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<title>
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Entry
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- *601978 - SIGMA NONOPIOID INTRACELLULAR RECEPTOR 1; SIGMAR1
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- OMIM
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<input type="hidden" id="mimSearchIndex" name="index" value="entry" />
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<input type="hidden" id="mimSearchLimit" name="limit" value="10" />
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<input type="search" id="mimEntrySearch" name="search" class="form-control" value="" placeholder="Search OMIM..." maxlength="5000" autocomplete="off" autocorrect="off" autocapitalize="none" spellcheck="false" autofocus />
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Advanced Search
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<a href="/search/advanced/entry"> OMIM </a>
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<li style="margin-left: 0.5em;">
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<a href="/search/advanced/clinicalSynopsis"> Clinical Synopses </a>
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<a href="/search/advanced/geneMap"> Gene Map </a>
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</form>
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<p />
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<div class="row">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601978</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<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="#geneStructure">Gene Structure</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/601978">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000147955;t=ENST00000277010" 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=10280" 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=601978" 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=ENSG00000147955;t=ENST00000277010" 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_001282205,NM_001282206,NM_001282207,NM_001282208,NM_001282209,NM_005866,NM_147157,NR_104108" 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_005866" 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=601978" 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=03580&isoform_id=03580_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/SIGMAR1" 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/1783387,1916800,5032117,7582320,13436170,21758465,22212934,31805330,48146267,54303908,62897357,74752153,109288136,109639387,109809962,119578835,119578838,119578839,119578840,119578841,158255620,194386746,532524982,532524984,532524986,532524988,532524990" 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/Q99720" 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=10280" 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=ENSG00000147955;t=ENST00000277010" 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=SIGMAR1" 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=SIGMAR1" 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+10280" 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/SIGMAR1" 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:10280" 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/10280" 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=chr9&hgg_gene=ENST00000277010.9&hgg_start=34634722&hgg_end=34637787&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=601978[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=601978[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://www.deciphergenomics.org/gene/SIGMAR1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000147955" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.gwascentral.org/search?q=SIGMAR1" 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=SIGMAR1" 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=SIGMAR1&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/PA164725706" 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:8157" 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://www.mousephenotype.org/data/genes/MGI:1195268" 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/SIGMAR1#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:1195268" 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/10280/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=10280" 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=WBGene00021093;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-040426-1006" 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">
|
|
<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:10280" 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=SIGMAR1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 763533003<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
601978
|
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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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SIGMA NONOPIOID INTRACELLULAR RECEPTOR 1; SIGMAR1
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SIGMA RECEPTOR, TYPE 1<br />
|
|
SR31747A-BINDING PROTEIN; SRBP
|
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</span>
|
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</h4>
|
|
</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>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SIGMAR1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SIGMAR1</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/9/152?start=-3&limit=10&highlight=152">9p13.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:34634722-34637787&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'})">9:34,634,722-34,637,787</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
|
</div>
|
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<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">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
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Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
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|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=614373,605726" 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="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/9/152?start=-3&limit=10&highlight=152">
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<p>The SIGMAR1 gene encodes an endoplasmic reticulum (ER) chaperone that binds a wide variety of ligands, including neurosteroids, psychostimulants, and dextrobenzomorphans. It is ubiquitously expressed, and is enriched in motor neurons of the brain and spinal cord (summary by <a href="#1" class="mim-tip-reference" title="Al-Saif, A., Al-Mohanna, F., Bohlega, S. <strong>A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis.</strong> Ann. Neurol. 70: 913-919, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21842496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21842496</a>] [<a href="https://doi.org/10.1002/ana.22534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21842496">Al-Saif et al., 2011</a>). SIGMAR1 has the ability to translocate from the ER to the plasma membrane or to mitochondrial-associated membranes (MAMs), and plays an important role in the regulation of ion channels (summary by <a href="#15" class="mim-tip-reference" title="Mavlyutov, T. A., Epstein, M. L., Andersen, K. A., Ziskind-Conhaim, L., Ruoho, A. E. <strong>The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons: an anatomical and behavioral study.</strong> Neuroscience 167: 247-255, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20167253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20167253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20167253[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.neuroscience.2010.02.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20167253">Mavlyutov et al., 2010</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21842496+20167253" 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>Sigma receptors are defined as nonopiate and nonphencyclidine sites that bind certain benzomorphan opioids with high affinity. <a href="#11" class="mim-tip-reference" title="Kekuda, R., Prasad, P. D., Fei, Y.-J., Leibach, F. H., Ganapathy, V. <strong>Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1).</strong> Biochem. Biophys. Res. Commun. 229: 553-558, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8954936/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8954936</a>] [<a href="https://doi.org/10.1006/bbrc.1996.1842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8954936">Kekuda et al. (1996)</a> cloned a functional sigma receptor type 1 cDNA from a human placental choriocarcinoma cell (JAR) library using a guinea pig-specific mRNA RT-PCR product (<a href="#9" class="mim-tip-reference" title="Hanner, M., Moebius, F. F., Flandorfer, A., Knaus, H. G., Striessnig, J., Kempner, E., Glossmann, H. <strong>Purification, molecular cloning, and expression of the mammalian sigma1-binding site.</strong> Proc. Nat. Acad. Sci. 93: 8072-8077, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755605</a>] [<a href="https://doi.org/10.1073/pnas.93.15.8072" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8755605">Hanner et al., 1996</a>). The human cDNA predicts a protein of 223 amino acids with a single putative transmembrane domain. It shares 93% identity with the guinea pig sigma receptor. The amino acid sequence motif MQWAVGRR, which is thought to be an endoplasmic reticulum retention signal, is present at the N terminus of both proteins. When functionally expressed in HeLa cells, the cDNA enhanced the binding of tritiated haloperidol, a sigma receptor ligand, to HeLa cell membranes. Several human tissues, including placenta, liver, pancreas, and brain, and several human intestinal and JAR cell lines express the sigma receptor type 1 to a variable degree. