is located in both the ER and the ER-Golgi intermediate compartment.</strong> J. Cell Sci. 112: 1477-1486, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10212142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10212142</a>] [<a href="https://doi.org/10.1242/jcs.112.10.1477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10212142">Greenfield and High (1999)</a> determined that the Sec61 complex distributed to both the ER and the ER-Golgi intermediate compartment, but not to the trans-Golgi network. Endogenous Sec61b and Sec61g showed the same distribution. Another translocon component, the glycoprotein Tram (see <a href="/entry/605190">605190</a>) was also present in post-ER compartments, suggesting that the core components of the mammalian ER translocon are not permanently resident in the ER, but rather they are maintained in the ER by a specific retrieval mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10212142" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Hessa, T., Kim, H., Bihlmaier, K., Lundin, C., Boekel, J., Andersson, H., Nilsson, I., White, S. H., von Heijne, G. <strong>Recognition of transmembrane helices by the endoplasmic reticulum translocon.</strong> Nature 433: 377-381, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15674282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15674282</a>] [<a href="https://doi.org/10.1038/nature03216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15674282">Hessa et al. (2005)</a> challenged the endoplasmic reticulum Sec61 translocon with an extensive set of designed polypeptide segments and determined the basic features of the code for recognition of transmembrane helices, including a 'biological' hydrophobicity scale. They found that membrane insertion depends strongly on the position of polar residues within transmembrane segments, adding a new dimension to the problem of predicting transmembrane helices from amino acid sequences. <a href="#9" class="mim-tip-reference" title="Hessa, T., Kim, H., Bihlmaier, K., Lundin, C., Boekel, J., Andersson, H., Nilsson, I., White, S. H., von Heijne, G. <strong>Recognition of transmembrane helices by the endoplasmic reticulum translocon.</strong> Nature 433: 377-381, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15674282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15674282</a>] [<a href="https://doi.org/10.1038/nature03216" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15674282">Hessa et al. (2005)</a> concluded that direct protein-lipid interactions are critical during translocon-mediated membrane insertion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15674282" 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>Transmembrane alpha-helices in integral membrane proteins are recognized cotranslationally and inserted into the membrane of the endoplasmic reticulum by the Sec61 translocon. Using in vitro translation of a model protein in the presence of dog pancreas rough microsomes to analyze a large number of systematically designed hydrophobic segments, <a href="#10" class="mim-tip-reference" title="Hessa, T., Meindl-Beinker, N. M., Bernsel, A., Kim, H., Sato, Y., Lerch-Bader, M., Nilsson, I., White, S. H., von Heijne, G. <strong>Molecular code for transmembrane-helix recognition by the Sec61 translocon.</strong> Nature 450: 1026-1030, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18075582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18075582</a>] [<a href="https://doi.org/10.1038/nature06387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18075582">Hessa et al. (2007)</a> presented a quantitative analysis of the position-dependent contribution of all 20 amino acids to membrane insertion efficiency, as well as of the effects of transmembrane segment length and flanking amino acids. The resulting picture of translocon-mediated transmembrane helix assembly is simple, with the critical sequence characteristics mirroring the physical properties of the lipid bilayer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18075582" 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>Mycolactone is an immunosuppressive and cytotoxic virulence factor of Mycobacterium ulcerans, the causative agent of Buruli ulcer (<a href="/entry/610446">610446</a>). By competitive binding analyses, <a href="#1" class="mim-tip-reference" title="Baron, L., Paatero, A. O., Morel, J.-D., Impens, F., Guenin-Mace, L., Saint-Auret, S., Blanchard, N., Dillmann, R., Niang, F., Pellegrini, S., Taunton, J., Paavilainen, V. O., Demangel, C. <strong>Mycolactone subverts immunity by selectively blocking the Sec61 translocon.</strong> J. Exp. Med. 213: 2885-2896, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27821549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27821549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27821549[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/10.1084/jem.20160662" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27821549">Baron et al. (2016)</a> showed that mycolactone bound tightly to SEC61A and had a slow dissociation rate. Screening of SEC61A mutants expressed in embryonic kidney cells revealed that mutations at arg66 or ser82 conferred resistance to cytotoxicity and mycolactone-mediated blockade of protein secretion and translocation. These mutations are located near the luminal plug of SEC61A. Proteomic analysis and in vitro translation experiments showed that a broad spectrum of proteins, particularly secreted proteins (e.g., IFNG; <a href="/entry/147570">147570</a>) and single-pass type I/II membrane proteins (e.g., TNF; <a href="/entry/191160">191160</a>), as well as the ER-resident protein BIP (HSPA5; <a href="/entry/138120">138120</a>), were affected by mycolactone inhibition of SEC61A. Mycolactone inhibition of wildtype, but not mutant, Sec61 activity prevented production of Ifng by mouse T cells and responsiveness to Ifng through Ifngr (see <a href="/entry/107470">107470</a>) in mouse macrophages. Mycolactone also affected Sec61-dependent Cd62l (<a href="/entry/153240">153240</a>) expression and Cd62l-dependent lymphocyte homing in mice. <a href="#1" class="mim-tip-reference" title="Baron, L., Paatero, A. O., Morel, J.-D., Impens, F., Guenin-Mace, L., Saint-Auret, S., Blanchard, N., Dillmann, R., Niang, F., Pellegrini, S., Taunton, J., Paavilainen, V. O., Demangel, C. <strong>Mycolactone subverts immunity by selectively blocking the Sec61 translocon.</strong> J. Exp. Med. 213: 2885-2896, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27821549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27821549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27821549[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/10.1084/jem.20160662" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27821549">Baron et al. (2016)</a> concluded that mycolactone inhibition of SEC61 prevents the production of key mediators of innate and adaptive immune responses against intracellular pathogens. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27821549" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#3" class="mim-tip-reference" title="Becker, T., Bhushan, S., Jarasch, A., Armache, J.-P., Funes, S., Jossinet, F., Gumbart, J., Mielke, T., Berninghausen, O., Schulten, K., Westhof, E., Gilmore, R., Mandon, E. C., Beckmann, R. <strong>Structure of monomeric yeast and mammalian Sec61 complexes interacting with the translating ribosome.</strong> Science 326: 1369-1373, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19933108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19933108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19933108[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1178535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19933108">Becker et al. (2009)</a> determined subnanometer-resolution cryoelectron microscopy structures of eukaryotic ribosome-Sec61 complexes. In combination with biochemical data, they found that in both idle and active states, the Sec complex is not oligomeric and interacts mainly via 2 cytoplasmic loops with the universal ribosomal adaptor site. In the active state, the ribosomal tunnel and a central pore of the monomeric protein-conducting channel were occupied by the nascent chain, contacting loop 6 of the Sec complex. <a href="#3" class="mim-tip-reference" title="Becker, T., Bhushan, S., Jarasch, A., Armache, J.-P., Funes, S., Jossinet, F., Gumbart, J., Mielke, T., Berninghausen, O., Schulten, K., Westhof, E., Gilmore, R., Mandon, E. C., Beckmann, R. <strong>Structure of monomeric yeast and mammalian Sec61 complexes interacting with the translating ribosome.</strong> Science 326: 1369-1373, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19933108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19933108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19933108[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1178535" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19933108">Becker et al. (2009)</a> concluded that this provides a structural basis for the activity of a solitary Sec complex in cotranslational protein translocation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19933108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Gogala, M., Becker, T., Beatrix, B., Armache, J.-P., Barrio-Garcia, C., Berninghausen, O., Beckmann, R. <strong>Structures of the Sec61 complex engaged in nascent peptide translocation or membrane insertion.