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Entry
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- *603415 - SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 9; SCN9A
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*603415</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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<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="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#evolution">Evolution</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/603415">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div 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=ENSG00000169432;t=ENST00000642356" 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=6335" 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=603415" 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=ENSG00000169432;t=ENST00000642356" 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_001365536,NM_002977,XM_011511616,XM_011511617,XM_011511618,XM_011511619,XM_017004669,XR_001738886" 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_001365536" 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=603415" 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=04565&isoform_id=04565_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/SCN9A" 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/758110,18073669,18073671,18073697,37496891,37496893,50897541,50897543,50897545,62822245,73537195,114150659,119631719,119631720,119631721,327478559,767919207,767919209,767919211,767919213,1034615764,1465729077,2462575913,2462575915,2462575917,2462575919,2462575921,2462575923,2462575925,2636059578" 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/Q15858" 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=6335" 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=ENSG00000169432;t=ENST00000642356" 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=SCN9A" 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=SCN9A" 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+6335" 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/SCN9A" 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:6335" 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/6335" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr2&hgg_gene=ENST00000642356.2&hgg_start=166195185&hgg_end=166375987&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:10597" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603415[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=603415[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/SCN9A/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/ENSG00000169432" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=SCN9A" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=SCN9A" 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=SCN9A" 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=SCN9A&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/PA35010" 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:10597" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0285944.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:107636" 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/SCN9A#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:107636" 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/6335/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://omia.org/OMIA002616/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=6335" 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>
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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="mimCellLines">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" 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="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</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="mimCellLinesLinksFold" 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://catalog.coriell.org/Search?q=OmimNum:603415" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:6335" 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=SCN9A&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> 403390002, 699190008, 709489006<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>
|
|
603415
|
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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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SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 9; SCN9A
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SODIUM CHANNEL, VOLTAGE-GATED, TYPE IX, ALPHA SUBUNIT<br />
|
|
NAV1.7<br />
|
|
NEUROENDOCRINE SODIUM CHANNEL; NENA<br />
|
|
PERIPHERAL SODIUM CHANNEL 1; PN1
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=SCN9A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SCN9A</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/2/741?start=-3&limit=10&highlight=741">2q24.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:166195185-166375987&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">2:166,195,185-166,375,987</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=133020,243000,243000,167400,133020" 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="5">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/741?start=-3&limit=10&highlight=741">
|
|
2q24.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
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|
|
<td>
|
|
<span class="mim-font">
|
|
Erythermalgia, primary
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/133020"> 133020 </a>
|
|
|
|
</span>
|
|
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<p>SCN9A is a voltage-gated sodium channel that is enriched in nociceptive and sympathetic neurons of the peripheral nervous system. It is also expressed in subcortical structures of brain (summary by <a href="#21" class="mim-tip-reference" title="McDermott, L. A., Weir, G. A., Themistocleous, A. C., Segerdahl, A. R., Blesneac, I., Baskozos, G., Clark, A. J., Millar, V., Peck, L. J., Ebner, D., Tracey, I., Serra, J., Bennett, D. L. <strong>Defining the functional role of NaV1.7 in human nociception.</strong> Neuron 101: 905-919, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30795902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30795902</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30795902[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.neuron.2019.01.047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30795902">McDermott et al., 2019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30795902" 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="#19" class="mim-tip-reference" title="Klugbauer, N., Lacinova, L., Flockerzi, V., Hofmann, F. <strong>Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells.</strong> EMBO J. 14: 1084-1090, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7720699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7720699</a>] [<a href="https://doi.org/10.1002/j.1460-2075.1995.tb07091.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7720699">Klugbauer et al. (1995)</a> cloned a novel voltage-gated sodium channel, which they termed NENA, from a human medullary thyroid carcinoma cell cDNA library. Sequence analysis revealed that the cDNA encodes a 1,977-amino acid polypeptide (Nav1.7) composed of 4 domains, each with 6 transmembrane domains and 2 highly conserved pore-forming segments. The sequence is highly similar to brain and skeletal muscle voltage-gated sodium channels; the authors stated that this channel represents an evolutionary link between sodium channels found in brain and skeletal muscle. Northern blot analysis detected 9.4- and 7.0-kb NENA transcripts in a human C-cell carcinoma cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7720699" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By RT-PCR, <a href="#28" class="mim-tip-reference" title="Sangameswaran, L., Fish, L. M., Koch, B. D., Rabert, D. K., Delgado, S. G., Ilnicka, M., Jakeman, L. B., Novakovic, S., Wong, K., Sze, P., Tzoumaka, E., Stewart, G. R., Herman, R. C., Chan, H., Eglen, R. M., Hunter, J. C. <strong>A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia.</strong> J. Biol. Chem. 272: 14805-14809, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9169448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9169448</a>] [<a href="https://doi.org/10.1074/jbc.272.23.14805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9169448">Sangameswaran et al. (1997)</a> determined that NENA, which they designated NE for neuroendocrine channel, was expressed in the same tissues as rat PN1 (peripheral sodium channel-1), including dorsal root ganglia, adrenal, and thyroid tissue. Neither rat PN1 nor human NE was expressed in skeletal muscle. <a href="#28" class="mim-tip-reference" title="Sangameswaran, L., Fish, L. M., Koch, B. D., Rabert, D. K., Delgado, S. G., Ilnicka, M., Jakeman, L. B., Novakovic, S., Wong, K., Sze, P., Tzoumaka, E., Stewart, G. R., Herman, R. C., Chan, H., Eglen, R. M., Hunter, J. C. <strong>A novel tetrodotoxin-sensitive, voltage-gated sodium channel expressed in rat and human dorsal root ganglia.</strong> J. Biol. Chem. 272: 14805-14809, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9169448/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9169448</a>] [<a href="https://doi.org/10.1074/jbc.272.23.14805" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9169448">Sangameswaran et al. (1997)</a> stated that NE is the human ortholog of the rat PN1 sodium channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9169448" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By electrophysiologic and inhibitor studies and quantitative RT-PCR analysis, <a href="#18" class="mim-tip-reference" title="Jo, T., Nagata, T., Iida, H., Imuta, H., Iwasawa, K., Ma, J., Hara, K., Omata, M., Nagai, O., Takizawa, H., Nagase, T., Nakajima, T. <strong>Voltage-gated sodium channel expressed in cultured human smooth muscle cells: involvement of SCN9A</strong> FEBS Lett. 567: 339-343, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15178348/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15178348</a>] [<a href="https://doi.org/10.1016/j.febslet.2004.04.092" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15178348">Jo et al. (2004)</a> found that SCN9A was the major sodium channel expressed in smooth muscle cells cultured from normal human bronchus, main pulmonary artery, and large coronary artery. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15178348" 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="#21" class="mim-tip-reference" title="McDermott, L. A., Weir, G. A., Themistocleous, A. C., Segerdahl, A. R., Blesneac, I., Baskozos, G., Clark, A. J., Millar, V., Peck, L. J., Ebner, D., Tracey, I., Serra, J., Bennett, D. L. <strong>Defining the functional role of NaV1.7 in human nociception.</strong> Neuron 101: 905-919, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30795902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30795902</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30795902[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.neuron.2019.01.047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30795902">McDermott et al. (2019)</a> found that endogenous epitope-tagged SCN9A was highly expressed in human induced pluripotent stem cell (iPSC) nociceptors and was trafficked appropriately to polarized neuronal compartments, such as soma membrane, axon, axon terminals, and nodes of Ranvier. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30795902" 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 SCN9A gene contains 26 exons (<a href="#23" class="mim-tip-reference" title="Michiels, J. J., te Morsche, R. H. M., Jansen, J. B. M. J., Drenth, J. P. H. <strong>Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha-subunit Nav1.7.</strong> Arch. Neurol. 