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8954936+8755605" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The sigma receptor ligand SR31747A is an immunosuppressive agent that blocks lymphocyte proliferation. It also blocks yeast proliferation by inhibiting Erg2, a sterol isomerase. <a href="#10" class="mim-tip-reference" title="Jbilo, O., Vidal, H., Paul, R., De Nys, N., Bensaid, M., Silve, S., Carayon, P., Davi, D., Galiegue, S., Bourrie, B., Guillemot, J.-C., Ferrara, P., Loison, G., Maffrand, J.-P., Le Fur, G., Casellas, P. <strong>Purification and characterization of the human SR 31747A-binding protein: a nuclear membrane protein related to yeast sterol isomerase.</strong> J. Biol. Chem. 272: 27107-27115, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341151</a>] [<a href="https://doi.org/10.1074/jbc.272.43.27107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9341151">Jbilo et al. (1997)</a> purified an SR31747A-binding protein from membrane preparations of a human T leukemia cell line, and using primers based on peptide fragments, followed by 5-prime RACE and screening a Burkitt lymphoma cell line cDNA library, <a href="#10" class="mim-tip-reference" title="Jbilo, O., Vidal, H., Paul, R., De Nys, N., Bensaid, M., Silve, S., Carayon, P., Davi, D., Galiegue, S., Bourrie, B., Guillemot, J.-C., Ferrara, P., Loison, G., Maffrand, J.-P., Le Fur, G., Casellas, P. <strong>Purification and characterization of the human SR 31747A-binding protein: a nuclear membrane protein related to yeast sterol isomerase.</strong> J. Biol. Chem. 272: 27107-27115, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341151</a>] [<a href="https://doi.org/10.1074/jbc.272.43.27107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9341151">Jbilo et al. (1997)</a> cloned SIGMAR1, which they called SRBP. The deduced 223-amino acid protein has a calculated molecular mass of 24.8 kD. SIGMAR1 has 2 hydrophobic stretches, one of which is a conserved central domain similar to that of yeast Erg2. SIGMAR1 shares 93% identity with guinea pig Sigmar1 and 29.9% identity with yeast Erg2. Northern blot analysis detected a 2.0-kb SIGMAR1 transcript in all tissues examined, with highest expression in liver and lowest expression in brain. RNA dot blot analysis confirmed ubiquitous expression and highest expression in adult and fetal liver. Immunohistochemical analysis and confocal microscopy showed SIGMAR1 associated with the nuclear envelope in several human cell types. SDS-PAGE and Western blot analysis showed that SIGMAR1 has an apparent molecular mass of 28 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9341151" 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 mouse tissue, <a href="#15" class="mim-tip-reference" title="Mavlyutov, T. A., Epstein, M. L., Andersen, K. A., Ziskind-Conhaim, L., Ruoho, A. E. <strong>The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons: an anatomical and behavioral study.</strong> Neuroscience 167: 247-255, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20167253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20167253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20167253[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.neuroscience.2010.02.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20167253">Mavlyutov et al. (2010)</a> found that Sigmar1 was localized primarily in motoneurons in the brainstem and spinal cord. Expression was restricted to large cholinergic postsynaptic densities on the soma of motoneurons, and colocalized with the Kv2.1 potassium channel (KCNB1; <a href="/entry/600397">600397</a>) and the muscarinic type 2 cholinergic receptor (CHRM2; <a href="/entry/118493">118493</a>). Ultrastructural studies showed that Sigmar1 was located close to, but separate from, the plasma membrane, possibly in cisternae formed from the ER. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20167253" 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 sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT), which also acts as a hallucinogen. <a href="#7" class="mim-tip-reference" title="Fontanilla, D., Johannessen, M., Hajipour, A. R., Cozzi, N. V., Jackson, M. B., Ruoho, A. E. <strong>The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator.</strong> Science 323: 934-937, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19213917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19213917</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19213917[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.1166127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19213917">Fontanilla et al. (2009)</a> demonstrated that DMT1 binds to sigma-1 receptors and inhibits voltage-gated sodium ion channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors. DMT induced hypermobility in wildtype mice but not in sigma-1 receptor knockout mice. <a href="#7" class="mim-tip-reference" title="Fontanilla, D., Johannessen, M., Hajipour, A. R., Cozzi, N. V., Jackson, M. B., Ruoho, A. E. <strong>The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator.</strong> Science 323: 934-937, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19213917/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19213917</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19213917[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.1166127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19213917">Fontanilla et al. (2009)</a> concluded that these biochemical, physiologic, and behavioral experiments indicated that DMT is an endogenous agonist for the sigma-1 receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19213917" 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 binding studies using yeast membranes, <a href="#10" class="mim-tip-reference" title="Jbilo, O., Vidal, H., Paul, R., De Nys, N., Bensaid, M., Silve, S., Carayon, P., Davi, D., Galiegue, S., Bourrie, B., Guillemot, J.-C., Ferrara, P., Loison, G., Maffrand, J.-P., Le Fur, G., Casellas, P. <strong>Purification and characterization of the human SR 31747A-binding protein: a nuclear membrane protein related to yeast sterol isomerase.</strong> J. Biol. Chem. 272: 27107-27115, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9341151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9341151</a>] [<a href="https://doi.org/10.1074/jbc.272.43.27107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9341151">Jbilo et al. (1997)</a> confirmed that human SIGMAR1 has a high affinity for SR31747A and has a pharmacologic profile identical to that determined for purified human and guinea pig sigma-1 receptors and yeast Erg2. Using Xenopus oocytes expressing guinea pig or rat sigma-1 receptors together with voltage-gated K+ channels (see Kv1.4, <a href="/entry/176266">176266</a>), <a href="#2" class="mim-tip-reference" title="Aydar, E., Palmer, C. P., Klyachko, V. A., Jackson, M. B. <strong>The sigma receptor as a ligand-regulated auxiliary potassium channel subunit.</strong> Neuron 34: 399-410, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11988171/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11988171</a>] [<a href="https://doi.org/10.1016/s0896-6273(02)00677-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11988171">Aydar et al. (2002)</a> showed that sigma-1 receptors function as ligand-regulated potassium channel subunits and modulate channel activity. Immunoprecipitation analysis of rat posterior pituitary membrane lysates confirmed that the sigma-1 receptor and Kv1.4 interact directly in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11988171+9341151" 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 alpha-motor neurons, SIGMAR1 is normally located at the plasma membrane in postsynaptic densities associated with cholinergic synapses. <a href="#18" class="mim-tip-reference" title="Prause, J., Goswami, A., Katona, I., Roos, A., Schnizler, M., Bushuven, E., Dreier, A., Buchkremer, S., Johann, S., Beyer, C., Deschauer, M., Troost, D., Weis, J. <strong>Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis.</strong> Hum. Molec. Genet. 22: 1581-1600, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23314020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23314020</a>] [<a href="https://doi.org/10.1093/hmg/ddt008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23314020">Prause et al. (2013)</a> found abnormal localization of SIGMAR1 in spinal cord sections from patients with various forms of amyotrophic lateral sclerosis (ALS; <a href="/entry/105400">105400</a>). In ALS tissue, SIGMAR1 localized in larger structures at the plasma membrane, as well as in the proximal axon and in the cytoplasm. These large accumulations of SIGMAR1 were ubiquitinated and costained with the 20S proteasome. However, SIGMAR1 was not present in p62 (<a href="/entry/601530">601530</a>) ubiquitinated protein aggregates. Skin fibroblasts from patients with ALS8 (<a href="/entry/608627">608627</a>) due to a P56S mutation in the VAPB gene (<a href="/entry/605704#0001">605704.0001</a>) showed accumulation of SIGMAR1 with mutant VAPB in ubiquitinated aggregates. Soluble SIGMAR1 protein levels were decreased in ALS and Sod1 (<a href="/entry/147450">147450</a>)-mutant mouse lumbar spinal cord. Knockdown of SIGMAR1 in neuronal cells resulted in activation of the unfolded protein response mechanism, increased ER stress, and proteasomal dysfunction. This was associated with increased intracellular calcium, apoptosis, and abnormalities in ER and Golgi structures. Pharmacologic activation of SIGMAR1 decreased the mutant VAPB aggregation and had a neuroprotective effect. <a href="#18" class="mim-tip-reference" title="Prause, J., Goswami, A., Katona, I., Roos, A., Schnizler, M., Bushuven, E., Dreier, A., Buchkremer, S., Johann, S., Beyer, C., Deschauer, M., Troost, D., Weis, J. <strong>Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis.</strong> Hum. Molec. Genet. 