</strong> Nature 506: 107-110, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24499919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24499919</a>] [<a href="https://doi.org/10.1038/nature12950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24499919">Gogala et al. (2014)</a> presented cryoelectron microscopy structures of ribosome-bound SEC61 complexes engaged in translocation or membrane insertion of nascent peptides. The data showed that a hydrophilic peptide can translocate through the SEC complex with an essentially closed lateral gate and an only slightly rearranged central channel. Membrane insertion of a hydrophobic domain seems to occur with the SEC complex opening the proposed lateral gate while rearranging the plug to maintain an ion permeability barrier. <a href="#7" class="mim-tip-reference" title="Gogala, M., Becker, T., Beatrix, B., Armache, J.-P., Barrio-Garcia, C., Berninghausen, O., Beckmann, R. <strong>Structures of the Sec61 complex engaged in nascent peptide translocation or membrane insertion.</strong> Nature 506: 107-110, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24499919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24499919</a>] [<a href="https://doi.org/10.1038/nature12950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24499919">Gogala et al. (2014)</a> provided a structural model for the basic activities of the SEC61 complex as a protein-conducting channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24499919" 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="#15" class="mim-tip-reference" title="Stumpf, A. M. <strong>Personal Communication.</strong> Baltimore, Md. 01/12/2024."None>Stumpf (2024)</a> mapped the SEC61A1 gene to chromosome 3q21.3 based on an alignment of the SEC61A1 sequence (GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=BC156688" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">BC156688</a>) with the genomic sequence (GRCh38).</p>
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<p><strong><em>Autosomal Dominant Tubulointerstitial Kidney Disease 5</em></strong></p><p>
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In affected members of 2 unrelated families with autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5; <a href="/entry/617056">617056</a>), <a href="#4" class="mim-tip-reference" title="Bolar, N. A., Golzio, C., Zivna, M., Hayot, G., Van Hemelrijk, C., Schepers, D., Vandeweyer, G., Hoischen, A., Huyghe, J. R., Raes, A., Matthys, E., Sys, E., and 26 others. <strong>Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia.</strong> Am. J. Hum. Genet. 99: 174-187, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27392076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27392076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27392076[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.05.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27392076">Bolar et al. (2016)</a> identified 2 different heterozygous missense mutations in the SEC61A1 gene (T185A, <a href="#0001">609213.0001</a> and V67G, <a href="#0002">609213.0002</a>). The mutation in the first family was found by a combination of linkage analysis and whole-exome sequencing, whereas the mutation in the second family was found by custom gene panel sequencing of 46 unrelated probands with a renal disorder; the mutations segregated with the disorder in both families. The mutations affected the selectivity and permeability of the pore of the translocon channel. Transfection of the mutations into HEK293 cells resulted in decreased protein levels compared to wildtype, and both mutant proteins formed intracellular clumps that were localized in the endoplasmic reticulum and partially in the Golgi apparatus. The findings suggested that the mutant proteins were subjected to endoplasmic-reticulum-associated degradation (ERAD) and increased ER stress. The mutant T185A protein was unable to rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 ortholog, suggesting that this mutation results in a complete loss of function. The V67G protein showed partial rescue of the zebrafish phenotype. The findings suggested that SEC61A1 is necessary for proper tubular organization of the nephron, and that the disorder results from protein translocation defects across the endoplasmic reticulum membrane. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27392076" 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 4-year-old girl with ADTKD5 and CD4+ T cell lymphopenia, <a href="#6" class="mim-tip-reference" title="Espino-Hernandez, M., Palma Milla, C., Vara-Martin, J., Gonzalez-Granado, L. I. <strong>De novo SEC61A1 mutation in autosomal dominant tubulo-interstitial kidney disease: phenotype expansion and review of literature.</strong> J. Paediat. Child Health 57: 1305-1307, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33185949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33185949</a>] [<a href="https://doi.org/10.1111/jpc.15148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33185949">Espino-Hernandez et al. (2021)</a> identified a de novo heterozygous T185A mutation in the SEC61A1 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed. Neutrophil count and immunoglobulin levels were normal. <a href="#6" class="mim-tip-reference" title="Espino-Hernandez, M., Palma Milla, C., Vara-Martin, J., Gonzalez-Granado, L. I. <strong>De novo SEC61A1 mutation in autosomal dominant tubulo-interstitial kidney disease: phenotype expansion and review of literature.</strong> J. Paediat. Child Health 57: 1305-1307, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33185949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33185949</a>] [<a href="https://doi.org/10.1111/jpc.15148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33185949">Espino-Hernandez et al. (2021)</a> noted that ADTKD5 may manifest as a syndromic form of progressive chronic kidney disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33185949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Common Variable Immunodeficiency 15</em></strong></p><p>
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In 10 affected members of a family of northern European descent (family 1) with common variable immunodeficiency-15 (CVID15; <a href="/entry/620670">620670</a>), <a href="#14" class="mim-tip-reference" title="Schubert, D., Klein, M.-C., Hassdenteufel, S., Caballero-Oteyza, A., Yang, L., Proietti, M., Bulashevska, A., Kemming, J., Kuhn, J., Winzer, S., Rusch, S., Fliegauf, M., and 16 others. <strong>Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).</strong> J. Allergy Clin. Immun. 141: 1427-1438, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28782633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28782633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28782633[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.06.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28782633">Schubert et al. (2018)</a> identified a heterozygous missense mutation in the SEC61A1 gene (V85D; <a href="#0003">609213.0003</a>). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Subsequent targeted next-generation sequencing of more than 200 patients with primary antibody deficiencies identified a second family in which 3 members had a heterozygous nonsense mutation in the SEC61A1 gene (E381X; <a href="#0004">609213.0004</a>). Patient-derived B cells from both families showed reduced SEC61A1 mRNA and protein levels and significantly reduced immunoglobulin secretion compared to controls. Studies of patient B cells and in vitro studies of transfected cells (including plasma cell-specific multiple myeloma cell lines) showed that the V85D mutation exerted a dominant-negative effect with increased ER/cytosolic calcium leakage depleting the calcium gradient, impaired protein translocation, increased ER stress, and activation of the terminal UPR pathway with increased levels of XBP1 (<a href="/entry/194355">194355</a>), CHOP (<a href="/entry/126337">126337</a>), and ATF4 (<a href="/entry/604064">604064</a>). Although the E381X mutation resulted in haploinsufficiency with a loss-of-function effect, the effect was similar: an inability to maintain ER homeostasis in times of stress, such as immunoglobulin production. Of note, the disorder in the second family showed incomplete penetrance and variable expressivity. Affected individuals from both families had early onset of recurrent infections associated with possibly transient antibody deficiency (IgM, IgG, and IgA), but normal numbers and subsets of peripheral B cells, T cells, and NK cells. Patient B cells did not differentiate into plasma cells in vitro, indicating a specific impairment of plasma cell homeostasis. <a href="#14" class="mim-tip-reference" title="Schubert, D., Klein, M.-C., Hassdenteufel, S., Caballero-Oteyza, A., Yang, L., Proietti, M., Bulashevska, A., Kemming, J., Kuhn, J., Winzer, S., Rusch, S., Fliegauf, M., and 16 others. <strong>Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).</strong> J. Allergy Clin. Immun. 141: 1427-1438, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28782633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28782633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28782633[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.06.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28782633">Schubert et al. (2018)</a> noted that studies in mice in which Xbp1 was conditionally deleted in B cells resulted in reduced immunoglobulin production by plasma cells and reduced expression of the Xbp1 target gene Sec61a1 (see, e.g., <a href="#13" class="mim-tip-reference" title="Reimold, A. M., Iwakoshi, N. N., Manis, J., Vallabhajosyula, P., Szomolanyi-Tsuda, E., Gravallese, E. M., Friend, D., Grusby, M. J., Alt, F., Glimcher, L. H. <strong>Plasma cell differentiation requires the transcription factor XBP-1.</strong> Nature 412: 300-307, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11460154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11460154</a>] [<a href="https://doi.org/10.1038/35085509" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11460154">Reimold et al., 2001</a> and <a href="#16" class="mim-tip-reference" title="Taubenheim, N., Tarlinton, D. M., Crawford, S., Corcoran, L. M., Hodgkin, P. D., Nutt, S. L. <strong>High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency.</strong> J. Immun. 189: 3328-3338, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22925926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22925926</a>] [<a href="https://doi.org/10.4049/jimmunol.1201042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22925926">Taubenheim et al., 2012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28782633+22925926+11460154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Autosomal Dominant Severe Congenital Neutropenia 11</em></strong></p><p>