62: 1587-1590, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16216943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16216943</a>] [<a href="https://doi.org/10.1001/archneur.62.10.1587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16216943">Michiels et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16216943" 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 SCN9A gene maps to chromosome 2q24.3 (<a href="#23" class="mim-tip-reference" title="Michiels, J. J., te Morsche, R. H. M., Jansen, J. B. M. J., Drenth, J. P. H. <strong>Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha-subunit Nav1.7.</strong> Arch. Neurol. 62: 1587-1590, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16216943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16216943</a>] [<a href="https://doi.org/10.1001/archneur.62.10.1587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16216943">Michiels et al., 2005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16216943" 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 RT-PCR analysis, <a href="#13" class="mim-tip-reference" title="Fu, W., Vasylyev, D., Bi, Y., Zhang, M., Sun, G., Khleborodova, A., Huang, G., Zhao, L., Zhou, R., Li, Y., Liu, S., Cai, X., and 15 others. <strong>Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis.</strong> Nature 625: 557-565, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38172636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38172636</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38172636[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/10.1038/s41586-023-06888-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38172636">Fu et al. (2024)</a> showed that Nav1.7 was expressed in human chondrocytes and was upregulated in human osteoarthritic (OA) cartilage, which they confirmed electrophysiologically. Analysis of mice with Nav1.7 deletion in neurons, chondrocytes, or both revealed that loss of Nav1.7 in chondrocytes protected mice from OA, as Nav1.7 expressed in chondrocytes modulated OA progression and resultant OA-associated pain behavior, whereas Nav1.7 expressed by neurons contributed to OA-associated pain without affecting OA progression. Pharmacologic inhibition of Nav1.7 protected mice against OA, and treatment with carbamazepine, a clinically used Na channel inhibitor that acts on Nav1.7, reduced cartilage loss and pain from OA. HSP70 (see <a href="/entry/140550">140550</a>) and midkine (MDK; <a href="/entry/162096">162096</a>) were important for maintaining the protective effects of Nav1.7 inhibition against OA, and blockade of Nav1.7 regulated human chondrocyte biology by enhancing HSP70 and midkine secretion in chondrocytes. Moreover, intracellular Ca(2+) signals were essential for enhanced secretion of HSP70 and midkine following Nav1.7 blockade, and Nav1.7 blockade altered chondrocyte Ca(2+). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38172636" 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="#31" class="mim-tip-reference" title="Shen, H., Liu, D., Wu, K., Lei, J., Yan, N. <strong>Structures of human Nav1.7 channel in complex with auxiliary subunits and animal toxins.</strong> Science 363: 1303-1308, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30765606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30765606</a>] [<a href="https://doi.org/10.1126/science.aaw2493" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30765606">Shen et al. (2019)</a> reported the cryoelectron microscopy structures of the human Nav1.7-beta1-beta2 complex bound to 2 combinations of pore blockers and gating modifier toxins, tetrodotoxin with protoxin-II and saxitoxin with huwentoxin-IV, both determined at overall resolutions of 3.2 angstroms. The 2 structures were nearly identical except for minor shifts of voltage-sensing domain II, whose S3-S4 linker accommodates the 2 gating modifier toxins in a similar manner. One additional protoxin-II sits on top of the S3-S4 linker in voltage sensing domain IV. The structures may represent an inactivated state with all 4 voltage-sensing domains 'up' and the intracellular gate closed. The structures illuminated the path toward mechanistic understanding of the function and disease of Nav1.7 and established the foundation for structure-aided development of analgesics. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30765606" 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>Primary Erythermalgia</em></strong></p><p>
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In affected members of a Chinese family with primary erythermalgia (<a href="/entry/133020">133020</a>) linked to chromosome 2q and in a sporadic patient, <a href="#35" class="mim-tip-reference" title="Yang, Y., Wang, Y., Li, S., Xu, Z., Li, H., Ma, L., Fan, J., Bu, D., Liu, B., Fan, Z., Wu, G., Jin, J., Ding, B., Zhu, X., Shen, Y. <strong>Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia.</strong> J. Med. Genet. 41: 171-174, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14985375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14985375</a>] [<a href="https://doi.org/10.1136/jmg.2003.012153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14985375">Yang et al. (2004)</a> identified mutations in the SCN9A gene (<a href="#0001">603415.0001</a>-<a href="#0002">603415.0002</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14985375" 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 5 affected members of a Flemish family with primary erythermalgia, <a href="#23" class="mim-tip-reference" title="Michiels, J. J., te Morsche, R. H. M., Jansen, J. B. M. J., Drenth, J. P. H. <strong>Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha-subunit Nav1.7.</strong> Arch. Neurol. 62: 1587-1590, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16216943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16216943</a>] [<a href="https://doi.org/10.1001/archneur.62.10.1587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16216943">Michiels et al. (2005)</a> identified a heterozygous mutation in the SCN9A gene (<a href="#0003">603415.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16216943" 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>Small Fiber Neuropathy</em></strong></p><p>
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In 8 (28.6%) of 28 unrelated Dutch Caucasian patients with biopsy-confirmed small fiber neuropathy (SFNP; see <a href="/entry/133020">133020</a>), <a href="#9" class="mim-tip-reference" title="Faber, C. G., Hoeijmakers, J. G. J., Ahn, H.-S., Cheng, X., Han, C., Choi, J.-S., Estacion, M., Lauria, G., Vanhoutte, E. K., Gerrits, M. M., Dib-Hajj, S., Drenth, J. P. H., Waxman, S. G., Merkies, I. S. J. <strong>Gain of function Na(v) 1.7 mutations in idiopathic small fiber neuropathy.</strong> Ann. Neurol. 71: 26-39, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21698661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21698661</a>] [<a href="https://doi.org/10.1002/ana.22485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21698661">Faber et al. (2012)</a> identified 7 different heterozygous gain-of-function mutations in the SCN9A gene (see, e.g., <a href="#0023">603415.0023</a>-<a href="#0025">603415.0025</a>). The patients presented with adult-onset pain, most commonly a burning sensation in the extremities, although 2 patients had generalized bodily pain. Seven of 8 complained of autonomic symptoms, such as dry eyes or mouth, orthostatic dizziness, or gastrointestinal problems. All had significantly decreased intraepithelial fiber densities compared to controls, and all had distally impaired sensation to warmth and/or cold. Three had family members with a similar condition. In vitro functional expression studies in HEK293 cells and dorsal root ganglion neurons showed that all the mutations caused hyperexcitability of dorsal root ganglion neurons, either by impairing slow inactivation, depolarizing slow and fast inactivation, or causing enhanced resurgent currents and increasing the number of action potentials evoked by depolarization. <a href="#9" class="mim-tip-reference" title="Faber, C. G., Hoeijmakers, J. G. J., Ahn, H.-S., Cheng, X., Han, C., Choi, J.-S., Estacion, M., Lauria, G., Vanhoutte, E. K., Gerrits, M. M., Dib-Hajj, S., Drenth, J. P. H., Waxman, S. G., Merkies, I. S. J. <strong>Gain of function Na(v) 1.7 mutations in idiopathic small fiber neuropathy.</strong> Ann. Neurol. 71: 26-39, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21698661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21698661</a>] [<a href="https://doi.org/10.1002/ana.22485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21698661">Faber et al. (2012)</a> postulated that increased sodium channel activity may also trigger axonal degeneration via calcium-importing reverse sodium-calcium exchange. The findings expanded the phenotype associated with SCN9A mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21698661" 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>Channelopathy-Associated Insensitivity to Pain</em></strong></p><p>
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In affected members of 3 consanguineous northern Pakistani families with autosomal recessive 'channelopathy-associated insensitivity to pain' (<a href="/entry/243000">243000</a>) mapping to chromosome 2q24.3, <a href="#4" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/10.1038/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> identified 3 distinct homozygous mutations in the SCN9A gene: S459X (<a href="#0005">603415.0005</a>), I767X (<a href="#0006">603415.0006</a>), and W897X (<a href="#0007">603415.0007</a>). By coexpression of wildtype or mutant human Nav1.7 with sodium channel beta-1 (SCN1B; <a href="/entry/600235">600235</a>) and beta-2 (SCN2B; <a href="/entry/601327">601327</a>) in cultured cells, they showed that these mutations cause loss of function of Nav1.7. In cells expressing mutant Nav1.7, the currents were no greater than background. <a href="#4" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/10.1038/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> noted that the autosomal dominant pain disorder primary erythermalgia, and the autosomal recessive pain disorder channelopathy-associated insensitivity to pain, are the result, respectively, of gain-of-function and loss-of-function mutations in the SCN9A gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17167479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Goldberg, Y. P., MacFarlane, J., MacDonald, M. L., Thompson, J., Dube, M.-P., Mattice, M., Fraser, R., Young, C., Hossain, S., Pape, T., Payne, B., Radomski, C., and 18 others. <strong>Loss-of-function mutations in the Na(v)1.7 gene underlie congenital indifference to pain in multiple human populations.</strong> Clin. Genet. 71: 311-319, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17470132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17470132</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00790.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17470132">Goldberg et al. (2007)</a> identified 10 different mutations in the SCN9A gene (see, e.g., <a href="#0014">603415.0014</a>-<a href="#0015">603415.0015</a>), 9 of which were truncating mutations, in affected members of 9 different families with congenital insensitivity to pain. The families were from various countries in Europe as well as Canada, the U.S., and Argentina. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17470132" 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="#34" class="mim-tip-reference" title="Weiss, J., Pyrski, M., Jacobi, E., Bufe, B., Willnecker, V., Schick, B., Zizzari, P., Gossage, S. J., Greer, C. A., Leinders-Zufall, T., Woods, C. G., Wood, J. N., Zufall, F. <strong>Loss-of-function mutations in sodium channel NaV1.7 cause anosmia.