22: 1581-1600, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23314020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23314020</a>] [<a href="https://doi.org/10.1093/hmg/ddt008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23314020">Prause et al. (2013)</a> suggested that SIGMAR1 is critical for neuronal survival and maintenance, and that alteration of its normal function may contribute to ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23314020" 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="#17" class="mim-tip-reference" title="Prasad, P. D., Li, H. W., Fei, Y.-J., Ganapathy, M. E., Fujita, T., Plumley, L. H., Yang-Feng, T. L., Leibach, F. H., Ganapathy, V. <strong>Exon-intron structure, analysis or promoter region, and chromosomal localization of the human type 1 sigma receptor gene.</strong> J. Neurochem. 70: 443-451, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9453537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9453537</a>] [<a href="https://doi.org/10.1046/j.1471-4159.1998.70020443.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9453537">Prasad et al. (1998)</a> determined that the SIGMAR1 gene contains 4 exons and spans about 7 kb. The upstream region contains a CCAATC box on the reverse strand, but no TATA box. It also contains several GC boxes for SP1 (<a href="/entry/189906">189906</a>) binding and consensus sequences for liver-specific factors, cytokine-responsive factors, and a xenobiotic-responsive factor (AHR; <a href="/entry/600253">600253</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9453537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By Southern blot analysis of Chinese hamster-human and mouse-human hybrid cell lines and FISH, <a href="#17" class="mim-tip-reference" title="Prasad, P. D., Li, H. W., Fei, Y.-J., Ganapathy, M. E., Fujita, T., Plumley, L. H., Yang-Feng, T. L., Leibach, F. H., Ganapathy, V. <strong>Exon-intron structure, analysis or promoter region, and chromosomal localization of the human type 1 sigma receptor gene.</strong> J. Neurochem. 70: 443-451, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9453537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9453537</a>] [<a href="https://doi.org/10.1046/j.1471-4159.1998.70020443.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9453537">Prasad et al. (1998)</a> mapped the SIGMAR1 gene to chromosome 9p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9453537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Juvenile Amyotrophic Lateral Sclerosis 16</em></strong></p><p>
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In affected members of a consanguineous Saudi Arabian family with juvenile amyotrophic lateral sclerosis-16 (ALS16; <a href="/entry/614373">614373</a>), <a href="#1" class="mim-tip-reference" title="Al-Saif, A., Al-Mohanna, F., Bohlega, S. <strong>A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis.</strong> Ann. Neurol. 70: 913-919, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21842496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21842496</a>] [<a href="https://doi.org/10.1002/ana.22534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21842496">Al-Saif et al. (2011)</a> identified a homozygous mutation in the SIGMAR1 gene (E102Q; <a href="#0001">601978.0001</a>). In vitro functional expression assays in the motor neuron-like cell line NSC34 showed that the mutant protein was shifted to lower density membranes and formed detergent-resistant complexes. Transfected cells also showed an almost 2-fold increase in apoptosis in response to stress compared to controls. The findings indicated that the mutation decreases the viability of motor neurons. The patients had a very early age of onset, at 1 to 2 years, of lower limb spasticity and weakness. The disorder was slowly progressive, and later involved the upper limbs. Two patients were wheelchair-bound by age 20 years. None of the patients had bulbar or respiratory involvement, and all had normal cognition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21842496" 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 Recessive Distal Hereditary Motor Neuronopathy 2</em></strong></p><p>
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In 3 members of a consanguineous Chinese family with childhood-onset autosomal recessive distal hereditary motor neuronopathy-2 (HMNR2; <a href="/entry/605726">605726</a>), <a href="#13" class="mim-tip-reference" title="Li, X., Hu, Z., Liu, L., Xie, Y., Zhan, Y., Zi, X., Wang, J., Wu, L., Xia, K., Tang, B., Zhang, R. <strong>A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.</strong> Neurology 84: 2430-2437, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26078401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26078401</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001680" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26078401">Li et al. (2015)</a> identified a homozygous mutation in the SIGMAR1 gene (<a href="#0003">601978.0003</a>). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression assays in HEK293 cells showed that the mutation resulted in reduced levels of the protein due to increased proteasomal degradation through the ER-associated degradation (ERAD) pathway. The mutant cell lines showed increased ER stress and apoptosis compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26078401" 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>Associations Pending Confirmation</em></strong></p><p>
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In affected members of an Australian family (AUS-14) with frontotemporal dementia and/or motor neuron disease (<a href="/entry/105550">105550</a>), <a href="#14" class="mim-tip-reference" title="Luty, A. A., Kwok, J. B., Dobson-Stone, C., Loy, C. T., Coupland, K. G., Karlstrom, H., Sobow, T., Tchorzewska, J., Maruszak, A., Barcikowska, M., Panegyres, P. K., Zekanowski, C., Brooks, W. S., Williams, K. L., Blair, I. P., Mather, K. A, Sachdev, P. S, Halliday, G. M., Schofield, P. R. <strong>Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.</strong> Ann. Neurol. 68: 639-649, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21031579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21031579</a>] [<a href="https://doi.org/10.1002/ana.22274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21031579">Luty et al. (2010)</a> identified a heterozygous G-to-T transversion (672*51G-T) in the 3-prime untranslated region (UTR) of the SIGMAR1 gene. The mutation was not found in 1,269 normal controls. In vitro functional expression studies in human neuroblastoma, HEK293 cells, and patient lymphocytes showed that the substitution resulted in about 2-fold increased expression of SIGMAR1 compared to wildtype, and neuropathologic study of affected individuals showed increased SIGMAR1 protein in frontal cortex tissue. Studies of brain tissue from controls and from individuals with unrelated form of FTLD showed that sigma-1 was localized on membranes within the cytoplasm of most neurons, astrocytes, and oligodendroglia, whereas in 2 patients with the 672*51G-T mutation, it was concentrated within the nucleus of degenerating neurons. Patients with the 672*51G-T mutation also had TDP43 (TARDBP; <a href="/entry/605078">605078</a>)- and FUS (<a href="/entry/137070">137070</a>)-positive inclusions in affected brain regions, although in different neuronal populations. Overexpression of SIGMAR1 in cell lines resulted in increased levels of TDP43 protein, but not TDP43 transcripts, and caused a change in localization of TDP43 from the nucleus to the cytoplasm. <a href="#14" class="mim-tip-reference" title="Luty, A. A., Kwok, J. B., Dobson-Stone, C., Loy, C. T., Coupland, K. G., Karlstrom, H., Sobow, T., Tchorzewska, J., Maruszak, A., Barcikowska, M., Panegyres, P. K., Zekanowski, C., Brooks, W. S., Williams, K. L., Blair, I. P., Mather, K. A, Sachdev, P. S, Halliday, G. M., Schofield, P. R. <strong>Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.</strong> Ann. Neurol. 68: 639-649, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21031579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21031579</a>] [<a href="https://doi.org/10.1002/ana.22274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21031579">Luty et al. (2010)</a> postulated that the 672*51G-T mutation, which occurs in the 3-prime UTR of the SIGMAR1 gene, alters transcript stability and increases gene expression, resulting in increased pathogenic alterations of TDP43 and FUS. An unrelated patient from another Australian family (AUS-47) with frontotemporal dementia without motor neuron disease carried a heterozygous c.672*26C-T transition, and an unrelated patient from a Polish family (POL-1) with a diagnosis of Alzheimer disease (AD; <a href="/entry/104300">104300</a>) and aphasia carried a heterozygous c.672*47G-A transition. Both variants occurred in the 3-prime UTR and were absent from 169 elderly controls and 1,110 normal controls, but segregation analysis in these 2 families was not possible. Neither patient had motor neuron disease. <a href="#6" class="mim-tip-reference" title="Dobson-Stone, C., Hallupp, M., Loy, C. T., Thompson, E. M., Haan, E., Sue, C. M., Panegyres, P. K., Razquin, C., Seijo-Martinez, M., Rene, R., Gascon, J., Campdelacreu, J., Schmoll, B., Volk, A. E., Brooks, W. S., Schofield, P. R., Pastor, P., Kwok, J. B. J. <strong>C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementia patients.</strong> PLoS One 8: e56899, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23437264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23437264</a>] [<a href="https://doi.org/10.1371/journal.pone.0056899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23437264">Dobson-Stone et al. (2013)</a> noted that the AUS-14 family reported by <a href="#14" class="mim-tip-reference" title="Luty, A. A., Kwok, J. B., Dobson-Stone, C., Loy, C. T., Coupland, K. G., Karlstrom, H., Sobow, T., Tchorzewska, J., Maruszak, A., Barcikowska, M., Panegyres, P. K., Zekanowski, C., Brooks, W. S., Williams, K. L., Blair, I. P., Mather, K. A, Sachdev, P. S, Halliday, G. M., Schofield, P. R. <strong>Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.</strong> Ann. Neurol. 