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In a 19-year-old woman, born of unrelated Belgian parents, with autosomal dominant severe congenital neutropenia-11 (SCN11; <a href="/entry/620674">620674</a>), <a href="#17" class="mim-tip-reference" title="Van Nieuwenhove, E., Barber, J. S., Neumann, J., Smeets, E., Willemsen, M., Pasciuto, E., Prezzemolo, T., Lagou, V., Seldeslachts, L., Malengier-Devlies, B., Metzemaekers, M., Hassdenteufel, S., and 18 others. <strong>Defective Sec61alpha1 underlies a novel cause of autosomal dominant severe congenital neutropenia.</strong> J. Allergy Clin. Immun. 146: 1180-1193, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32325141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32325141</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32325141[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jaci.2020.03.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32325141">Van Nieuwenhove et al. (2020)</a> identified a de novo heterozygous missense mutation in the SEC61A1 gene (Q92R; <a href="#0005">609213.0005</a>). The mutation, which was found by whole-exome sequencing, was not present in public databases. Patient peripheral blood mononuclear cells and fibroblasts showed decreased SEC61A1 protein expression that correlated with decreased SEC61-dependent protein translocation across the ER. Detailed in vitro studies in patient cells and HL-60 promyeloblasts showed that the mutation increased calcium leakage causing neutralization of the ER/cytosolic calcium gradient, increased ER stress, activation of the UPR, and increased susceptibility to apoptosis under ER stress conditions compared to controls. Patient CD34+ cells showed defective myeloid differentiation and neutrophil maturation in vitro. The patient had normal B-cell numbers, but there was maturation arrest of B-cell precursors at the transitional B-cell stage. However, she had increased plasmablasts and hypergammaglobulinemia. NK cells also showed a maturation defect. Thus, although the primary presentation of the patient was consistent with severe congenital neutropenia, the mutation also affected other leukocyte populations. The findings indicated that the mutation resulted in a combined quantitative and functional SEC61A1 protein defect. The authors stated that the clinical diversity in patients with SEC61A1 mutations is unclear, and that phenotypes cannot be predicted on the basis of location or nature of the mutation, as the effects are cell-intrinsic and cell-specific. However, a common disease mechanism appears to be that impaired SEC61A1 function leads to disrupted calcium flux, increased ER stress, and activation of the UPR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32325141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Lloyd, D. J., Wheeler, M. C., Gekakis, N. <strong>A point mutation in Sec6a1 leads to diabetes and hepatosteatosis in mice.</strong> Diabetes 59: 460-470, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19934005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19934005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19934005[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/10.2337/db08-1362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19934005">Lloyd et al. (2010)</a> described a recessive diabetic mouse mutant resulting from a homozygous Y344H mutation in the Sec61a1 gene. In addition to diabetes and hyperglycemia due to insulin insufficiency, the mice had poor growth, hyperlipidemia, hypercholesterolemia, and hepatosteatosis. Cirrhosis was apparent in older mice. The associated hypoinsulinemia indicated pancreatic beta-cell failure. Immunohistochemical studies of wildtype mice showed high Sec61a1 expression in beta-cells in the pancreas, and the pancreas of mutant mice contained multiple apoptotic beta-cells resulting from increased ER stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19934005" 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="#4" class="mim-tip-reference" title="Bolar, N. A., Golzio, C., Zivna, M., Hayot, G., Van Hemelrijk, C., Schepers, D., Vandeweyer, G., Hoischen, A., Huyghe, J. R., Raes, A., Matthys, E., Sys, E., and 26 others. <strong>Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia.</strong> Am. J. Hum. Genet. 99: 174-187, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27392076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27392076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27392076[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.05.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27392076">Bolar et al. (2016)</a> found that morpholino knockdown of the zebrafish sec61a1 ortholog in zebrafish embryos resulted in increased frequency of absence or decreased convolution of the pronephric tubules compared to wildtype, consistent with tubular atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27392076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=609213[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong><div class="mim-changed mim-change">.0001 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 5</div></strong>
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<p>In 7 affected members of a 3-generation family with autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5; <a href="/entry/617056">617056</a>) <a href="#4" class="mim-tip-reference" title="Bolar, N. A., Golzio, C., Zivna, M., Hayot, G., Van Hemelrijk, C., Schepers, D., Vandeweyer, G., Hoischen, A., Huyghe, J. R., Raes, A., Matthys, E., Sys, E., and 26 others. <strong>Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia.</strong> Am. J. Hum. Genet. 99: 174-187, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27392076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27392076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27392076[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.05.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27392076">Bolar et al. (2016)</a> identified a heterozygous c.553A-G transition (c.553A-G, NM_013336.3) in the SEC61A1 gene, resulting in a thr185-to-ala (T185A) substitution at a conserved residue in transmembrane helix 5 that may affect the structural integrity of the channel. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases, in 204 Belgian control chromosomes, or in several in-house exome databases. Immunohistochemical staining of a patient-derived kidney biopsy showed abnormal intracellular localization and aggregation of the mutant protein, with coarse granular cytoplasmic staining in tubules and collecting ducts. There was also absence of REN (<a href="/entry/179820">179820</a>) immunostaining in juxtaglomerular cells. The mutant protein was unable to rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 ortholog, suggesting that the mutation results in a complete loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27392076" 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 4-year-old girl with ADTKD5, <a href="#6" class="mim-tip-reference" title="Espino-Hernandez, M., Palma Milla, C., Vara-Martin, J., Gonzalez-Granado, L. I. <strong>De novo SEC61A1 mutation in autosomal dominant tubulo-interstitial kidney disease: phenotype expansion and review of literature.</strong> J. Paediat. Child Health 57: 1305-1307, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33185949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33185949</a>] [<a href="https://doi.org/10.1111/jpc.15148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33185949">Espino-Hernandez et al. (2021)</a> identified a de novo heterozygous T185A mutation in the SEC61A1 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed. She presented in infancy with poor overall growth, elevated uric acid, and mild anemia. Urinary concentrating ability was reduced and kidneys were at the lower limit of normal size. She also had mild psychomotor delay. She did not have recurrent infections, but immunologic work-up showed CD4+ T cell lymphopenia. Neutrophil count and immunoglobulin levels were normal. <a href="#6" class="mim-tip-reference" title="Espino-Hernandez, M., Palma Milla, C., Vara-Martin, J., Gonzalez-Granado, L. I. <strong>De novo SEC61A1 mutation in autosomal dominant tubulo-interstitial kidney disease: phenotype expansion and review of literature.</strong> J. Paediat. Child Health 57: 1305-1307, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33185949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33185949</a>] [<a href="https://doi.org/10.1111/jpc.15148" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33185949">Espino-Hernandez et al. (2021)</a> noted that ADTKD5 may manifest as a syndromic form of progressive chronic kidney disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33185949" 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 father and daughter with autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5; <a href="/entry/617056">617056</a>), <a href="#4" class="mim-tip-reference" title="Bolar, N. A., Golzio, C., Zivna, M., Hayot, G., Van Hemelrijk, C., Schepers, D., Vandeweyer, G., Hoischen, A., Huyghe, J. R., Raes, A., Matthys, E., Sys, E., and 26 others. <strong>Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia.</strong> Am. J. Hum. Genet. 99: 174-187, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27392076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27392076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27392076[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2016.05.028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27392076">Bolar et al. (2016)</a> identified a heterozygous c.200T-G transversion (c.200T-G, NM_013336.3) in the SEC61A1 gene, resulting in a val67-to-gly (V67G) substitution at a conserved residue in the translocon pore; the residue is part of a plug domain that seals and stabilizes the pore during the closed state. The mutation, which was found by custom gene panel sequencing of 46 unrelated probands with a similar disorder, was not found in the 1000 Genomes Project, Exome Variant Server, or several in-house exome databases, but was found once in the ExAC database (1 of 121,410 alleles). Transfection of the mutation into HEK293 cells resulted in decreased protein levels compared to wildtype, and the mutant protein formed intracellular clumps that were localized in the endoplasmic reticulum and partially in the Golgi apparatus. The mutant protein was unable to fully rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 ortholog, suggesting that the mutation results in a partial loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27392076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000664064 OR RCV003482295" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000664064, RCV003482295" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000664064...</a>
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<p>In 10 affected members of a family of northern European descent (family 1) with common variable immunodeficiency-15 (CVID15; <a href="/entry/620670">620670</a>), <a href="#14" class="mim-tip-reference" title="Schubert, D., Klein, M.-C., Hassdenteufel, S., Caballero-Oteyza, A., Yang, L., Proietti, M., Bulashevska, A., Kemming, J., Kuhn, J., Winzer, S., Rusch, S., Fliegauf, M., and 16 others. <strong>Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).</strong> J. Allergy Clin. Immun. 141: 1427-1438, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28782633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28782633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28782633[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.06.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28782633">Schubert et al. (2018)</a> identified a heterozygous c.254T-A transversion in the SEC61A1 gene, resulting in a val85-to-asp (V85D) substitution at a highly conserved residue that forms the pore ring of the Sec61 channel. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Patient-derived B cells showed reduced SEC61A1 mRNA and protein levels and had significantly reduced immunoglobulin secretion compared to controls. Expression of the V85D mutation in HeLa cells caused increased ER/cytosol calcium leakage, impaired protein translocation, and increased ER stress. Multiple myeloma cells expressing the V85D mutation showed selectively impaired survival of plasma cells and strong activation of the terminal UPR. The V85D mutation showed a dominant-negative effect in the in vitro studies. Patient B cells did not differentiate into plasma cells in vitro, indicating a specific impairment of plasma cell homeostasis. Affected individuals had early onset of recurrent infections associated with antibody deficiency (IgM, IgG, and IgA), but normal levels of peripheral B cells, T cells, and NK cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28782633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003482899" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003482899" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003482899</a>
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<p>In 3 members of a 3-generation family (family 2) with common variable immunodeficiency-15 (CVID15; <a href="/entry/620670">620670</a>), <a href="#14" class="mim-tip-reference" title="Schubert, D., Klein, M.-C., Hassdenteufel, S., Caballero-Oteyza, A., Yang, L., Proietti, M., Bulashevska, A., Kemming, J., Kuhn, J., Winzer, S., Rusch, S., Fliegauf, M., and 16 others. <strong>Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).</strong> J. Allergy Clin. Immun. 141: 1427-1438, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28782633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28782633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28782633[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jaci.2017.06.042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28782633">Schubert et al. (2018)</a> identified a heterozygous c.1325G-T transversion in the SEC61A1 gene, resulting in a glu381-to-ter (E381X) substitution. The mutation, which was found by targeted next-generation sequencing of more than 200 patients with primary antibody deficiencies and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. SEC61A1 protein levels were decreased in patient naive B cells, but normal in patient CD8+ T cells. SEC61A1 mRNA levels were decreased in patient-derived B cells, and a truncated protein was not detected, suggesting that the mutation results in nonsense-mediated mRNA decay and haploinsufficiency. Patient B cells showed significantly reduced immunoglobulin secretion compared to controls. Affected individuals had early onset of recurrent infections associated with possibly transient antibody deficiency (IgM, IgG, and IgA), but normal numbers and subsets of peripheral B cells, T cells, and NK cells. Patient B cells did not differentiate into plasma cells in vitro, indicating a specific impairment of plasma cell homeostasis. However, the authors noted that the phenotype in this family showed variable expressivity and incomplete penetrance, likely due to SEC61A1 haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28782633" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 NEUTROPENIA, SEVERE CONGENITAL, 11, AUTOSOMAL DOMINANT (1 patient)</strong>
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SEC61A1, GLN92ARG
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV003482900" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV003482900" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV003482900</a>
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<p>In a 19-year-old woman, born of unrelated Belgian parents, with autosomal dominant severe congenital neutropenia-11 (SCN11; <a href="/entry/620674">620674</a>), <a href="#17" class="mim-tip-reference" title="Van Nieuwenhove, E., Barber, J. S., Neumann, J., Smeets, E., Willemsen, M., Pasciuto, E., Prezzemolo, T., Lagou, V., Seldeslachts, L., Malengier-Devlies, B., Metzemaekers, M., Hassdenteufel, S., and 18 others. <strong>Defective Sec61alpha1 underlies a novel cause of autosomal dominant severe congenital neutropenia.</strong> J. Allergy Clin. Immun. 146: 1180-1193, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32325141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32325141</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32325141[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.jaci.2020.03.034" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32325141">Van Nieuwenhove et al. (2020)</a> identified a de novo heterozygous c.275A-G transition (c.275A-G, NM_013336) in the SEC61A1 gene, resulting in a gln92-to-arg (Q92R) substitution at a conserved residue in transmembrane 2. The mutation, which was found by whole-exome sequencing, was not present in public databases. Patient peripheral blood mononuclear cells and fibroblasts showed decreased SEC61A1 protein expression, although mRNA levels were normal. The reduced protein expression correlated with decreased SEC61-dependent protein translocation across the ER. Patient CD34+ cells showed defective myeloid differentiation and neutrophil maturation in vitro. Patient bone marrow biopsy showed myeloid maturation arrest, and transcriptome analysis was consistent with decreased progenitor subsets of several populations, including B cells, common lymphoid progenitors, and granulocyte/myeloid progenitors. The macrophage/monocyte cluster demonstrated the most differentially expressed genes. There was also evidence of upregulation of the UPR and mitochondrial dysfunction. Accordingly, patient cells showed upregulation of the ER stress mechanism and increased susceptibility to apoptosis under ER stress conditions compared to controls. Similar cellular abnormalities, including arrested neutrophil differentiation, elevated ER stress, and activation of the UPR, were observed in HL-60 cells transduced with the mutation; this was associated with increased calcium leakage causing neutralization of the ER/cytosolic calcium gradient. The patient had normal B-cell numbers, but there was maturation arrest of B-cell precursors at the transitional B-cell stage. However, she had increased plasmablasts and hypergammaglobulinemia. NK cells also showed a maturation defect. Thus, although the primary presentation of the patient was consistent with severe congenital neutropenia, the mutation also affected other leukocyte populations. The findings indicated that the mutation resulted in a combined quantitative and functional SEC61A1 protein defect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32325141" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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<a id="Baron2016" class="mim-anchor"></a>
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Baron, L., Paatero, A. O., Morel, J.-D., Impens, F., Guenin-Mace, L., Saint-Auret, S., Blanchard, N., Dillmann, R., Niang, F., Pellegrini, S., Taunton, J., Paavilainen, V. O., Demangel, C.