</strong> Nature 472: 186-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21441906[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/10.1038/nature09975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21441906">Weiss et al. (2011)</a> reported 3 additional individuals with channelopathy-associated insensitivity to pain. All of them were compound heterozygous for nonsense and frameshift mutations leading to complete loss of function. Interestingly, <a href="#34" class="mim-tip-reference" title="Weiss, J., Pyrski, M., Jacobi, E., Bufe, B., Willnecker, V., Schick, B., Zizzari, P., Gossage, S. J., Greer, C. A., Leinders-Zufall, T., Woods, C. G., Wood, J. N., Zufall, F. <strong>Loss-of-function mutations in sodium channel NaV1.7 cause anosmia.</strong> Nature 472: 186-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21441906[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/10.1038/nature09975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21441906">Weiss et al. (2011)</a> found that, in addition to insensitivity to pain, these people had congenital and complete anosmia, although none were aware. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21441906" 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="#21" class="mim-tip-reference" title="McDermott, L. A., Weir, G. A., Themistocleous, A. C., Segerdahl, A. R., Blesneac, I., Baskozos, G., Clark, A. J., Millar, V., Peck, L. J., Ebner, D., Tracey, I., Serra, J., Bennett, D. L. <strong>Defining the functional role of NaV1.7 in human nociception.</strong> Neuron 101: 905-919, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30795902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30795902</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30795902[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.neuron.2019.01.047" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30795902">McDermott et al. (2019)</a> heterologously expressed several NaV1.7 mutants associated with congenital insensitivity to pain in HEK293T cells and showed that all resulted in loss of NaV1.7 channel function. Both iPSC nociceptors derived from patients and NaV1.7-knockout iPSC lines exhibited inability to respond to depolarizing stimuli, demonstrating that NaV1.7 is a key regulator of excitability. The authors also showed that NaV1.7-knockout iPSC lines could be used for analgesic drug screening. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30795902" 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>Hereditary Sensory and Autonomic Neuropathy, Type IID</em></strong></p><p>
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In 3 Japanese patients from 2 unrelated families with hereditary sensory and autonomic neuropathy type IID (HSAN2D; see <a href="/entry/243000">243000</a>), <a href="#36" class="mim-tip-reference" title="Yuan, J., Matsuura, E., Higuchi, Y., Hashiguchi, A., Nakamura, T., Nozuma, S., Sakiyama, Y., Yoshimura, A., Izumo, S., Takashima, H. <strong>Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation.</strong> Neurology 80: 1641-1649, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23596073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23596073</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182904fdd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23596073">Yuan et al. (2013)</a> identified a homozygous truncating mutation in the SCN9A gene (<a href="#0028">603415.0028</a>). The mutation was predicted to result in nonsense-mediated mRNA decay and loss of SCN9A function in nociceptive neurons. The patients had early childhood onset of insensitivity to pain and temperature limited to the distal parts of the body, as well as variable autonomic nervous system dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23596073" 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>Paroxysmal Extreme Pain Disorder</em></strong></p><p>
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In affected members of 8 of 13 families with paroxysmal extreme pain disorder (PEXPD; <a href="/entry/167400">167400</a>), <a href="#11" class="mim-tip-reference" title="Fertleman, C. R., Baker, M. D., Parker, K. A., Moffatt, S., Elmslie, F. V., Abrahamsen, B., Ostman, J., Klugbauer, N., Wood, J. N., Gardiner, R. M., Rees, M. <strong>SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.</strong> Neuron 52: 767-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17145499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17145499</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17145499">Fertleman et al. (2006)</a> identified 8 missense mutations in the SCN9A gene. Three were located in the inactivation gate itself, 3 in the S4-S5 loop in domain III, and 1 in the S4-S5 loop in domain IV (<a href="#2" class="mim-tip-reference" title="Catterall, W. A., Yu, F. H. <strong>Painful channels.</strong> Neuron 52: 743-749, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17145494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17145494</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.11.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17145494">Catterall and Yu, 2006</a>). Functional analysis in vitro of 3 of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17145499+17145494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Catterall, W. A., Yu, F. H. <strong>Painful channels.</strong> Neuron 52: 743-749, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17145494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17145494</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.11.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17145494">Catterall and Yu (2006)</a> noted that SCN9A mutations that result in primary erythermalgia enhance the activation of sodium channels, while those resulting in paroxysmal extreme pain disorder impair inactivation of Na(v)1.7 channels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17145494" 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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For discussion of a possible association between generalized epilepsy with febrile seizures plus, type 7 (GEFSP7; see <a href="/entry/613863">613863</a>) and variation in the SCN9A gene, see <a href="#0018">603415.0018</a> and <a href="#0019">603415.0019</a>.</p><p>For discussion of a possible association between isolated febrile seizures (FEB3B; see <a href="/entry/613863">613863</a>) and variation in the SCN9A gene, see <a href="#0020">603415.0020</a> and <a href="#0021">603415.0021</a>.</p><p><a href="#32" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a> presented preliminary evidence that mutation in the SCN9A gene may act as a genetic modifier of Dravet syndrome when found in conjunction with an SCN1A mutation (<a href="/entry/182389">182389</a>). They identified a mutation in the SCN9A gene in 9 (8%) of 109 patients with Dravet syndrome, including 6 with SCN1A mutation. The authors noted that 'additional proconvulsive genes may act in concert with SCN9A' in the 3 patients without a mutation in SCN1A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19763161" 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="#33" class="mim-tip-reference" title="St. John Smith, E., Omerbasic, D., Lechner, S. G., Anirudhan, G., Lapatsina, L., Lewin, G. R. <strong>The molecular basis of acid insensitivity in the African naked mole-rat.</strong> Science 334: 1557-1560, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22174253/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22174253</a>] [<a href="https://doi.org/10.1126/science.1213760" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22174253">St. John Smith et al. (2011)</a> described a species-specific variant of the nociceptor sodium channel NaV1.7, which is potently blocked by protons and can account for acid insensitivity in the naked mole rat. They concluded that evolutionary pressure has selected for an NaV1.7 gene variant that tips the balance from proton-induced excitation to inhibition of action potential initiation to abolish acid nociception. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22174253" 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="#34" class="mim-tip-reference" title="Weiss, J., Pyrski, M., Jacobi, E., Bufe, B., Willnecker, V., Schick, B., Zizzari, P., Gossage, S. J., Greer, C. A., Leinders-Zufall, T., Woods, C. G., Wood, J. N., Zufall, F. <strong>Loss-of-function mutations in sodium channel NaV1.7 cause anosmia.</strong> Nature 472: 186-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21441906[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/10.1038/nature09975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21441906">Weiss et al. (2011)</a> developed conditional NaV1.7-null mice in which NaV1.7 was removed from olfactory sensory neurons. In the absence of NaV1.7, these neurons still produced odor-evoked action potentials but failed to initiate synaptic signaling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer displayed vital, odor-guided behaviors such as innate odor recognition and avoidance, short-term odor learning, and maternal pup retrieval. <a href="#34" class="mim-tip-reference" title="Weiss, J., Pyrski, M., Jacobi, E., Bufe, B., Willnecker, V., Schick, B., Zizzari, P., Gossage, S. J., Greer, C. A., Leinders-Zufall, T., Woods, C. G., Wood, J. N., Zufall, F. <strong>Loss-of-function mutations in sodium channel NaV1.7 cause anosmia.</strong> Nature 472: 186-190, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21441906[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/10.1038/nature09975" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21441906">Weiss et al. (2011)</a> concluded that their study created a mouse model of congenital general anosmia and provided new strategies to explore the genetic basis of the human sense of smell. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21441906" 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="#24" class="mim-tip-reference" title="Middleton, S. J., Perini, I., Themistocleous, A. C., Weir, G. A., McCann, K., Barry, A. M., Marshall, A., Lee, M., Mayo, L. M., Bohic, M., Baskozos, G., Morrison, I., and 12 others. <strong>Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.</strong> Brain 145: 3637-3653, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/34957475/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">34957475</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=34957475[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/10.1093/brain/awab482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="34957475">Middleton et al. (2022)</a> found that SCN9A mRNA was expressed in C-low threshold mechanoreceptors (C-LTMRs), peptidergic nociceptors, and myelinated fibers in mice. Selective knockout of SCN9A in C-LTMRs resulted in smaller sodium currents, decreased sensitivity to punctate mechanical stimuli, and reduced sensitivity to cooling. Similar findings were seen with pharmacologic inhibition of SCN9A. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=34957475" 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">rs80356475 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356475;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=rs80356475" 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=rs80356475" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In all affected members of a Chinese family with autosomal dominant primary erythermalgia (<a href="/entry/133020">133020</a>), <a href="#35" class="mim-tip-reference" title="Yang, Y., Wang, Y., Li, S., Xu, Z., Li, H., Ma, L., Fan, J., Bu, D., Liu, B., Fan, Z., Wu, G., Jin, J., Ding, B., Zhu, X., Shen, Y. <strong>Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia.</strong> J. Med. Genet. 