68: 639-649, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21031579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21031579</a>] [<a href="https://doi.org/10.1002/ana.22274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21031579">Luty et al. (2010)</a> also carried a pathogenic expansion in the C9ORF72 gene (<a href="/entry/614260#0001">614260.0001</a>) that segregated with the disorder and was thus likely responsible for the phenotype. However, <a href="#6" class="mim-tip-reference" title="Dobson-Stone, C., Hallupp, M., Loy, C. T., Thompson, E. M., Haan, E., Sue, C. M., Panegyres, P. K., Razquin, C., Seijo-Martinez, M., Rene, R., Gascon, J., Campdelacreu, J., Schmoll, B., Volk, A. E., Brooks, W. S., Schofield, P. R., Pastor, P., Kwok, J. B. J. <strong>C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementia patients.</strong> PLoS One 8: e56899, 2013. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23437264/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23437264</a>] [<a href="https://doi.org/10.1371/journal.pone.0056899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23437264">Dobson-Stone et al. (2013)</a> excluded a pathogenic expansion of the C9ORF72 gene in the proband of the AUS-47 family. <a href="#16" class="mim-tip-reference" title="Pickering-Brown, S., Hardy, J. <strong>Is SIGMAR1 a confirmed FTD/MND gene? (Letter)</strong> Brain 138: e393, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26088964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26088964</a>] [<a href="https://doi.org/10.1093/brain/awv173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26088964">Pickering-Brown and Hardy (2015)</a> commented that the disease in the AUS-14 family reported by <a href="#14" class="mim-tip-reference" title="Luty, A. A., Kwok, J. B., Dobson-Stone, C., Loy, C. T., Coupland, K. G., Karlstrom, H., Sobow, T., Tchorzewska, J., Maruszak, A., Barcikowska, M., Panegyres, P. K., Zekanowski, C., Brooks, W. S., Williams, K. L., Blair, I. P., Mather, K. A, Sachdev, P. S, Halliday, G. M., Schofield, P. R. <strong>Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.</strong> Ann. Neurol. 68: 639-649, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21031579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21031579</a>] [<a href="https://doi.org/10.1002/ana.22274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21031579">Luty et al. (2010)</a> was likely caused by the C9ORF72 expansion rather than the SIGMAR1 variant, and questioned the role of SIGMA1 variants in frontotemporal dementia/motor neuron disease (FTD/MND). In a reply to <a href="#16" class="mim-tip-reference" title="Pickering-Brown, S., Hardy, J. <strong>Is SIGMAR1 a confirmed FTD/MND gene? (Letter)</strong> Brain 138: e393, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26088964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26088964</a>] [<a href="https://doi.org/10.1093/brain/awv173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26088964">Pickering-Brown and Hardy (2015)</a>, <a href="#5" class="mim-tip-reference" title="Bernard-Marissal, N., Medard, J.-J., Azzedine, H., Chrast, R. <strong>Reply to Pickering-Brown and Hardy. (Letter)</strong> Brain 138: e394, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26088963/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26088963</a>] [<a href="https://doi.org/10.1093/brain/awv174" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26088963">Bernard-Marissal et al. (2015)</a> reiterated that their interest in the role of SIGMAR1 in motor neurons was based on several previous findings, including the presence of motor disabilities in the Sigmar1 knockout mouse, high expression of SIGMAR1 in motor neurons, dysregulation of SIGMAR1 in tissues from patients with amyotrophic lateral sclerosis, and implication of SIGMAR1 in other motor neuron disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26088963+21031579+26088964+23437264" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Belzil, V. V., Daoud, H., Camu, W., Strong, M. J., Dion, P. A., Rouleau, G. A. <strong>Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia.</strong> Europ. J. Hum. Genet. 21: 237-239, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22739338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22739338</a>] [<a href="https://doi.org/10.1038/ejhg.2012.135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22739338">Belzil et al. (2013)</a> did not identify any coding or noncoding variants in the SIGMAR1 gene among 25 patients with ALS and a family history of dementia. A G-to-T transversion (672*43G-T) in the 3-prime untranslated region was found in 1 patient, but this was also found in 1 of 190 controls. Moreover, a C9ORF72 repeat expansion (<a href="/entry/614260#0001">614260.0001</a>) was subsequently identified in this patient and in 52% of the entire cohort. <a href="#3" class="mim-tip-reference" title="Belzil, V. V., Daoud, H., Camu, W., Strong, M. J., Dion, P. A., Rouleau, G. A. <strong>Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia.</strong> Europ. J. Hum. Genet. 21: 237-239, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22739338/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22739338</a>] [<a href="https://doi.org/10.1038/ejhg.2012.135" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22739338">Belzil et al. (2013)</a> suggested that the SIGMAR1 variants identified by <a href="#14" class="mim-tip-reference" title="Luty, A. A., Kwok, J. B., Dobson-Stone, C., Loy, C. T., Coupland, K. G., Karlstrom, H., Sobow, T., Tchorzewska, J., Maruszak, A., Barcikowska, M., Panegyres, P. K., Zekanowski, C., Brooks, W. S., Williams, K. L., Blair, I. P., Mather, K. A, Sachdev, P. S, Halliday, G. M., Schofield, P. R. <strong>Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.</strong> Ann. Neurol. 68: 639-649, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21031579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21031579</a>] [<a href="https://doi.org/10.1002/ana.22274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21031579">Luty et al. (2010)</a> actually segregated with C9ORF72 expansions, and that SIGMAR1 variants are not a cause of ALS with dementia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21031579+22739338" 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="#12" class="mim-tip-reference" title="Langa, F., Codony, X., Tovar, V., Lavado, A., Gimenez, E., Cozar, P., Cantero, M., Dordal, A., Hernandez, E., Perez, R., Monroy, X., Zamanillo, D., Guitart, X., Montoliu, L. <strong>Generation and phenotypic analysis of sigma receptor type 1 (sigma1) knockout mice.</strong> Europ. J. Neurosci. 18: 2188-2196, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14622179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14622179</a>] [<a href="https://doi.org/10.1046/j.1460-9568.2003.02950.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14622179">Langa et al. (2003)</a> found that Sigmar1-null mice were viable and fertile, and did not display any overt phenotype compared to wildtype mice. However, mutant mice showed a decrease in the hypermotility response upon challenge with a ligand. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14622179" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Mavlyutov, T. A., Epstein, M. L., Andersen, K. A., Ziskind-Conhaim, L., Ruoho, A. E. <strong>The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons: an anatomical and behavioral study.</strong> Neuroscience 167: 247-255, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20167253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20167253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20167253[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.neuroscience.2010.02.022" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20167253">Mavlyutov et al. (2010)</a> found that Sigmar1-null mice had impaired motor coordination and function on the rotorod test compared to wildtype mice. Knockout mice also showed motor differences compared to wildtype mice in a swimming test: knockout mice used their tails, but not their front paws, whereas wildtype mice used their front paws and not their tails. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20167253" 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="Bernard-Marissal, N., Medard, J.-J., Azzedine, H., Chrast, R. <strong>Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration.</strong> Brain 138: 875-890, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25678561/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25678561</a>] [<a href="https://doi.org/10.1093/brain/awv008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25678561">Bernard-Marissal et al. (2015)</a> found that Sigmar1-null mice had motor deficits and muscle weakness associated with denervation at the neuromuscular junction and loss of motor neurons in the spinal cord; fast motor neurons and muscle fibers were particularly affected. Motor neurons derived from Sigmar1-null mice showed a decrease in the ER-mitochondria connection compared to wildtype, suggesting a disruption of MAMs. Mutant cells showed defective calcium signaling as well as disrupted intracellular calcium homeostasis and increased ER stress, resulting in motor neuron and axonal degeneration. Additional findings included abnormal mitochondrial morphology in motor neurons and disruption of mitochondrial axonal transport. Intracellular calcium scavenging and ER stress inhibition were able to restore mitochondrial function and prevent motor neuron degeneration. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25678561" 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 affected members of a consanguineous Saudi Arabian family with juvenile ALS16 (<a href="/entry/614373">614373</a>), <a href="#1" class="mim-tip-reference" title="Al-Saif, A., Al-Mohanna, F., Bohlega, S. <strong>A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis.</strong> Ann. Neurol. 