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<strong>Mycolactone subverts immunity by selectively blocking the Sec61 translocon.</strong>
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J. Exp. Med. 213: 2885-2896, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27821549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27821549</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27821549[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=27821549" 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/10.1084/jem.20160662" target="_blank">Full Text</a>]
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<a id="Bebok1998" class="mim-anchor"></a>
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Bebok, Z., Mazzochi, C., King, S. A., Hong, J. S., Sorscher, E. J.
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<strong>The mechanism underlying cystic fibrosis transmembrane conductance regulator transport from the endoplasmic reticulum to the proteasome includes Sec61-beta and a cytosolic, deglycosylated intermediary.</strong>
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J. Biol. Chem. 273: 29873-29878, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9792704/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9792704</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9792704" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.273.45.29873" target="_blank">Full Text</a>]
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<a id="Becker2009" class="mim-anchor"></a>
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Becker, T., Bhushan, S., Jarasch, A., Armache, J.-P., Funes, S., Jossinet, F., Gumbart, J., Mielke, T., Berninghausen, O., Schulten, K., Westhof, E., Gilmore, R., Mandon, E. C., Beckmann, R.
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<strong>Structure of monomeric yeast and mammalian Sec61 complexes interacting with the translating ribosome.</strong>
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Science 326: 1369-1373, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19933108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19933108</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19933108[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=19933108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1178535" target="_blank">Full Text</a>]
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<a id="Bolar2016" class="mim-anchor"></a>
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Bolar, N. A., Golzio, C., Zivna, M., Hayot, G., Van Hemelrijk, C., Schepers, D., Vandeweyer, G., Hoischen, A., Huyghe, J. R., Raes, A., Matthys, E., Sys, E., and 26 others.
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<strong>Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia.</strong>
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Am. J. Hum. Genet. 99: 174-187, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27392076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27392076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27392076[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=27392076" 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.2016.05.028" target="_blank">Full Text</a>]
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<a id="Chen1998" class="mim-anchor"></a>
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Chen, Y., Le Caherec, F., Chuck, S. L.
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<strong>Calnexin and other factors that alter translocation affect the rapid binding of ubiquitin to apoB in the Sec61 complex.</strong>
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J. Biol. Chem. 273: 11887-11894, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9565615/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9565615</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9565615" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.273.19.11887" target="_blank">Full Text</a>]
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<a id="Espino-Hernandez2021" class="mim-anchor"></a>
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<div class="">
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Espino-Hernandez, M., Palma Milla, C., Vara-Martin, J., Gonzalez-Granado, L. I.
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<strong>De novo SEC61A1 mutation in autosomal dominant tubulo-interstitial kidney disease: phenotype expansion and review of literature.</strong>
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J. Paediat. Child Health 57: 1305-1307, 2021.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33185949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33185949</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33185949" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/jpc.15148" target="_blank">Full Text</a>]
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<a id="Gogala2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Gogala, M., Becker, T., Beatrix, B., Armache, J.-P., Barrio-Garcia, C., Berninghausen, O., Beckmann, R.
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<strong>Structures of the Sec61 complex engaged in nascent peptide translocation or membrane insertion.</strong>
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Nature 506: 107-110, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24499919/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24499919</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24499919" 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/nature12950" target="_blank">Full Text</a>]
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<a id="Greenfield1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Greenfield, J. J. A., High, S.
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<strong>The Sec61 complex is located in both the ER and the ER-Golgi intermediate compartment.</strong>
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J. Cell Sci. 112: 1477-1486, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10212142/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10212142</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10212142" 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/10.1242/jcs.112.10.1477" target="_blank">Full Text</a>]
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<a id="Hessa2005" class="mim-anchor"></a>
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Hessa, T., Kim, H., Bihlmaier, K., Lundin, C., Boekel, J., Andersson, H., Nilsson, I., White, S. H., von Heijne, G.
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<strong>Recognition of transmembrane helices by the endoplasmic reticulum translocon.</strong>
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Nature 433: 377-381, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15674282/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15674282</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15674282" 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/nature03216" target="_blank">Full Text</a>]
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<a id="Hessa2007" class="mim-anchor"></a>
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Hessa, T., Meindl-Beinker, N. M., Bernsel, A., Kim, H., Sato, Y., Lerch-Bader, M., Nilsson, I., White, S. H., von Heijne, G.
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<strong>Molecular code for transmembrane-helix recognition by the Sec61 translocon.</strong>
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Nature 450: 1026-1030, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18075582/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18075582</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18075582" 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/nature06387" target="_blank">Full Text</a>]
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Lloyd, D. J., Wheeler, M. C., Gekakis, N.
|
|
<strong>A point mutation in Sec6a1 leads to diabetes and hepatosteatosis in mice.</strong>
|
|
Diabetes 59: 460-470, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19934005/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19934005</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19934005[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=19934005" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
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[<a href="https://doi.org/10.2337/db08-1362" target="_blank">Full Text</a>]
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</p>
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</div>
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|
</li>
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<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Petaja-Repo2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Petaja-Repo, U. E., Hogue, M., Laperriere, A., Bhalla, S., Walker, P., Bouvier, M.
|
|
<strong>Newly synthesized human delta opioid receptors retained in the endoplasmic reticulum are retrotranslocated to the cytosol, deglycosylated, ubiquitinated, and degraded by the proteasome.</strong>
|
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J. Biol. Chem. 276: 4416-4423, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11054417/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11054417</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11054417" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.M007151200" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
|
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<a id="Reimold2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Reimold, A. M., Iwakoshi, N. N., Manis, J., Vallabhajosyula, P., Szomolanyi-Tsuda, E., Gravallese, E. M., Friend, D., Grusby, M. J., Alt, F., Glimcher, L. H.
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<strong>Plasma cell differentiation requires the transcription factor XBP-1.</strong>
|
|
Nature 412: 300-307, 2001.
|
|
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|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11460154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11460154</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11460154" 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/10.1038/35085509" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
|
|
<a id="Schubert2018" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schubert, D., Klein, M.-C., Hassdenteufel, S., Caballero-Oteyza, A., Yang, L., Proietti, M., Bulashevska, A., Kemming, J., Kuhn, J., Winzer, S., Rusch, S., Fliegauf, M., and 16 others.
|
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<strong>Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).</strong>
|
|
J. Allergy Clin. Immun. 141: 1427-1438, 2018.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28782633/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28782633</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28782633[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=28782633" 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.jaci.2017.06.042" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="15" class="mim-anchor"></a>
|
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<a id="Stumpf2024" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Stumpf, A. M.
|
|
<strong>Personal Communication.</strong>
|
|
Baltimore, Md. 01/12/2024.
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
|
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<a id="Taubenheim2012" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Taubenheim, N., Tarlinton, D. M., Crawford, S., Corcoran, L. M., Hodgkin, P. D., Nutt, S. L.
|
|
<strong>High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency.</strong>
|
|
J. Immun. 189: 3328-3338, 2012.
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22925926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22925926</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22925926" 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/10.4049/jimmunol.1201042" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Van Nieuwenhove2020" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Van Nieuwenhove, E., Barber, J. S., Neumann, J., Smeets, E., Willemsen, M., Pasciuto, E., Prezzemolo, T., Lagou, V., Seldeslachts, L., Malengier-Devlies, B., Metzemaekers, M., Hassdenteufel, S., and 18 others.
|
|
<strong>Defective Sec61alpha1 underlies a novel cause of autosomal dominant severe congenital neutropenia.</strong>
|
|
J. Allergy Clin. Immun. 146: 1180-1193, 2020.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32325141/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32325141</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32325141[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=32325141" 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.jaci.2020.03.034" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Wiertz1996" class="mim-anchor"></a>
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<div class="">
|
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<p class="mim-text-font">
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Wiertz, E. J. H. J., Tortorella, D., Bogyo, M., Yu, J., Mothes, W., Jones, T. R., Rapoport, T. A., Ploegh, H. L.
|
|
<strong>Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction.</strong>
|
|
Nature 384: 432-438, 1996.