41: 171-174, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14985375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14985375</a>] [<a href="https://doi.org/10.1136/jmg.2003.012153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14985375">Yang et al. (2004)</a> identified heterozygosity for a 2573T-A transversion in the SCN9A gene, resulting in a leu858-to-his (L858H) substitution. The mutation was not found in unaffected members of the family or in 400 alleles from normal Chinese controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14985375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using functional expression studies, <a href="#5" class="mim-tip-reference" title="Cummins, T. R., Dib-Hajj, S. D., Waxman, S. G. <strong>Electrophysiological properties of mutant Na(v)1.7 sodium channels in a painful inherited neuropathy.</strong> J. Neurosci. 24: 8232-8236, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385606</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15385606[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/10.1523/JNEUROSCI.2695-04.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385606">Cummins et al. (2004)</a> showed that the L858H mutant SCN9A channel was activated at more negative potentials and had approximately 10-fold slower inactivation kinetics than wildtype channels. The findings indicated that the mutant channel confers hyperexcitability to peripheral sensory and sympathetic neurons, contributing to symptom production in erythermalgia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15385606" 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="#27" class="mim-tip-reference" title="Rush, A. M., Dib-Hajj, S. D., Liu, S., Cummins, T. R., Black, J. A., Waxman, S. G. <strong>A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons.</strong> Proc. Nat. Acad. Sci. 103: 8245-8250, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16702558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16702558</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16702558[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/10.1073/pnas.0602813103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16702558">Rush et al. (2006)</a> found that expression of the L858H mutant SCN9A channel in rat dorsal root ganglion (DRG) neurons and sympathetic ganglion neurons in vitro resulted in a depolarization of the resting membrane potential by about 5 mV compared to wildtype cells. In DRG neurons, the current threshold was reduced by approximately 40%, resulting in hyperexcitability and enhanced repetitive firing. By contrast, in sympathetic ganglion cells, the current threshold was increased by approximately 88%, resulting in hypoexcitability and attenuated repetitive firing. In DRG, the action potential overshoot was unchanged; in sympathetic neurons, there was a 50% attenuation of the action potential overshoot. Expression studies showed that DRG neurons, but not sympathetic neurons, also expressed SCN10A channels (<a href="/entry/604427">604427</a>), which presumably accounted for the opposing effects. The findings indicated that a single ion channel mutation can result in opposing phenotypes in different cell types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16702558" 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">rs80356474 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356474;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=rs80356474" 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=rs80356474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a sporadic patient with primary erythermalgia (<a href="/entry/133020">133020</a>), <a href="#35" class="mim-tip-reference" title="Yang, Y., Wang, Y., Li, S., Xu, Z., Li, H., Ma, L., Fan, J., Bu, D., Liu, B., Fan, Z., Wu, G., Jin, J., Ding, B., Zhu, X., Shen, Y. <strong>Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia.</strong> J. Med. Genet. 41: 171-174, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14985375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14985375</a>] [<a href="https://doi.org/10.1136/jmg.2003.012153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14985375">Yang et al. (2004)</a> identified heterozygosity for a 2543T-C transition in the SCN9A gene, resulting in an ile848-to-thr (I848T) substitution. The mutation was not found in his unaffected parents or in 400 alleles from normal Chinese controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14985375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using functional expression studies, <a href="#5" class="mim-tip-reference" title="Cummins, T. R., Dib-Hajj, S. D., Waxman, S. G. <strong>Electrophysiological properties of mutant Na(v)1.7 sodium channels in a painful inherited neuropathy.</strong> J. Neurosci. 24: 8232-8236, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15385606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15385606</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15385606[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/10.1523/JNEUROSCI.2695-04.2004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15385606">Cummins et al. (2004)</a> showed that the I848T mutant SCN9A channel was activated at more negative potentials and had approximately 3-fold slower inactivation kinetics than wildtype channels. The findings indicated that the mutant channel confers hyperexcitability to peripheral sensory and sympathetic neurons, contributing to symptom production in erythermalgia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15385606" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 ERYTHERMALGIA, PRIMARY</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80356470 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356470;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=rs80356470" 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=rs80356470" 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=RCV000006723" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006723" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006723</a>
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<p>In 5 affected members of a Flemish family with primary erythermalgia (<a href="/entry/133020">133020</a>), <a href="#23" class="mim-tip-reference" title="Michiels, J. J., te Morsche, R. H. M., Jansen, J. B. M. J., Drenth, J. P. H. <strong>Autosomal dominant erythermalgia associated with a novel mutation in the voltage-gated sodium channel alpha-subunit Nav1.7.</strong> Arch. Neurol. 62: 1587-1590, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16216943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16216943</a>] [<a href="https://doi.org/10.1001/archneur.62.10.1587" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16216943">Michiels et al. (2005)</a> identified a heterozygous 721T-A transversion in exon 6 of the SCN9A gene, resulting in a ser241-to-thr (S241T) substitution. The mutation occurs in a highly conserved residue within the sodium ion transport-associated domain that determines ion selectivity and is central to channel function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16216943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 ERYTHERMALGIA, PRIMARY</strong>
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SCN9A, PHE1449VAL
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80356478 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356478;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=rs80356478" 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=rs80356478" 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=RCV000006724" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006724" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006724</a>
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<p>In 17 affected members of a large family with primary erythermalgia (<a href="/entry/133020">133020</a>) reported by <a href="#12" class="mim-tip-reference" title="Finley, W. H., Lindsey, J. R., Jr., Fine, J.-D., Dixon, G. A., Burbank, M. K. <strong>Autosomal dominant erythromelalgia.</strong> Am. J. Med. Genet. 42: 310-315, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1536168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1536168</a>] [<a href="https://doi.org/10.1002/ajmg.1320420310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1536168">Finley et al. (1992)</a>, <a href="#7" class="mim-tip-reference" title="Dib-Hajj, S. D., Rush, A. M., Cummins, T. R., Hisama, F. M., Novella, S., Tyrrell, L., Marshall, L., Waxman, S. G. <strong>Gain-of-function mutation in Nav1.7 in familial erythromelalgia induces bursting of sensory neurons.</strong> Brain 128: 1847-1854, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15958509/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15958509</a>] [<a href="https://doi.org/10.1093/brain/awh514" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15958509">Dib-Hajj et al. (2005)</a> identified a heterozygous 4393T-G transversion in exon 23 of the SCN9A gene, resulting in a phe1449-to-val (F1449V) substitution in the N terminus of loop 3, which joins domains III and IV of the protein. The mutation was not identified in 5 unaffected family members or in 100 control chromosomes. In vitro functional expression studies showed that the F1449V mutant protein produced a hyperpolarizing shift in channel activation and a depolarizing shift in steady-state activation, lowering the threshold for single action potentials and high frequency firing in dorsal root ganglion neurons. The findings were consistent with a gain-of-function mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1536168+15958509" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED</strong>
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SCN9A, SER459TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908908 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908908;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908908?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908908" 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=rs121908908" 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=RCV000006725" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006725" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006725</a>
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<p>In a consanguineous northern Pakistani family segregating autosomal recessive congenital insensitivity to pain (<a href="/entry/243000">243000</a>), <a href="#4" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/10.1038/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> identified homozygosity for a 1376C-G transversion in exon 10 of the SCN9A gene, resulting in a ser459-to-ter (S459X) substitution. The mutation was not found in 300 northern Pakistani control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17167479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1574856736 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1574856736;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=rs1574856736" 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=rs1574856736" 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=RCV000006726" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006726" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006726</a>
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<p>In a consanguineous northern Pakistani family segregating autosomal recessive congenital insensitivity to pain (<a href="/entry/243000">243000</a>), <a href="#4" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/10.1038/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> identified homozygosity for a 1-bp deletion (2298delT) in exon 13 of the SCN9A gene, resulting in a frameshift and an ile767-to-ter (I767X) substitution. The mutation was not found in 300 northern Pakistani control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17167479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED</strong>