70: 913-919, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21842496/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21842496</a>] [<a href="https://doi.org/10.1002/ana.22534" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21842496">Al-Saif et al. (2011)</a> identified a homozygous 304G-C transversion in exon 2 of the SIGMAR1 gene, resulting in a glu102-to-gln (E102Q) substitution in a highly conserved residue in the predicted transmembrane domain. The mutation was not found in 271 controls. In vitro functional expression assays in the motor neuron-like cell line NSC34 showed that the mutant protein was shifted to lower density membranes and formed detergent-resistant complexes. Transfected cells also showed an almost 2-fold increase in apoptosis in response to stress compared to controls. The findings indicated that the mutation decreases the viability of motor neurons. The patients had a very early age of onset, at 1 to 2 years, of lower limb spasticity and weakness. The disorder was slowly progressive, and involved the upper limbs. Two patients were wheelchair-bound by age 20 years. None of the patients had bulbar or respiratory involvement, and all had normal cognition. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21842496" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Fukunaga, K., Shinoda, Y., Tagashira, H. <strong>The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis.</strong> J. Pharm. Sci. 127: 36-41, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25704016/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25704016</a>] [<a href="https://doi.org/10.1016/j.jphs.2014.12.012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25704016">Fukunaga et al. (2015)</a> found that transfection of the E102Q mutation into neuro2A cells resulted in dissociation of the mutant protein from the ER membrane and subsequent cytoplasmic aggregation. This was associated with disruption of mitochondrial structure, mitochondrial damage, decreased ATP production, and autophagic cell death. Cells overexpressing E102Q showed aberrant extranuclear localization of TDP43 (<a href="/entry/605078">605078</a>), a hallmark of ALS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25704016" 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=RCV000190342 OR RCV001515374 OR RCV001721241 OR RCV001807120" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190342, RCV001515374, RCV001721241, RCV001807120" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190342...</a>
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<p>This variant is classified as a variant of unknown significance because its contribution to amyotrophic lateral sclerosis-16 (ALS16; <a href="/entry/614373">614373</a>) has not been confirmed.</p><p>In 2 sibs, born of consanguineous Pakistani parents, with amyotrophic lateral sclerosis, <a href="#19" class="mim-tip-reference" title="Ullah, M. I., Ahmad, A., Raza, S. I., Amar, A., Ali, A., Bhatti, A., John, P., Mohyuddin, A., Ahmad, W., Hassan, M. J. <strong>In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia.</strong> Neurogenetics 16: 299-306, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26205306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26205306</a>] [<a href="https://doi.org/10.1007/s10048-015-0453-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26205306">Ullah et al. (2015)</a> identified a homozygous A-to-G transition in the 3-prime UTR of the SIGMAR1 gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4879809;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs4879809</a>) The variant was not found in 100 healthy ethnically matched controls. Functional studies of the variant were not performed, but the variant was predicted to disturb miRNA binding, which could affect regulation of gene expression. The patients had no signs of dementia. Linkage analysis excluded a pathogenic expanded hexanucleotide repeat in the C9ORF72 gene (<a href="/entry/614260">614260</a>) in this family. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26205306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs796065352 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs796065352;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs796065352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs796065352" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000190343" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000190343" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000190343</a>
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<p>In 3 members of a consanguineous Chinese family with childhood-onset autosomal recessive distal hereditary motor neuronopathy-2 (HMNR2; <a href="/entry/605726">605726</a>), <a href="#13" class="mim-tip-reference" title="Li, X., Hu, Z., Liu, L., Xie, Y., Zhan, Y., Zi, X., Wang, J., Wu, L., Xia, K., Tang, B., Zhang, R. <strong>A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.</strong> Neurology 84: 2430-2437, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26078401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26078401</a>] [<a href="https://doi.org/10.1212/WNL.0000000000001680" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26078401">Li et al. (2015)</a> identified a homozygous G-to-T transversion (c.151+1G-T, NM_005866.3) affecting a splice site in the SIGMAR1 gene, resulting in an in-frame deletion of 20 amino acids in exon 1 (c.92_151del, p.31_50del) in the putative extracellular loop. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in 500 Chinese controls. In vitro functional expression assays in HEK293 cells showed that the mutation resulted in lower levels of the protein due to increased proteasomal degradation through the ER-associated degradation (ERAD) pathway. The mutant cell lines showed increased ER stress and apoptosis compared to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26078401" 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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Li, X., Hu, Z., Liu, L., Xie, Y., Zhan, Y., Zi, X., Wang, J., Wu, L., Xia, K., Tang, B., Zhang, R.
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<strong>A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.</strong>
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Neurology 84: 2430-2437, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26078401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26078401</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26078401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0000000000001680" target="_blank">Full Text</a>]
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Luty, A. A., Kwok, J. B., Dobson-Stone, C., Loy, C. T., Coupland, K. G., Karlstrom, H., Sobow, T., Tchorzewska, J., Maruszak, A., Barcikowska, M., Panegyres, P. K., Zekanowski, C., Brooks, W. S., Williams, K. L., Blair, I. P., Mather, K. A, Sachdev, P. S, Halliday, G. M., Schofield, P. R.
|
|
<strong>Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.</strong>
|
|
Ann. Neurol. 68: 639-649, 2010.
|
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21031579/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21031579</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21031579" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.22274" 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="Mavlyutov2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mavlyutov, T. A., Epstein, M. L., Andersen, K. A., Ziskind-Conhaim, L., Ruoho, A. E.
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<strong>The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons: an anatomical and behavioral study.</strong>
|
|
Neuroscience 167: 247-255, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20167253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20167253</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20167253[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=20167253" 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.neuroscience.2010.02.022" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Pickering-Brown2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pickering-Brown, S., Hardy, J.
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<strong>Is SIGMAR1 a confirmed FTD/MND gene? (Letter)</strong>
|
|
Brain 138: e393, 2015. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26088964/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26088964</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26088964" 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/10.1093/brain/awv173" 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="Prasad1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Prasad, P. D., Li, H. W., Fei, Y.-J., Ganapathy, M. E., Fujita, T., Plumley, L. H., Yang-Feng, T. L., Leibach, F. H., Ganapathy, V.
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<strong>Exon-intron structure, analysis or promoter region, and chromosomal localization of the human type 1 sigma receptor gene.</strong>
|
|
J. Neurochem. 70: 443-451, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9453537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9453537</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9453537" 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/10.1046/j.1471-4159.1998.70020443.x" 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="Prause2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Prause, J., Goswami, A., Katona, I., Roos, A., Schnizler, M., Bushuven, E., Dreier, A., Buchkremer, S., Johann, S., Beyer, C., Deschauer, M., Troost, D., Weis, J.
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<strong>Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis.</strong>
|
|
Hum. Molec. Genet. 22: 1581-1600, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23314020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23314020</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23314020" 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/10.1093/hmg/ddt008" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Ullah2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ullah, M. I., Ahmad, A., Raza, S. I., Amar, A., Ali, A., Bhatti, A., John, P., Mohyuddin, A., Ahmad, W., Hassan, M. J.