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8945469/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8945469</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8945469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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[<a href="https://doi.org/10.1038/384432a0" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Anne M. Stumpf - updated : 01/12/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
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<span class="mim-text-font">
|
|
Cassandra L. Kniffin - updated : 01/10/2024<br>Paul J. Converse - updated : 01/11/2017<br>Cassandra L. Kniffin - updated : 07/27/2016<br>Ada Hamosh - updated : 05/05/2014<br>Ada Hamosh - updated : 1/6/2010<br>Ada Hamosh - updated : 4/22/2008<br>Ada Hamosh - updated : 2/23/2005
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
|
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
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Creation Date:
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
|
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Patricia A. Hartz : 2/22/2005
|
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/26/2025
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 01/12/2024<br>ckniffin : 01/10/2024<br>alopez : 02/09/2021<br>ckniffin : 01/26/2021<br>mgross : 01/03/2019<br>alopez : 02/22/2018<br>mgross : 01/11/2017<br>carol : 07/29/2016<br>ckniffin : 07/27/2016<br>alopez : 05/05/2014<br>alopez : 1/12/2010<br>terry : 1/6/2010<br>alopez : 5/14/2008<br>terry : 4/22/2008<br>alopez : 2/23/2005<br>terry : 2/23/2005<br>mgross : 2/22/2005
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
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<strong>*</strong> 609213
|
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</span>
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</h3>
|
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</div>
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<div>
|
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<h3>
|
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<span class="mim-font">
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|
|
SEC61 TRANSLOCON, ALPHA-1 SUBUNIT; SEC61A1
|
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</span>
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</h3>
|
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
SEC61 COMPLEX, ALPHA-1 SUBUNIT<br />
|
|
SEC61A<br />
|
|
SEC61, S. CEREVISIAE, HOMOLOG OF; SEC61
|
|
</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: SEC61A1</em></strong>
|
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</span>
|
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 3q21.3
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 3:128,051,641-128,071,683 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
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</p>
|
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</div>
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<div>
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
3q21.3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
?Neutropenia, severe congenital, 11, autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
620674
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
</tr>
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|
|
|
|
|
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|
|
|
|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Immunodeficiency, common variable, 15
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
620670
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Tubulointerstitial kidney disease, autosomal dominant, 5
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
617056
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
|
|
</tbody>
|
|
</table>
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|
</div>
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</div>
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<div>
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<br />
|
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</div>
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<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
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<span class="mim-font">
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<strong>Description</strong>
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<span class="mim-text-font">
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<p>SEC61A1 is a subunit of the heteromeric SEC61 complex, which also contains beta (SEC61B; 609214) and gamma (SEC61G; 609215) subunits. The SEC61 complex forms the core of the mammalian endoplasmic reticulum (ER) translocon, a transmembrane channel for the translocation of proteins across the ER membrane (Greenfield and High, 1999). Genes encoding the SEC61 complex are involved in the unfolded protein response (UPR) in the ER. The SEC61 complex also acts as a passive calcium leakage channel between the ER and the cytoplasm (summary by Schubert et al., 2018). </p>
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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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</h4>
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<p>Schubert et al. (2018) found that the relative abundance of SEC61A protein in plasmablasts from human peripheral blood was about 2-fold higher when compared to naive and memory B cells. This is consistent with a SEC61A1 being a target gene of XBP1 (194355) during plasma cell differentiation. XBP1 induces the transcription of genes encoding mediators of protein synthesis, transport, folding, and degradation, and plays a role in activation of the UPR during ER stress. </p>
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<h4>
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<strong>Gene Function</strong>
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<p>The SEC61 complex is an essential translocation component that can associate with either ribosomes or the SEC62 (602173)/SEC63 (608648) complex to perform cotranslational or posttranslational transport, respectively (Wiertz et al., 1996). It was originally thought to have a role only in translocation of proteins from the cytosol into the ER. However, Wiertz et al. (1996), Bebok et al. (1998), Chen et al. (1998), and Petaja-Repo et al. (2001) presented evidence suggesting that the human SEC61 complex can also function in retrograde transport of multidomain integral membrane proteins from the ER to the cytosol for proteasomal degradation. </p><p>By immunolocalization of fluorescence-tagged canine Sec61a transfected into COS-1 cells, Greenfield and High (1999) determined that the Sec61 complex distributed to both the ER and the ER-Golgi intermediate compartment, but not to the trans-Golgi network. Endogenous Sec61b and Sec61g showed the same distribution. Another translocon component, the glycoprotein Tram (see 605190) was also present in post-ER compartments, suggesting that the core components of the mammalian ER translocon are not permanently resident in the ER, but rather they are maintained in the ER by a specific retrieval mechanism. </p><p>Hessa et al. (2005) challenged the endoplasmic reticulum Sec61 translocon with an extensive set of designed polypeptide segments and determined the basic features of the code for recognition of transmembrane helices, including a 'biological' hydrophobicity scale. They found that membrane insertion depends strongly on the position of polar residues within transmembrane segments, adding a new dimension to the problem of predicting transmembrane helices from amino acid sequences. Hessa et al. (2005) concluded that direct protein-lipid interactions are critical during translocon-mediated membrane insertion. </p><p>Transmembrane alpha-helices in integral membrane proteins are recognized cotranslationally and inserted into the membrane of the endoplasmic reticulum by the Sec61 translocon. Using in vitro translation of a model protein in the presence of dog pancreas rough microsomes to analyze a large number of systematically designed hydrophobic segments, Hessa et al. (2007) presented a quantitative analysis of the position-dependent contribution of all 20 amino acids to membrane insertion efficiency, as well as of the effects of transmembrane segment length and flanking amino acids. The resulting picture of translocon-mediated transmembrane helix assembly is simple, with the critical sequence characteristics mirroring the physical properties of the lipid bilayer. </p><p>Mycolactone is an immunosuppressive and cytotoxic virulence factor of Mycobacterium ulcerans, the causative agent of Buruli ulcer (610446). By competitive binding analyses, Baron et al. (2016) showed that mycolactone bound tightly to SEC61A and had a slow dissociation rate. Screening of SEC61A mutants expressed in embryonic kidney cells revealed that mutations at arg66 or ser82 conferred resistance to cytotoxicity and mycolactone-mediated blockade of protein secretion and translocation. These mutations are located near the luminal plug of SEC61A. Proteomic analysis and in vitro translation experiments showed that a broad spectrum of proteins, particularly secreted proteins (e.g., IFNG; 147570) and single-pass type I/II membrane proteins (e.g., TNF; 191160), as well as the ER-resident protein BIP (HSPA5; 138120), were affected by mycolactone inhibition of SEC61A. Mycolactone inhibition of wildtype, but not mutant, Sec61 activity prevented production of Ifng by mouse T cells and responsiveness to Ifng through Ifngr (see 107470) in mouse macrophages. Mycolactone also affected Sec61-dependent Cd62l (153240) expression and Cd62l-dependent lymphocyte homing in mice. Baron et al. (2016) concluded that mycolactone inhibition of SEC61 prevents the production of key mediators of innate and adaptive immune responses against intracellular pathogens. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Becker et al. (2009) determined subnanometer-resolution cryoelectron microscopy structures of eukaryotic ribosome-Sec61 complexes. In combination with biochemical data, they found that in both idle and active states, the Sec complex is not oligomeric and interacts mainly via 2 cytoplasmic loops with the universal ribosomal adaptor site. In the active state, the ribosomal tunnel and a central pore of the monomeric protein-conducting channel were occupied by the nascent chain, contacting loop 6 of the Sec complex. Becker et al. (2009) concluded that this provides a structural basis for the activity of a solitary Sec complex in cotranslational protein translocation. </p><p>Gogala et al. (2014) presented cryoelectron microscopy structures of ribosome-bound SEC61 complexes engaged in translocation or membrane insertion of nascent peptides. The data showed that a hydrophilic peptide can translocate through the SEC complex with an essentially closed lateral gate and an only slightly rearranged central channel. Membrane insertion of a hydrophobic domain seems to occur with the SEC complex opening the proposed lateral gate while rearranging the plug to maintain an ion permeability barrier. Gogala et al. (2014) provided a structural model for the basic activities of the SEC61 complex as a protein-conducting channel. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Stumpf (2024) mapped the SEC61A1 gene to chromosome 3q21.3 based on an alignment of the SEC61A1 sequence (GenBank BC156688) with the genomic sequence (GRCh38).</p>
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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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</h4>
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<p><strong><em>Autosomal Dominant Tubulointerstitial Kidney Disease 5</em></strong></p><p>
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In affected members of 2 unrelated families with autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5; 617056), Bolar et al. (2016) identified 2 different heterozygous missense mutations in the SEC61A1 gene (T185A, 609213.0001 and V67G, 609213.0002). The mutation in the first family was found by a combination of linkage analysis and whole-exome sequencing, whereas the mutation in the second family was found by custom gene panel sequencing of 46 unrelated probands with a renal disorder; the mutations segregated with the disorder in both families. The mutations affected the selectivity and permeability of the pore of the translocon channel. Transfection of the mutations into HEK293 cells resulted in decreased protein levels compared to wildtype, and both mutant proteins formed intracellular clumps that were localized in the endoplasmic reticulum and partially in the Golgi apparatus. The findings suggested that the mutant proteins were subjected to endoplasmic-reticulum-associated degradation (ERAD) and increased ER stress. The mutant T185A protein was unable to rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 ortholog, suggesting that this mutation results in a complete loss of function. The V67G protein showed partial rescue of the zebrafish phenotype. The findings suggested that SEC61A1 is necessary for proper tubular organization of the nephron, and that the disorder results from protein translocation defects across the endoplasmic reticulum membrane. </p><p>In a 4-year-old girl with ADTKD5 and CD4+ T cell lymphopenia, Espino-Hernandez et al. (2021) identified a de novo heterozygous T185A mutation in the SEC61A1 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed. Neutrophil count and immunoglobulin levels were normal. Espino-Hernandez et al. (2021) noted that ADTKD5 may manifest as a syndromic form of progressive chronic kidney disease. </p><p><strong><em>Common Variable Immunodeficiency 15</em></strong></p><p>
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In 10 affected members of a family of northern European descent (family 1) with common variable immunodeficiency-15 (CVID15; 620670), Schubert et al. (2018) identified a heterozygous missense mutation in the SEC61A1 gene (V85D; 609213.0003). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Subsequent targeted next-generation sequencing of more than 200 patients with primary antibody deficiencies identified a second family in which 3 members had a heterozygous nonsense mutation in the SEC61A1 gene (E381X; 609213.0004). Patient-derived B cells from both families showed reduced SEC61A1 mRNA and protein levels and significantly reduced immunoglobulin secretion compared to controls. Studies of patient B cells and in vitro studies of transfected cells (including plasma cell-specific multiple myeloma cell lines) showed that the V85D mutation exerted a dominant-negative effect with increased ER/cytosolic calcium leakage depleting the calcium gradient, impaired protein translocation, increased ER stress, and activation of the terminal UPR pathway with increased levels of XBP1 (194355), CHOP (126337), and ATF4 (604064). Although the E381X mutation resulted in haploinsufficiency with a loss-of-function effect, the effect was similar: an inability to maintain ER homeostasis in times of stress, such as immunoglobulin production. Of note, the disorder in the second family showed incomplete penetrance and variable expressivity. Affected individuals from both families had early onset of recurrent infections associated with possibly transient antibody deficiency (IgM, IgG, and IgA), but normal numbers and subsets of peripheral B cells, T cells, and NK cells. Patient B cells did not differentiate into plasma cells in vitro, indicating a specific impairment of plasma cell homeostasis. Schubert et al. (2018) noted that studies in mice in which Xbp1 was conditionally deleted in B cells resulted in reduced immunoglobulin production by plasma cells and reduced expression of the Xbp1 target gene Sec61a1 (see, e.g., Reimold et al., 2001 and Taubenheim et al., 2012). </p><p><strong><em>Autosomal Dominant Severe Congenital Neutropenia 11</em></strong></p><p>
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In a 19-year-old woman, born of unrelated Belgian parents, with autosomal dominant severe congenital neutropenia-11 (SCN11; 620674), Van Nieuwenhove et al. (2020) identified a de novo heterozygous missense mutation in the SEC61A1 gene (Q92R; 609213.0005). The mutation, which was found by whole-exome sequencing, was not present in public databases. Patient peripheral blood mononuclear cells and fibroblasts showed decreased SEC61A1 protein expression that correlated with decreased SEC61-dependent protein translocation across the ER. Detailed in vitro studies in patient cells and HL-60 promyeloblasts showed that the mutation increased calcium leakage causing neutralization of the ER/cytosolic calcium gradient, increased ER stress, activation of the UPR, and increased susceptibility to apoptosis under ER stress conditions compared to controls. Patient CD34+ cells showed defective myeloid differentiation and neutrophil maturation in vitro. The patient had normal B-cell numbers, but there was maturation arrest of B-cell precursors at the transitional B-cell stage. However, she had increased plasmablasts and hypergammaglobulinemia. NK cells also showed a maturation defect. Thus, although the primary presentation of the patient was consistent with severe congenital neutropenia, the mutation also affected other leukocyte populations. The findings indicated that the mutation resulted in a combined quantitative and functional SEC61A1 protein defect. The authors stated that the clinical diversity in patients with SEC61A1 mutations is unclear, and that phenotypes cannot be predicted on the basis of location or nature of the mutation, as the effects are cell-intrinsic and cell-specific. However, a common disease mechanism appears to be that impaired SEC61A1 function leads to disrupted calcium flux, increased ER stress, and activation of the UPR. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>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>Lloyd et al. (2010) described a recessive diabetic mouse mutant resulting from a homozygous Y344H mutation in the Sec61a1 gene. In addition to diabetes and hyperglycemia due to insulin insufficiency, the mice had poor growth, hyperlipidemia, hypercholesterolemia, and hepatosteatosis. Cirrhosis was apparent in older mice. The associated hypoinsulinemia indicated pancreatic beta-cell failure. Immunohistochemical studies of wildtype mice showed high Sec61a1 expression in beta-cells in the pancreas, and the pancreas of mutant mice contained multiple apoptotic beta-cells resulting from increased ER stress. </p><p>Bolar et al. (2016) found that morpholino knockdown of the zebrafish sec61a1 ortholog in zebrafish embryos resulted in increased frequency of absence or decreased convolution of the pronephric tubules compared to wildtype, consistent with tubular atrophy. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>5 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 5</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SEC61A1, THR185ALA
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<br />
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SNP: rs879255648,
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ClinVar: RCV000239594