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SCN9A, TRP897TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908909 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908909;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=rs121908909" 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=rs121908909" 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=RCV000006727" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006727" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006727</a>
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<p>In a consanguineous northern Pakistani family segregating autosomal recessive congenital insensitivity to pain (<a href="/entry/243000">243000</a>), <a href="#4" class="mim-tip-reference" title="Cox, J. J., Reimann, F., Nicholas, A. K., Thornton, G., Roberts, E., Springell, K., Karbani, G., Jafri, H., Mannan, J., Raashid, Y., Al-Gazali, L., Hamamy, H., Valente, E. M., Gorman, S., Williams, R., McHale, D. P., Wood, J. N., Gribble, F. M., Woods, C. G. <strong>An SCN9A channelopathy causes congenital inability to experience pain.</strong> Nature 444: 894-898, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17167479/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17167479</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17167479[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/10.1038/nature05413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17167479">Cox et al. (2006)</a> identified homozygosity for a 2691G-A transition in exon 15 of the SCN9A gene, resulting in a trp897-to-ter (W897X) substitution. The mutation was not found in 300 northern Pakistani control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17167479" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0008" class="mim-anchor"></a>
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<strong>.0008 PAROXYSMAL EXTREME PAIN DISORDER</strong>
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SCN9A, ARG996CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908910 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908910;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908910?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908910" 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=rs121908910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006728 OR RCV000559164 OR RCV001559739" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006728, RCV000559164, RCV001559739" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006728...</a>
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<p>In 2 families segregating paroxysmal extreme pain disorder (PEXPD; <a href="/entry/167400">167400</a>), <a href="#11" class="mim-tip-reference" title="Fertleman, C. R., Baker, M. D., Parker, K. A., Moffatt, S., Elmslie, F. V., Abrahamsen, B., Ostman, J., Klugbauer, N., Wood, J. N., Gardiner, R. M., Rees, M. <strong>SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.</strong> Neuron 52: 767-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17145499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17145499</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17145499">Fertleman et al. (2006)</a> identified a C-to-T transition in exon 16 of the SCN9A gene resulting in an arginine-to-cysteine substitution at codon 996 (R996C). Affected members of 1 family who carried this mutation in heterozygosity had a less severe phenotype not requiring medication. In another family, the R996C mutation was found in the proband in compound heterozygosity with a V1298D mutation (<a href="#0009">603415.0009</a>) and in his affected father in heterozygosity. The proband was more severely affected than his father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17145499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0009 PAROXYSMAL EXTREME PAIN DISORDER</strong>
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</h4>
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SCN9A, VAL1298ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908911 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908911;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=rs121908911" 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=rs121908911" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006729" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006729" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006729</a>
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<span class="mim-text-font">
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<p>In an individual with paroxysmal extreme pain disorder (PEXPD; <a href="/entry/167400">167400</a>) who inherited an R996C (<a href="#0008">603415.0008</a>) mutation from his affected father, <a href="#11" class="mim-tip-reference" title="Fertleman, C. R., Baker, M. D., Parker, K. A., Moffatt, S., Elmslie, F. V., Abrahamsen, B., Ostman, J., Klugbauer, N., Wood, J. N., Gardiner, R. M., Rees, M. <strong>SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.</strong> Neuron 52: 767-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17145499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17145499</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17145499">Fertleman et al. (2006)</a> found a de novo T-to-A transversion in exon 21 of the SCN9A gene, which resulted in a valine-to-aspartic acid substitution at codon 1298 (V1298D), as well. The valine at position 1298 is completely conserved through evolution and among paralogous human voltage-gated sodium channels, and is critical to inactivation of the sodium channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17145499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0010 PAROXYSMAL EXTREME PAIN DISORDER</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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SCN9A, VAL1298PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908912 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908912;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=rs121908912" 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=rs121908912" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006730" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006730" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006730</a>
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</span>
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<span class="mim-text-font">
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<p>In a family segregating paroxysmal extreme pain disorder (PEXPD; <a href="/entry/167400">167400</a>), <a href="#11" class="mim-tip-reference" title="Fertleman, C. R., Baker, M. D., Parker, K. A., Moffatt, S., Elmslie, F. V., Abrahamsen, B., Ostman, J., Klugbauer, N., Wood, J. N., Gardiner, R. M., Rees, M. <strong>SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.</strong> Neuron 52: 767-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17145499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17145499</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17145499">Fertleman et al. (2006)</a> identified a heterozygous G-to-T transversion in exon 21 of the SCN9A gene, resulting in a valine-to-phenylalanine substitution at codon 1298 (V1298F). The valine at position 1298 is completely conserved through evolution and among paralogous human voltage-gated sodium channels, and is critical to inactivation of the sodium channel. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17145499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0011 PAROXYSMAL EXTREME PAIN DISORDER</strong>
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</h4>
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SCN9A, VAL1299PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908913 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908913;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=rs121908913" 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=rs121908913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006731 OR RCV000691966 OR RCV001090456" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006731, RCV000691966, RCV001090456" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006731...</a>
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<span class="mim-text-font">
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<p>In a large 5-generation family segregating autosomal dominant paroxysmal extreme pain disorder (PEXPD; <a href="/entry/167400">167400</a>), <a href="#11" class="mim-tip-reference" title="Fertleman, C. R., Baker, M. D., Parker, K. A., Moffatt, S., Elmslie, F. V., Abrahamsen, B., Ostman, J., Klugbauer, N., Wood, J. N., Gardiner, R. M., Rees, M. <strong>SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.</strong> Neuron 52: 767-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17145499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17145499</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17145499">Fertleman et al. (2006)</a> identified a heterozygous G-to-T transversion in exon 21 of the SCN9A gene, resulting in a valine-to-phenylalanine substitution at codon 1299 (V1299F). The valine at codon 1299 is completely conserved through evolution and among paralogous human voltage-gated sodium channels. It occurs in the loop between domain III S4-S5 and is believed to interact with domain III-IV inactivation motif. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17145499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0012" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0012 PAROXYSMAL EXTREME PAIN DISORDER</strong>
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</h4>
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SCN9A, ILE1461THR
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908914 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908914;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=rs121908914" 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=rs121908914" 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=RCV000006732 OR RCV002512850" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006732, RCV002512850" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006732...</a>
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<p>In a family segregating paroxysmal extreme pain disorder (PEXPD; <a href="/entry/167400">167400</a>), <a href="#11" class="mim-tip-reference" title="Fertleman, C. R., Baker, M. D., Parker, K. A., Moffatt, S., Elmslie, F. V., Abrahamsen, B., Ostman, J., Klugbauer, N., Wood, J. N., Gardiner, R. M., Rees, M. <strong>SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.</strong> Neuron 52: 767-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17145499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17145499</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17145499">Fertleman et al. (2006)</a> identified a heterozygous T-to-C transition in exon 24 of the SCN9A gene, resulting in an isoleucine-to-threonine substitution at codon 1461 (I1461T). Functional analysis of this mutation showed that there was altered inactivation with persistent currents which were maintained for more than several hundred milliseconds. In vitro assessment showed that Na(v)1.7 channels carrying this mutant were sensitive to carbamazepine, as was seen in the patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17145499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 PAROXYSMAL EXTREME PAIN DISORDER</strong>
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SCN9A, THR1464ILE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908915 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908915;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=rs121908915" 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=rs121908915" 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=RCV000006733" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006733" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006733</a>