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<strong>In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia.</strong>
|
|
Neurogenetics 16: 299-306, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26205306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26205306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26205306" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-015-0453-1" 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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Cassandra L. Kniffin - updated : 8/3/2015
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 3/19/2014<br>Cassandra L. Kniffin - updated : 3/20/2013<br>Cassandra L. Kniffin - updated : 12/8/2011<br>Cassandra L. Kniffin - updated : 3/8/2011<br>Patricia A. Hartz - updated : 6/30/2009<br>Ada Hamosh - updated : 2/23/2009
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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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Ethylin Wang Jabs : 8/21/1997
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/17/2023
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 12/17/2015<br>alopez : 11/24/2015<br>alopez : 8/11/2015<br>mcolton : 8/3/2015<br>ckniffin : 8/3/2015<br>carol : 3/25/2014<br>mcolton : 3/24/2014<br>ckniffin : 3/19/2014<br>carol : 3/27/2013<br>ckniffin : 3/20/2013<br>terry : 4/30/2012<br>carol : 12/8/2011<br>ckniffin : 12/8/2011<br>wwang : 3/9/2011<br>ckniffin : 3/8/2011<br>alopez : 7/7/2009<br>terry : 6/30/2009<br>alopez : 2/25/2009<br>terry : 2/23/2009<br>mark : 9/5/1997<br>mark : 9/5/1997
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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> 601978
|
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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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SIGMA NONOPIOID INTRACELLULAR RECEPTOR 1; SIGMAR1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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SIGMA RECEPTOR, TYPE 1<br />
|
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SR31747A-BINDING PROTEIN; SRBP
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SIGMAR1</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 763533003;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 9p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:34,634,722-34,637,787 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
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|
Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
|
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<td rowspan="2">
|
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<span class="mim-font">
|
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9p13.3
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
?Amyotrophic lateral sclerosis 16, juvenile
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
614373
|
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</span>
|
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</td>
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<td>
|
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<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
?Neuronopathy, distal hereditary motor, autosomal recessive 2
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
605726
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>The SIGMAR1 gene encodes an endoplasmic reticulum (ER) chaperone that binds a wide variety of ligands, including neurosteroids, psychostimulants, and dextrobenzomorphans. It is ubiquitously expressed, and is enriched in motor neurons of the brain and spinal cord (summary by Al-Saif et al., 2011). SIGMAR1 has the ability to translocate from the ER to the plasma membrane or to mitochondrial-associated membranes (MAMs), and plays an important role in the regulation of ion channels (summary by Mavlyutov et al., 2010). </p>
|
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</span>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</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>Sigma receptors are defined as nonopiate and nonphencyclidine sites that bind certain benzomorphan opioids with high affinity. Kekuda et al. (1996) cloned a functional sigma receptor type 1 cDNA from a human placental choriocarcinoma cell (JAR) library using a guinea pig-specific mRNA RT-PCR product (Hanner et al., 1996). The human cDNA predicts a protein of 223 amino acids with a single putative transmembrane domain. It shares 93% identity with the guinea pig sigma receptor. The amino acid sequence motif MQWAVGRR, which is thought to be an endoplasmic reticulum retention signal, is present at the N terminus of both proteins. When functionally expressed in HeLa cells, the cDNA enhanced the binding of tritiated haloperidol, a sigma receptor ligand, to HeLa cell membranes. Several human tissues, including placenta, liver, pancreas, and brain, and several human intestinal and JAR cell lines express the sigma receptor type 1 to a variable degree. </p><p>The sigma receptor ligand SR31747A is an immunosuppressive agent that blocks lymphocyte proliferation. It also blocks yeast proliferation by inhibiting Erg2, a sterol isomerase. Jbilo et al. (1997) purified an SR31747A-binding protein from membrane preparations of a human T leukemia cell line, and using primers based on peptide fragments, followed by 5-prime RACE and screening a Burkitt lymphoma cell line cDNA library, Jbilo et al. (1997) cloned SIGMAR1, which they called SRBP. The deduced 223-amino acid protein has a calculated molecular mass of 24.8 kD. SIGMAR1 has 2 hydrophobic stretches, one of which is a conserved central domain similar to that of yeast Erg2. SIGMAR1 shares 93% identity with guinea pig Sigmar1 and 29.9% identity with yeast Erg2. Northern blot analysis detected a 2.0-kb SIGMAR1 transcript in all tissues examined, with highest expression in liver and lowest expression in brain. RNA dot blot analysis confirmed ubiquitous expression and highest expression in adult and fetal liver. Immunohistochemical analysis and confocal microscopy showed SIGMAR1 associated with the nuclear envelope in several human cell types. SDS-PAGE and Western blot analysis showed that SIGMAR1 has an apparent molecular mass of 28 kD. </p><p>In mouse tissue, Mavlyutov et al. (2010) found that Sigmar1 was localized primarily in motoneurons in the brainstem and spinal cord. Expression was restricted to large cholinergic postsynaptic densities on the soma of motoneurons, and colocalized with the Kv2.1 potassium channel (KCNB1; 600397) and the muscarinic type 2 cholinergic receptor (CHRM2; 118493). Ultrastructural studies showed that Sigmar1 was located close to, but separate from, the plasma membrane, possibly in cisternae formed from the ER. </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>Gene Function</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>The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT), which also acts as a hallucinogen. Fontanilla et al. (2009) demonstrated that DMT1 binds to sigma-1 receptors and inhibits voltage-gated sodium ion channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors. DMT induced hypermobility in wildtype mice but not in sigma-1 receptor knockout mice. Fontanilla et al. (2009) concluded that these biochemical, physiologic, and behavioral experiments indicated that DMT is an endogenous agonist for the sigma-1 receptor. </p><p>In binding studies using yeast membranes, Jbilo et al. (1997) confirmed that human SIGMAR1 has a high affinity for SR31747A and has a pharmacologic profile identical to that determined for purified human and guinea pig sigma-1 receptors and yeast Erg2. Using Xenopus oocytes expressing guinea pig or rat sigma-1 receptors together with voltage-gated K+ channels (see Kv1.4, 176266), Aydar et al. (2002) showed that sigma-1 receptors function as ligand-regulated potassium channel subunits and modulate channel activity. Immunoprecipitation analysis of rat posterior pituitary membrane lysates confirmed that the sigma-1 receptor and Kv1.4 interact directly in vivo. </p><p>In alpha-motor neurons, SIGMAR1 is normally located at the plasma membrane in postsynaptic densities associated with cholinergic synapses. Prause et al. (2013) found abnormal localization of SIGMAR1 in spinal cord sections from patients with various forms of amyotrophic lateral sclerosis (ALS; 105400). In ALS tissue, SIGMAR1 localized in larger structures at the plasma membrane, as well as in the proximal axon and in the cytoplasm. These large accumulations of SIGMAR1 were ubiquitinated and costained with the 20S proteasome. However, SIGMAR1 was not present in p62 (601530) ubiquitinated protein aggregates. Skin fibroblasts from patients with ALS8 (608627) due to a P56S mutation in the VAPB gene (605704.0001) showed accumulation of SIGMAR1 with mutant VAPB in ubiquitinated aggregates. Soluble SIGMAR1 protein levels were decreased in ALS and Sod1 (147450)-mutant mouse lumbar spinal cord. Knockdown of SIGMAR1 in neuronal cells resulted in activation of the unfolded protein response mechanism, increased ER stress, and proteasomal dysfunction. This was associated with increased intracellular calcium, apoptosis, and abnormalities in ER and Golgi structures. Pharmacologic activation of SIGMAR1 decreased the mutant VAPB aggregation and had a neuroprotective effect. Prause et al. (2013) suggested that SIGMAR1 is critical for neuronal survival and maintenance, and that alteration of its normal function may contribute to ALS. </p>
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</span>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p>Prasad et al. (1998) determined that the SIGMAR1 gene contains 4 exons and spans about 7 kb. The upstream region contains a CCAATC box on the reverse strand, but no TATA box. It also contains several GC boxes for SP1 (189906) binding and consensus sequences for liver-specific factors, cytokine-responsive factors, and a xenobiotic-responsive factor (AHR; 600253). </p>