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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 7 affected members of a 3-generation family with autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5; 617056) Bolar et al. (2016) identified a heterozygous c.553A-G transition (c.553A-G, NM_013336.3) in the SEC61A1 gene, resulting in a thr185-to-ala (T185A) substitution at a conserved residue in transmembrane helix 5 that may affect the structural integrity of the channel. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project, Exome Variant Server, or ExAC databases, in 204 Belgian control chromosomes, or in several in-house exome databases. Immunohistochemical staining of a patient-derived kidney biopsy showed abnormal intracellular localization and aggregation of the mutant protein, with coarse granular cytoplasmic staining in tubules and collecting ducts. There was also absence of REN (179820) immunostaining in juxtaglomerular cells. The mutant protein was unable to rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 ortholog, suggesting that the mutation results in a complete loss of function. </p><p>In a 4-year-old girl with ADTKD5, Espino-Hernandez et al. (2021) identified a de novo heterozygous T185A mutation in the SEC61A1 gene. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed. She presented in infancy with poor overall growth, elevated uric acid, and mild anemia. Urinary concentrating ability was reduced and kidneys were at the lower limit of normal size. She also had mild psychomotor delay. She did not have recurrent infections, but immunologic work-up showed CD4+ T cell lymphopenia. Neutrophil count and immunoglobulin levels were normal. Espino-Hernandez et al. (2021) noted that ADTKD5 may manifest as a syndromic form of progressive chronic kidney disease. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 TUBULOINTERSTITIAL KIDNEY DISEASE, AUTOSOMAL DOMINANT 5</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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SEC61A1, VAL67GLY
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<br />
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SNP: rs752745051,
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ClinVar: RCV000239508
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a father and daughter with autosomal dominant tubulointerstitial kidney disease-5 (ADTKD5; 617056), Bolar et al. (2016) identified a heterozygous c.200T-G transversion (c.200T-G, NM_013336.3) in the SEC61A1 gene, resulting in a val67-to-gly (V67G) substitution at a conserved residue in the translocon pore; the residue is part of a plug domain that seals and stabilizes the pore during the closed state. The mutation, which was found by custom gene panel sequencing of 46 unrelated probands with a similar disorder, was not found in the 1000 Genomes Project, Exome Variant Server, or several in-house exome databases, but was found once in the ExAC database (1 of 121,410 alleles). Transfection of the mutation into HEK293 cells resulted in decreased protein levels compared to wildtype, and the mutant protein formed intracellular clumps that were localized in the endoplasmic reticulum and partially in the Golgi apparatus. The mutant protein was unable to fully rescue the tubular atrophy phenotype in zebrafish embryos with morpholino knockdown of the sec61a1 ortholog, suggesting that the mutation results in a partial loss of function. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 IMMUNODEFICIENCY, COMMON VARIABLE, 15</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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SEC61A1, VAL85ASP
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<br />
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SNP: rs1553721236,
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ClinVar: RCV000664064, RCV003482295
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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 10 affected members of a family of northern European descent (family 1) with common variable immunodeficiency-15 (CVID15; 620670), Schubert et al. (2018) identified a heterozygous c.254T-A transversion in the SEC61A1 gene, resulting in a val85-to-asp (V85D) substitution at a highly conserved residue that forms the pore ring of the Sec61 channel. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. Patient-derived B cells showed reduced SEC61A1 mRNA and protein levels and had significantly reduced immunoglobulin secretion compared to controls. Expression of the V85D mutation in HeLa cells caused increased ER/cytosol calcium leakage, impaired protein translocation, and increased ER stress. Multiple myeloma cells expressing the V85D mutation showed selectively impaired survival of plasma cells and strong activation of the terminal UPR. The V85D mutation showed a dominant-negative effect in the in vitro studies. Patient B cells did not differentiate into plasma cells in vitro, indicating a specific impairment of plasma cell homeostasis. Affected individuals had early onset of recurrent infections associated with antibody deficiency (IgM, IgG, and IgA), but normal levels of peripheral B cells, T cells, and NK cells. </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 IMMUNODEFICIENCY, COMMON VARIABLE, 15</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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SEC61A1, GLU381TER
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<br />
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ClinVar: RCV003482899
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 members of a 3-generation family (family 2) with common variable immunodeficiency-15 (CVID15; 620670), Schubert et al. (2018) identified a heterozygous c.1325G-T transversion in the SEC61A1 gene, resulting in a glu381-to-ter (E381X) substitution. The mutation, which was found by targeted next-generation sequencing of more than 200 patients with primary antibody deficiencies and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the gnomAD database. SEC61A1 protein levels were decreased in patient naive B cells, but normal in patient CD8+ T cells. SEC61A1 mRNA levels were decreased in patient-derived B cells, and a truncated protein was not detected, suggesting that the mutation results in nonsense-mediated mRNA decay and haploinsufficiency. Patient B cells showed significantly reduced immunoglobulin secretion compared to controls. Affected individuals had early onset of recurrent infections associated with possibly transient antibody deficiency (IgM, IgG, and IgA), but normal numbers and subsets of peripheral B cells, T cells, and NK cells. Patient B cells did not differentiate into plasma cells in vitro, indicating a specific impairment of plasma cell homeostasis. However, the authors noted that the phenotype in this family showed variable expressivity and incomplete penetrance, likely due to SEC61A1 haploinsufficiency. </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 NEUTROPENIA, SEVERE CONGENITAL, 11, AUTOSOMAL DOMINANT (1 patient)</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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SEC61A1, GLN92ARG
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<br />
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ClinVar: RCV003482900
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 19-year-old woman, born of unrelated Belgian parents, with autosomal dominant severe congenital neutropenia-11 (SCN11; 620674), Van Nieuwenhove et al. (2020) identified a de novo heterozygous c.275A-G transition (c.275A-G, NM_013336) in the SEC61A1 gene, resulting in a gln92-to-arg (Q92R) substitution at a conserved residue in transmembrane 2. The mutation, which was found by whole-exome sequencing, was not present in public databases. Patient peripheral blood mononuclear cells and fibroblasts showed decreased SEC61A1 protein expression, although mRNA levels were normal. The reduced protein expression correlated with decreased SEC61-dependent protein translocation across the ER. Patient CD34+ cells showed defective myeloid differentiation and neutrophil maturation in vitro. Patient bone marrow biopsy showed myeloid maturation arrest, and transcriptome analysis was consistent with decreased progenitor subsets of several populations, including B cells, common lymphoid progenitors, and granulocyte/myeloid progenitors. The macrophage/monocyte cluster demonstrated the most differentially expressed genes. There was also evidence of upregulation of the UPR and mitochondrial dysfunction. Accordingly, patient cells showed upregulation of the ER stress mechanism and increased susceptibility to apoptosis under ER stress conditions compared to controls. Similar cellular abnormalities, including arrested neutrophil differentiation, elevated ER stress, and activation of the UPR, were observed in HL-60 cells transduced with the mutation; this was associated with increased calcium leakage causing neutralization of the ER/cytosolic calcium gradient. The patient had normal B-cell numbers, but there was maturation arrest of B-cell precursors at the transitional B-cell stage. However, she had increased plasmablasts and hypergammaglobulinemia. NK cells also showed a maturation defect. Thus, although the primary presentation of the patient was consistent with severe congenital neutropenia, the mutation also affected other leukocyte populations. The findings indicated that the mutation resulted in a combined quantitative and functional SEC61A1 protein defect. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Anne M. Stumpf - updated : 01/12/2024<br>Cassandra L. Kniffin - updated : 01/10/2024<br>Paul J. Converse - updated : 01/11/2017<br>Cassandra L. Kniffin - updated : 07/27/2016<br>Ada Hamosh - updated : 05/05/2014<br>Ada Hamosh - updated : 1/6/2010<br>Ada Hamosh - updated : 4/22/2008<br>Ada Hamosh - updated : 2/23/2005
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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