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<p>In a family segregating paroxysmal extreme pain disorder (PXPD; <a href="/entry/167400">167400</a>), <a href="#11" class="mim-tip-reference" title="Fertleman, C. R., Baker, M. D., Parker, K. A., Moffatt, S., Elmslie, F. V., Abrahamsen, B., Ostman, J., Klugbauer, N., Wood, J. N., Gardiner, R. M., Rees, M. <strong>SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes.</strong> Neuron 52: 767-774, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17145499/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17145499</a>] [<a href="https://doi.org/10.1016/j.neuron.2006.10.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17145499">Fertleman et al. (2006)</a> identified a heterozygous C-to-T transition in exon 24 of the SCN9A gene that resulted in a threonine-to-isoleucine substitution at codon 1464 (T1464I). This mutation occurred in the domain III-IV linker region and was shown in in vitro assays to result in altered inactivation with associated persistent currents. In the presence of carbamazepine this current was reduced in a concentration-dependent manner. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17145499" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0014" class="mim-anchor"></a>
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<strong>.0014 INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED</strong>
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SCN9A, ARG277TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908916 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908916;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908916?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908916" 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=rs121908916" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006734 OR RCV001383702 OR RCV002426494" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006734, RCV001383702, RCV002426494" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006734...</a>
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<p>In affected members of 2 unrelated Swiss families with congenital insensitivity to pain (<a href="/entry/243000">243000</a>), <a href="#14" class="mim-tip-reference" title="Goldberg, Y. P., MacFarlane, J., MacDonald, M. L., Thompson, J., Dube, M.-P., Mattice, M., Fraser, R., Young, C., Hossain, S., Pape, T., Payne, B., Radomski, C., and 18 others. <strong>Loss-of-function mutations in the Na(v)1.7 gene underlie congenital indifference to pain in multiple human populations.</strong> Clin. Genet. 71: 311-319, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17470132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17470132</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00790.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17470132">Goldberg et al. (2007)</a> identified a homozygous 829C-T transition in exon 6 of the SCN9A gene, resulting in an arg277-to-ter (R277X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17470132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0015" class="mim-anchor"></a>
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<h4>
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<strong>.0015 INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED</strong>
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SCN9A, TYR328TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908917 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908917;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908917?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908917" 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=rs121908917" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006735 OR RCV002281698" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006735, RCV002281698" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006735...</a>
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<p>In affected members of a large Canadian family with congenital insensitivity to pain (<a href="/entry/243000">243000</a>), <a href="#14" class="mim-tip-reference" title="Goldberg, Y. P., MacFarlane, J., MacDonald, M. L., Thompson, J., Dube, M.-P., Mattice, M., Fraser, R., Young, C., Hossain, S., Pape, T., Payne, B., Radomski, C., and 18 others. <strong>Loss-of-function mutations in the Na(v)1.7 gene underlie congenital indifference to pain in multiple human populations.</strong> Clin. Genet. 71: 311-319, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17470132/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17470132</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00790.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17470132">Goldberg et al. (2007)</a> identified a homozygous 984C-A transversion in exon 8 of the SCN9A gene, resulting in a tyr328-to-ter (Y328X) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17470132" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0016" class="mim-anchor"></a>
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<strong>.0016 ERYTHERMALGIA, PRIMARY</strong>
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SCN9A, LEU858PHE
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80356476 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356476;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=rs80356476" 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=rs80356476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006736" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006736" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006736</a>
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<p>In 2 Chinese brothers with primary erythermalgia (<a href="/entry/133020">133020</a>), <a href="#17" class="mim-tip-reference" title="Han, C., Rush, A. M., Dib-Hajj, S. D., Li, S., Xu, Z., Wang, Y., Tyrrell, L., Wang, X., Yang, Y., Waxman, S. G. <strong>Sporadic onset of erythermalgia: gain-of-function mutation in Nav1.7.</strong> Ann. Neurol. 59: 553-558, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16392115/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16392115</a>] [<a href="https://doi.org/10.1002/ana.20776" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16392115">Han et al. (2006)</a> identified a 2572C-T transition in exon 15 of the SCN9A gene, resulting in a leu858-to-phe (L858F) substitution in the linker region between transmembrane segments 4 and 5 in domain 2. The asymptomatic father was found to be a somatic mosaic for the mutation, which was present in 13% of his leukocytes. In vitro functional expression studies showed that the L858F protein caused a hyperpolarizing shift in channel activation, a depolarizing shift of inactivation, and an 18-fold increase in deactivation time compared to wildtype. In addition, the mean ramp current amplitude in response to slow depolarization was higher in L858F-mutant channels. The mutation was not identified in 200 alleles from Chinese controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16392115" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0017" class="mim-anchor"></a>
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<strong>.0017 ERYTHERMALGIA, PRIMARY</strong>
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SCN9A, PHE216SER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs80356469 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs80356469;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=rs80356469" 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=rs80356469" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000006737" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006737" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006737</a>
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<p>In a father and daughter with primary erythermalgia (<a href="/entry/133020">133020</a>), <a href="#8" class="mim-tip-reference" title="Drenth, J. P. H., te Morsche, R. H. M., Guillet, G., Taieb, A., Kirby, R. L., Jansen, J. B. M. J. <strong>SCN9A mutations define primary erythermalgia as a neuropathic disorder of voltage gated sodium channels.</strong> J. Invest. Derm. 124: 1333-1338, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15955112/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15955112</a>] [<a href="https://doi.org/10.1111/j.0022-202X.2005.23737.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15955112">Drenth et al. (2005)</a> identified heterozygosity for a 647T-C transition in exon 5 of the SCN9A gene, resulting in a phe216-to-ser (F216S) substitution within the S4 membrane-spanning segment of the first domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15955112" 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="Choi, J.-S., Dib-Hajj, S. D., Waxman, S. G. <strong>Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy.</strong> Neurology 67: 1563-1567, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16988069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16988069</a>] [<a href="https://doi.org/10.1212/01.wnl.0000231514.33603.1e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16988069">Choi et al. (2006)</a> noted that the phe216 residue is strictly conserved in all known voltage-gated sodium channels. By patch-clamp studies in HEK293 cells, <a href="#3" class="mim-tip-reference" title="Choi, J.-S., Dib-Hajj, S. D., Waxman, S. G. <strong>Inherited erythermalgia: limb pain from an S4 charge-neutral Na channelopathy.</strong> Neurology 67: 1563-1567, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16988069/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16988069</a>] [<a href="https://doi.org/10.1212/01.wnl.0000231514.33603.1e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16988069">Choi et al. (2006)</a> found that the F216S-mutant protein hyperpolarized the voltage dependence of activation by 10 mV, accelerated activation, slowed deactivation, and enhanced the response to slow, small depolarizations. These changes were predicted to increase excitability of nociceptive dorsal root ganglion neurons in which the mutant channel is present, thus contributing to pain. In an accompanying editorial, <a href="#30" class="mim-tip-reference" title="Schorge, S., Ptacek, L. J. <strong>Inherited erythermalgia moves a sodium channel into focus.</strong> Neurology 67: 1538-1539, 2006. Note: Erratum: Neurology 70: 244 only, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17101882/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17101882</a>] [<a href="https://doi.org/10.1212/01.wnl.0000242618.60344.8c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17101882">Schorge and Ptacek (2006)</a> noted that the F216S mutation involves a noncharged aromatic amino acid being replaced by a noncharged slightly polar amino acid, which may not have been predicted to have major biophysical effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17101882+16988069" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908918 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908918;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908918?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908918" 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=rs121908918" 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=RCV000006738 OR RCV000557785 OR RCV001535456 OR RCV002408454" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006738, RCV000557785, RCV001535456, RCV002408454" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006738...</a>