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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>By Southern blot analysis of Chinese hamster-human and mouse-human hybrid cell lines and FISH, Prasad et al. (1998) mapped the SIGMAR1 gene to chromosome 9p13. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Juvenile Amyotrophic Lateral Sclerosis 16</em></strong></p><p>
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In affected members of a consanguineous Saudi Arabian family with juvenile amyotrophic lateral sclerosis-16 (ALS16; 614373), Al-Saif et al. (2011) identified a homozygous mutation in the SIGMAR1 gene (E102Q; 601978.0001). In vitro functional expression assays in the motor neuron-like cell line NSC34 showed that the mutant protein was shifted to lower density membranes and formed detergent-resistant complexes. Transfected cells also showed an almost 2-fold increase in apoptosis in response to stress compared to controls. The findings indicated that the mutation decreases the viability of motor neurons. The patients had a very early age of onset, at 1 to 2 years, of lower limb spasticity and weakness. The disorder was slowly progressive, and later involved the upper limbs. Two patients were wheelchair-bound by age 20 years. None of the patients had bulbar or respiratory involvement, and all had normal cognition. </p><p><strong><em>Autosomal Recessive Distal Hereditary Motor Neuronopathy 2</em></strong></p><p>
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In 3 members of a consanguineous Chinese family with childhood-onset autosomal recessive distal hereditary motor neuronopathy-2 (HMNR2; 605726), Li et al. (2015) identified a homozygous mutation in the SIGMAR1 gene (601978.0003). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression assays in HEK293 cells showed that the mutation resulted in reduced levels of the protein due to increased proteasomal degradation through the ER-associated degradation (ERAD) pathway. The mutant cell lines showed increased ER stress and apoptosis compared to wildtype. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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In affected members of an Australian family (AUS-14) with frontotemporal dementia and/or motor neuron disease (105550), Luty et al. (2010) identified a heterozygous G-to-T transversion (672*51G-T) in the 3-prime untranslated region (UTR) of the SIGMAR1 gene. The mutation was not found in 1,269 normal controls. In vitro functional expression studies in human neuroblastoma, HEK293 cells, and patient lymphocytes showed that the substitution resulted in about 2-fold increased expression of SIGMAR1 compared to wildtype, and neuropathologic study of affected individuals showed increased SIGMAR1 protein in frontal cortex tissue. Studies of brain tissue from controls and from individuals with unrelated form of FTLD showed that sigma-1 was localized on membranes within the cytoplasm of most neurons, astrocytes, and oligodendroglia, whereas in 2 patients with the 672*51G-T mutation, it was concentrated within the nucleus of degenerating neurons. Patients with the 672*51G-T mutation also had TDP43 (TARDBP; 605078)- and FUS (137070)-positive inclusions in affected brain regions, although in different neuronal populations. Overexpression of SIGMAR1 in cell lines resulted in increased levels of TDP43 protein, but not TDP43 transcripts, and caused a change in localization of TDP43 from the nucleus to the cytoplasm. Luty et al. (2010) postulated that the 672*51G-T mutation, which occurs in the 3-prime UTR of the SIGMAR1 gene, alters transcript stability and increases gene expression, resulting in increased pathogenic alterations of TDP43 and FUS. An unrelated patient from another Australian family (AUS-47) with frontotemporal dementia without motor neuron disease carried a heterozygous c.672*26C-T transition, and an unrelated patient from a Polish family (POL-1) with a diagnosis of Alzheimer disease (AD; 104300) and aphasia carried a heterozygous c.672*47G-A transition. Both variants occurred in the 3-prime UTR and were absent from 169 elderly controls and 1,110 normal controls, but segregation analysis in these 2 families was not possible. Neither patient had motor neuron disease. Dobson-Stone et al. (2013) noted that the AUS-14 family reported by Luty et al. (2010) also carried a pathogenic expansion in the C9ORF72 gene (614260.0001) that segregated with the disorder and was thus likely responsible for the phenotype. However, Dobson-Stone et al. (2013) excluded a pathogenic expansion of the C9ORF72 gene in the proband of the AUS-47 family. Pickering-Brown and Hardy (2015) commented that the disease in the AUS-14 family reported by Luty et al. (2010) was likely caused by the C9ORF72 expansion rather than the SIGMAR1 variant, and questioned the role of SIGMA1 variants in frontotemporal dementia/motor neuron disease (FTD/MND). In a reply to Pickering-Brown and Hardy (2015), Bernard-Marissal et al. (2015) reiterated that their interest in the role of SIGMAR1 in motor neurons was based on several previous findings, including the presence of motor disabilities in the Sigmar1 knockout mouse, high expression of SIGMAR1 in motor neurons, dysregulation of SIGMAR1 in tissues from patients with amyotrophic lateral sclerosis, and implication of SIGMAR1 in other motor neuron disease. </p><p>Belzil et al. (2013) did not identify any coding or noncoding variants in the SIGMAR1 gene among 25 patients with ALS and a family history of dementia. A G-to-T transversion (672*43G-T) in the 3-prime untranslated region was found in 1 patient, but this was also found in 1 of 190 controls. Moreover, a C9ORF72 repeat expansion (614260.0001) was subsequently identified in this patient and in 52% of the entire cohort. Belzil et al. (2013) suggested that the SIGMAR1 variants identified by Luty et al. (2010) actually segregated with C9ORF72 expansions, and that SIGMAR1 variants are not a cause of ALS with dementia. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Langa et al. (2003) found that Sigmar1-null mice were viable and fertile, and did not display any overt phenotype compared to wildtype mice. However, mutant mice showed a decrease in the hypermotility response upon challenge with a ligand. </p><p>Mavlyutov et al. (2010) found that Sigmar1-null mice had impaired motor coordination and function on the rotorod test compared to wildtype mice. Knockout mice also showed motor differences compared to wildtype mice in a swimming test: knockout mice used their tails, but not their front paws, whereas wildtype mice used their front paws and not their tails. </p><p>Bernard-Marissal et al. (2015) found that Sigmar1-null mice had motor deficits and muscle weakness associated with denervation at the neuromuscular junction and loss of motor neurons in the spinal cord; fast motor neurons and muscle fibers were particularly affected. Motor neurons derived from Sigmar1-null mice showed a decrease in the ER-mitochondria connection compared to wildtype, suggesting a disruption of MAMs. Mutant cells showed defective calcium signaling as well as disrupted intracellular calcium homeostasis and increased ER stress, resulting in motor neuron and axonal degeneration. Additional findings included abnormal mitochondrial morphology in motor neurons and disruption of mitochondrial axonal transport. Intracellular calcium scavenging and ER stress inhibition were able to restore mitochondrial function and prevent motor neuron degeneration. </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>3 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 AMYOTROPHIC LATERAL SCLEROSIS 16, JUVENILE (1 family)</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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SIGMAR1, GLU102GLN
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<br />
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SNP: rs387906829,
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gnomAD: rs387906829,
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ClinVar: RCV000023162, RCV001852015, RCV002444439
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In affected members of a consanguineous Saudi Arabian family with juvenile ALS16 (614373), Al-Saif et al. (2011) identified a homozygous 304G-C transversion in exon 2 of the SIGMAR1 gene, resulting in a glu102-to-gln (E102Q) substitution in a highly conserved residue in the predicted transmembrane domain. The mutation was not found in 271 controls. In vitro functional expression assays in the motor neuron-like cell line NSC34 showed that the mutant protein was shifted to lower density membranes and formed detergent-resistant complexes. Transfected cells also showed an almost 2-fold increase in apoptosis in response to stress compared to controls. The findings indicated that the mutation decreases the viability of motor neurons. The patients had a very early age of onset, at 1 to 2 years, of lower limb spasticity and weakness. The disorder was slowly progressive, and involved the upper limbs. Two patients were wheelchair-bound by age 20 years. None of the patients had bulbar or respiratory involvement, and all had normal cognition. </p><p>Fukunaga et al. (2015) found that transfection of the E102Q mutation into neuro2A cells resulted in dissociation of the mutant protein from the ER membrane and subsequent cytoplasmic aggregation. This was associated with disruption of mitochondrial structure, mitochondrial damage, decreased ATP production, and autophagic cell death. Cells overexpressing E102Q showed aberrant extranuclear localization of TDP43 (605078), a hallmark of ALS. </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 VARIANT OF UNKNOWN SIGNIFICANCE</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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SIGMAR1, +31A-G, 3-PRIME UTR ({dbSNP rs4879809})
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<br />
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SNP: rs4879809,
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gnomAD: rs4879809,
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ClinVar: RCV000190342, RCV001515374, RCV001721241, RCV001807120
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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>This variant is classified as a variant of unknown significance because its contribution to amyotrophic lateral sclerosis-16 (ALS16; 614373) has not been confirmed.</p><p>In 2 sibs, born of consanguineous Pakistani parents, with amyotrophic lateral sclerosis, Ullah et al. (2015) identified a homozygous A-to-G transition in the 3-prime UTR of the SIGMAR1 gene (rs4879809) The variant was not found in 100 healthy ethnically matched controls. Functional studies of the variant were not performed, but the variant was predicted to disturb miRNA binding, which could affect regulation of gene expression. The patients had no signs of dementia. Linkage analysis excluded a pathogenic expanded hexanucleotide repeat in the C9ORF72 gene (614260) in this family. </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 NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL RECESSIVE 2 (1 family)</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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SIGMAR1, IVS1DS, G-T, +1
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<br />
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SNP: rs796065352,
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ClinVar: RCV000190343
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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 consanguineous Chinese family with childhood-onset autosomal recessive distal hereditary motor neuronopathy-2 (HMNR2; 605726), Li et al. (2015) identified a homozygous G-to-T transversion (c.151+1G-T, NM_005866.3) affecting a splice site in the SIGMAR1 gene, resulting in an in-frame deletion of 20 amino acids in exon 1 (c.92_151del, p.31_50del) in the putative extracellular loop. The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in 500 Chinese controls. In vitro functional expression assays in HEK293 cells showed that the mutation resulted in lower levels of the protein due to increased proteasomal degradation through the ER-associated degradation (ERAD) pathway. The mutant cell lines showed increased ER stress and apoptosis compared to wildtype. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Al-Saif, A., Al-Mohanna, F., Bohlega, S.
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<strong>A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis.</strong>
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Ann. Neurol. 70: 913-919, 2011.
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[PubMed: 21842496]
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[Full Text: https://doi.org/10.1002/ana.22534]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Aydar, E., Palmer, C. P., Klyachko, V. A., Jackson, M. B.
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<strong>The sigma receptor as a ligand-regulated auxiliary potassium channel subunit.</strong>
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Neuron 34: 399-410, 2002.
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[PubMed: 11988171]
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[Full Text: https://doi.org/10.1016/s0896-6273(02)00677-3]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Belzil, V. V., Daoud, H., Camu, W., Strong, M. J., Dion, P. A., Rouleau, G. A.
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<strong>Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia.</strong>
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Europ. J. Hum. Genet. 21: 237-239, 2013.
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[PubMed: 22739338]
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[Full Text: https://doi.org/10.1038/ejhg.2012.135]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bernard-Marissal, N., Medard, J.-J., Azzedine, H., Chrast, R.
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<strong>Dysfunction in endoplasmic reticulum-mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration.</strong>
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Brain 138: 875-890, 2015.
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[PubMed: 25678561]
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[Full Text: https://doi.org/10.1093/brain/awv008]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bernard-Marissal, N., Medard, J.-J., Azzedine, H., Chrast, R.
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<strong>Reply to Pickering-Brown and Hardy. (Letter)</strong>
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Brain 138: e394, 2015. Note: Electronic Article.
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[PubMed: 26088963]
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[Full Text: https://doi.org/10.1093/brain/awv174]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Dobson-Stone, C., Hallupp, M., Loy, C. T., Thompson, E. M., Haan, E., Sue, C. M., Panegyres, P. K., Razquin, C., Seijo-Martinez, M., Rene, R., Gascon, J., Campdelacreu, J., Schmoll, B., Volk, A. E., Brooks, W. S., Schofield, P. R., Pastor, P., Kwok, J. B. J.
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<strong>C9ORF72 repeat expansion in Australian and Spanish frontotemporal dementia patients.</strong>
|
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PLoS One 8: e56899, 2013. Note: Electronic Article.
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[PubMed: 23437264]
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[Full Text: https://doi.org/10.1371/journal.pone.0056899]
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</p>
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</li>
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<li>
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Fontanilla, D., Johannessen, M., Hajipour, A. R., Cozzi, N. V., Jackson, M. B., Ruoho, A. E.
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<strong>The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator.</strong>
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Langa, F., Codony, X., Tovar, V., Lavado, A., Gimenez, E., Cozar, P., Cantero, M., Dordal, A., Hernandez, E., Perez, R., Monroy, X., Zamanillo, D., Guitart, X., Montoliu, L.
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<strong>Generation and phenotypic analysis of sigma receptor type 1 (sigma1) knockout mice.</strong>
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Li, X., Hu, Z., Liu, L., Xie, Y., Zhan, Y., Zi, X., Wang, J., Wu, L., Xia, K., Tang, B., Zhang, R.
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<strong>A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.</strong>
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Neurology 84: 2430-2437, 2015.
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Luty, A. A., Kwok, J. B., Dobson-Stone, C., Loy, C. T., Coupland, K. G., Karlstrom, H., Sobow, T., Tchorzewska, J., Maruszak, A., Barcikowska, M., Panegyres, P. K., Zekanowski, C., Brooks, W. S., Williams, K. L., Blair, I. P., Mather, K. A, Sachdev, P. S, Halliday, G. M., Schofield, P. R.
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<strong>Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease.</strong>
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Ann. Neurol. 68: 639-649, 2010.
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Mavlyutov, T. A., Epstein, M. L., Andersen, K. A., Ziskind-Conhaim, L., Ruoho, A. E.
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<strong>The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons: an anatomical and behavioral study.</strong>
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Neuroscience 167: 247-255, 2010.
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[PubMed: 20167253]
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Pickering-Brown, S., Hardy, J.
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<strong>Is SIGMAR1 a confirmed FTD/MND gene? (Letter)</strong>
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Brain 138: e393, 2015. Note: Electronic Article.
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Prasad, P. D., Li, H. W., Fei, Y.-J., Ganapathy, M. E., Fujita, T., Plumley, L. H., Yang-Feng, T. L., Leibach, F. H., Ganapathy, V.
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<strong>Exon-intron structure, analysis or promoter region, and chromosomal localization of the human type 1 sigma receptor gene.</strong>
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J. Neurochem. 70: 443-451, 1998.
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Prause, J., Goswami, A., Katona, I., Roos, A., Schnizler, M., Bushuven, E., Dreier, A., Buchkremer, S., Johann, S., Beyer, C., Deschauer, M., Troost, D., Weis, J.
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<strong>Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis.</strong>
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Ullah, M. I., Ahmad, A., Raza, S. I., Amar, A., Ali, A., Bhatti, A., John, P., Mohyuddin, A., Ahmad, W., Hassan, M. J.
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<strong>In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia.</strong>
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Neurogenetics 16: 299-306, 2015.
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