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<p>This variant, previously titled GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 7, has been reclassified based on the report by <a href="#10" class="mim-tip-reference" title="Fasham, J., Leslie, J. S., Harrison, J. W., Deline, J., Williams, K. B., Kuhl, A., Schwoerer, J. S., Cross, H. E., Crosby, A. H., Baple, E. L. <strong>No association between SCN9A and monogenic human epilepsy disorders.</strong> PLoS Genet. 16: e1009161, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33216760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33216760</a>] [<a href="https://doi.org/10.1371/journal.pgen.1009161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33216760">Fasham et al. (2020)</a>, which found that the N641Y variant was present at high frequency in the Amish involving hundreds of variant carriers with no history of seizure phenotypes. In addition, <a href="#10" class="mim-tip-reference" title="Fasham, J., Leslie, J. S., Harrison, J. W., Deline, J., Williams, K. B., Kuhl, A., Schwoerer, J. S., Cross, H. E., Crosby, A. H., Baple, E. L. <strong>No association between SCN9A and monogenic human epilepsy disorders.</strong> PLoS Genet. 16: e1009161, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33216760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33216760</a>] [<a href="https://doi.org/10.1371/journal.pgen.1009161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33216760">Fasham et al. (2020)</a> stated that the overall frequency of N641Y in the European population in the gnomAD database (v2.1.1), 1.4x10(-5), confirms that it represents a low frequency variant in the European population. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33216760" 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 affected members of a large Utah family with generalized epilepsy with febrile seizures plus, <a href="#32" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a> identified a heterozygous 1921A-T transversion in exon 11 of the SCN9A gene, resulting in an asn641-to-tyr (N641Y) substitution in the large intracellular loop between domains I and II. The mutation was not found in 586 control chromosomes. The was only 1 unaffected mutation carrier, indicating about 95% penetrance. The phenotype in this family, which was originally reported by <a href="#26" class="mim-tip-reference" title="Peiffer, A., Thompson, J., Charlier, C., Otterud, B., Varvil, T., Pappas, C., Barnitz, C., Gruenthal, K., Kuhn, R., Leppert, M. <strong>A locus for febrile seizures (FEB3) maps to chromosome 2q23-24.</strong> Ann. Neurol. 46: 671-678, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10514109/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10514109</a>] [<a href="https://doi.org/10.1002/1531-8249(199910)46:4<671::aid-ana20>3.0.co;2-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10514109">Peiffer et al. (1999)</a>, showed a broad clinical spectrum: 11 individuals experienced only febrile seizures before age 6 years, whereas 10 additional individuals later developed afebrile seizures. In 8 of the 10, seizures remitted by age 16 years. The remaining 2 affected individuals developed intractable epilepsy: 1 had complex-partial seizures associated with left mesial temporal sclerosis, and the other had afebrile generalized convulsive seizures requiring the placement of a vagal nerve stimulator. The phenotype was consistent with GEFS+ (<a href="#25" class="mim-tip-reference" title="Moulard, B., Chaigne, D., Malafosse, A. <strong>Clinical heterogeneity in pedigrees with 2q-linked febrile seizures. (Letter)</strong> Ann. Neurol. 47: 839-840, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852559/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852559</a>]" pmid="10852559">Moulard et al., 2000</a>; <a href="#29" class="mim-tip-reference" title="Scheffer, I. E., Wallace, R. H., Mulley, J. C., Berkovic, S. F. <strong>Locus for febrile seizures. (Letter)</strong> Ann. Neurol. 47: 840-841, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10852560/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10852560</a>] [<a href="https://doi.org/10.1002/1531-8249(200006)47:6<840::aid-ana28>3.0.co;2-v" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10852560">Scheffer et al., 2000</a>). <a href="#32" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a> reported that mice targeted with the N641Y mutation had reduced seizure thresholds and increased corneal kindling acquisition rates, indicating that the mutant channel had functional effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10852560+10514109+19763161+10852559" 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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SCN9A, LYS655ARG (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908919;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs121908919</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908919 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908919;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908919?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908919" 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=rs121908919" 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=RCV000006739 OR RCV000153918 OR RCV000415152 OR RCV000488281 OR RCV001083774 OR RCV001133028 OR RCV001133029 OR RCV001133030 OR RCV002415403 OR RCV004532301" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006739, RCV000153918, RCV000415152, RCV000488281, RCV001083774, RCV001133028, RCV001133029, RCV001133030, RCV002415403, RCV004532301" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006739...</a>
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<p>This variant, previously titled GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 7, has been reclassified based on the report by <a href="#10" class="mim-tip-reference" title="Fasham, J., Leslie, J. S., Harrison, J. W., Deline, J., Williams, K. B., Kuhl, A., Schwoerer, J. S., Cross, H. E., Crosby, A. H., Baple, E. L. <strong>No association between SCN9A and monogenic human epilepsy disorders.</strong> PLoS Genet. 16: e1009161, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33216760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33216760</a>] [<a href="https://doi.org/10.1371/journal.pgen.1009161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33216760">Fasham et al. (2020)</a>, which noted that the K655R variant has a high frequency (0.2%) and is present in homozygous state in the gnomAD database, inconsistent with it being causative of a monogenic seizure disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33216760" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with a phenotype consistent with GEFS+, <a href="#32" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a> identified a heterozygous 1964A-G transition in the SCN9A gene, resulting in a lys655-to-arg (K655R) substitution in a highly conserved residue in the large intracellular loop between domains I and II. The mutation was not identified in 562 control chromosomes. The patient had febrile seizures, idiopathic generalized epilepsy, and generalized spike-wave patterns on EEG. <a href="#32" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a> found this mutation in 2 patients diagnosed with Dravet syndrome (<a href="/entry/607208">607208</a>), one of whom also had a mutation in the SCN1A gene (<a href="/entry/182389">182389</a>). <a href="#32" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a> suggested that SCN9A mutations may have a modifier effect in partner with SCN1A mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19763161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 2 sisters from a nonconsanguineous Brazilian family with GEFS+, <a href="#1" class="mim-tip-reference" title="Alves, R. M., Uva, P., Veiga, M. F., Oppo, M., Zschaber, F. C. R., Porcu, G., Porto, H. P., Persico, I., Onano, S., Cuccuru, G., Atzeni, R., Vieira, L. C. N., Pires, M. V. A., Cucca, F., Toralles, M. B. P., Angius, A., Crisponi, L. <strong>Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report.</strong> BMC Med. Genet. 20: 16, 2019. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30642272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30642272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30642272[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/10.1186/s12881-019-0745-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30642272">Alves et al. (2019)</a> identified the K655R mutation in the SCN9A gene. The mutation, which was found by whole-exome sequencing, was also present in their unaffected father. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30642272" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908920 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908920;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908920?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908920" 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=rs121908920" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>This variant, previously titled FEBRILE SEIZURES, FAMILIAL, 3B, has been reclassified because its pathogenicity has not been confirmed.</p><p>From a panel of 92 unrelated patients with childhood seizures occurring in the setting of febrile seizures (see <a href="/entry/613863">613863</a>), <a href="#32" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a> identified a Hispanic patient who was heterozygous for a 184A-G transition in the SCN9A gene, resulting in an ile62-to-val (I62V) substitution at a highly conserved residue in the N-terminal region. The mutation was not identified in 276 ethnically matched control chromosomes. The authors did not find a mutation in the SCNA1 gene in this patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19763161" 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="#10" class="mim-tip-reference" title="Fasham, J., Leslie, J. S., Harrison, J. W., Deline, J., Williams, K. B., Kuhl, A., Schwoerer, J. S., Cross, H. E., Crosby, A. H., Baple, E. L. <strong>No association between SCN9A and monogenic human epilepsy disorders.</strong> PLoS Genet. 16: e1009161, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33216760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33216760</a>] [<a href="https://doi.org/10.1371/journal.pgen.1009161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33216760">Fasham et al. (2020)</a> noted the lack of segregation studies for this variant in the report by <a href="#32" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=33216760+19763161" 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>This variant, previously titled FEBRILE SEIZURES, FAMILIAL, 3B, has been reclassified because its pathogenicity has not been confirmed.</p><p>From a panel of 92 unrelated patients with childhood seizures occurring in the setting of febrile seizures (see <a href="/entry/613863">613863</a>), <a href="#32" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a> identified a Caucasian patient with a heterozygous 446C-A transversion in the SCN9A gene, resulting in a pro149-to-gln (P149Q) substitution in a highly conserved residue in domain I. The mutation was not identified in 562 ethnically matched control chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19763161" 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="#10" class="mim-tip-reference" title="Fasham, J., Leslie, J. S., Harrison, J. W., Deline, J., Williams, K. B., Kuhl, A., Schwoerer, J. S., Cross, H. E., Crosby, A. H., Baple, E. L. <strong>No association between SCN9A and monogenic human epilepsy disorders.</strong> PLoS Genet. 16: e1009161, 2020. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33216760/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33216760</a>] [<a href="https://doi.org/10.1371/journal.pgen.1009161" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33216760">Fasham et al. (2020)</a> noted the lack of segregation studies for this variant in the report by <a href="#32" class="mim-tip-reference" title="Singh, N. A., Pappas, C., Dahle, E. J., Claes, L. R. F., Pruess, T. H., De Jonghe, P., Thompson, J., Dixon, M., Gurnett, C., Peiffer, A., White, H. S., Filloux, F., Leppert, M. F. <strong>A role of SCN9A in human epilepsies, as a cause of febrile seizures and as a potential modifier of Dravet syndrome.</strong> PLoS Genet. 5: e1000649, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19763161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19763161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19763161[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/10.1371/journal.pgen.1000649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19763161">Singh et al. (2009)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=33216760+19763161" 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=RCV000006742 OR RCV000302710 OR RCV000309032 OR RCV000402111 OR RCV000532835" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000006742, RCV000302710, RCV000309032, RCV000402111, RCV000532835" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000006742...</a>
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<p>In a Chinese boy with relatively late onset of primary erythermalgia (<a href="/entry/133020">133020</a>) of the lower extremities at age 14 years, <a href="#15" class="mim-tip-reference" title="Han, C., Dib-Hajj, S. D., Lin, Z., Li, Y., Eastman, E. M., Tyrrell, L., Cao, X., Yang, Y., Waxman, S. G. <strong>Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation.</strong> Brain 132: 1711-1722, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19369487/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19369487</a>] [<a href="https://doi.org/10.1093/brain/awp078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19369487">Han et al. (2009)</a> identified a heterozygous 29A-G transition in exon 1 of the SCN9A gene, resulting in a gln10-to-arg (Q10R) substitution in the cytoplasmic N terminus of the channel. Neither unaffected parent carried the mutation, and it was not present in 200 Chinese control alleles. In vitro patch-clamp studies showed that the Q10R mutation caused a hyperpolarizing shift of -5.3 mV for the midpoint of activation, which is smaller than that seen in other SCN9A mutations causing early-onset erythromelalgia mutations. The Q10R mutation also caused a faster rate of activation and slower deactivation compared to wildtype. Expression of Q10R-mutant protein induced hyperexcitability in DRG neurons, but the increase was smaller than that produced by I848T (<a href="#0002">603415.0002</a>), an early-onset erythromelalgia mutation. The findings suggested a genotype-phenotype correlation, such that mutations resulting in smaller effects on sodium channel activation are associated with a smaller degree of neuron excitability and later onset of clinical signs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19369487" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs200945460 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200945460;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs200945460?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs200945460" 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=rs200945460" 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=RCV000023302 OR RCV000118297 OR RCV000191125 OR RCV000311897 OR RCV000393721 OR RCV000476046 OR RCV001546748 OR RCV002415425" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023302, RCV000118297, RCV000191125, RCV000311897, RCV000393721, RCV000476046, RCV001546748, RCV002415425" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023302...</a>
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<p>In a 39-year-old Dutch Caucasian man with small fiber neuropathy (SFNP; see <a href="/entry/133020">133020</a>), <a href="#9" class="mim-tip-reference" title="Faber, C. G., Hoeijmakers, J. G. J., Ahn, H.-S., Cheng, X., Han, C., Choi, J.-S., Estacion, M., Lauria, G., Vanhoutte, E. K., Gerrits, M. M., Dib-Hajj, S., Drenth, J. P. H., Waxman, S. G., Merkies, I. S. J. <strong>Gain of function Na(v) 1.7 mutations in idiopathic small fiber neuropathy.</strong> Ann. Neurol. 71: 26-39, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21698661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21698661</a>] [<a href="https://doi.org/10.1002/ana.22485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21698661">Faber et al. (2012)</a> identified a heterozygous 2159T-A transversion in the SCN9A gene, resulting in an ile720-to-lys (I720K) substitution in the cytoplasmic linker-1 region between domains I and II. The mutation was not found in 200 control chromosomes. The patient developed stabbing pain in the whole body at age 37 years. Two months later, he also had burning pain in the feet and lower legs, followed by pain in the lower arms. He also had numbness and hyperhidrosis in the feet. He had distally impaired warmth sensation and decreased intraepithelial nerve fiber density compared to controls. In vitro functional expression and electrophysiologic studies in HEK293 and dorsal root ganglion neurons showed that the mutant I720K protein resulted in impaired slow inactivation and hyperexcitability of dorsal root ganglion cells. I720K caused a depolarizing shift in the resting membrane potential and an increase in the number of action potentials evoked by a depolarizing stimulus compared to control. Activation, fast-inactivation, and ramp currents were similar to wildtype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21698661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs200398202 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs200398202;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs200398202?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs200398202" 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=rs200398202" 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=RCV000023303 OR RCV002513185" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023303, RCV002513185" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023303...</a>
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<p>In a 63-year-old Dutch Caucasian woman with small fiber neuropathy (see <a href="/entry/133020">133020</a>), <a href="#9" class="mim-tip-reference" title="Faber, C. G., Hoeijmakers, J. G. J., Ahn, H.-S., Cheng, X., Han, C., Choi, J.-S., Estacion, M., Lauria, G., Vanhoutte, E. K., Gerrits, M. M., Dib-Hajj, S., Drenth, J. P. H., Waxman, S. G., Merkies, I. S. J. <strong>Gain of function Na(v) 1.7 mutations in idiopathic small fiber neuropathy.</strong> Ann. Neurol. 71: 26-39, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21698661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21698661</a>] [<a href="https://doi.org/10.1002/ana.22485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21698661">Faber et al. (2012)</a> identified a heterozygous 1867G-A transition in the SCN9A gene, resulting in an asp623-to-asn (D623N) substitution in the cytoplasmic linker-1 region between domains I and II. The mutation was not found in 200 control chromosomes. The patient had onset of muscle pain at age 22 years. At age 58, she had severe burning pain in the soles, which progressed to involve other parts of the feet and the hands. She later developed patchy skin redness, dry eyes, dry mouth, and orthostatic dizziness, as well as tenderness and burning in other areas, such as the scalp, lips, mouth, and trunk. She had impaired cold sensation in the feet and decreased intraepithelial nerve fiber density compared to controls. A sister reportedly had similar complaints. In vitro functional expression and electrophysiologic studies in HEK293 and dorsal root ganglion neurons showed that the mutant D623N protein resulted in impaired fast and slow inactivation and hyperexcitability of dorsal root ganglion cells. D623N caused a depolarizing shift in the resting membrane potential, an increase in the number of action potentials evoked by a depolarizing stimulus, and an increase in the proportion of spontaneously firing cells compared to control. Current densities, activation, and ramp currents were not significantly different from control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21698661" 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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SCN9A, MET932LEU AND VAL991LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs12478318 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12478318;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs12478318?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs12478318" 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=rs12478318" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs4369876 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs4369876;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs4369876?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs4369876" 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=rs4369876" 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=RCV000023304 OR RCV000080038 OR RCV000080039 OR RCV000284177 OR RCV000375717 OR RCV000389941 OR RCV000399125 OR RCV000461431 OR RCV000469131 OR RCV000490436 OR RCV000986924 OR RCV000992914 OR RCV000992915 OR RCV001129274 OR RCV001129275 OR RCV003313935" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023304, RCV000080038, RCV000080039, RCV000284177, RCV000375717, RCV000389941, RCV000399125, RCV000461431, RCV000469131, RCV000490436, RCV000986924, RCV000992914, RCV000992915, RCV001129274, RCV001129275, RCV003313935" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023304...</a>
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<p>In a 22-year-old Dutch Caucasian man with small fiber neuropathy (see <a href="/entry/133020">133020</a>), <a href="#9" class="mim-tip-reference" title="Faber, C. G., Hoeijmakers, J. G. J., Ahn, H.-S., Cheng, X., Han, C., Choi, J.-S., Estacion, M., Lauria, G., Vanhoutte, E. K., Gerrits, M. M., Dib-Hajj, S., Drenth, J. P. H., Waxman, S. G., Merkies, I. S. J. <strong>Gain of function Na(v) 1.7 mutations in idiopathic small fiber neuropathy.</strong> Ann. Neurol. 71: 26-39, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21698661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21698661</a>] [<a href="https://doi.org/10.1002/ana.22485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21698661">Faber et al. (2012)</a> identified a heterozygous complex allele with 2 mutations in cis in the SCN9A gene: a 2794A-C transversion resulting in a met932-to-leu (M932L) substitution, and a 2971G-T transversion resulting in a val991-to-leu (V991L) substitution in the cytoplasmic linker-2 region between domains II and III. Neither mutation was found in 200 control chromosomes. The patient presented at age 16 years with burning pain in the feet and lower legs. The pain increased with exercise and interfered with standing. He also had autonomic symptoms, including orthostatic dizziness, dry mouth and eyes, and constipation. The symptoms were aggravated by warmth. He had impaired warmth sensation in the left foot and decreased intraepithelial nerve fiber density compared to controls. In vitro functional expression and electrophysiologic studies in HEK293 and dorsal root ganglion neurons showed that the mutant protein increased the generation of resurgent currents, but did not affect activation, fast or slow inactivation, ramp currents, or deactivation. The change in resurgent currents would produce repetitive neuronal firing. The mutant protein made dorsal root ganglion cells hyperexcitable, with a depolarizing shift in the resting membrane potential, an increase in the number of action potentials evoked by a depolarizing stimulus, and a trend toward an increase in the proportion of spontaneously firing cells compared to control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21698661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs73969684 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs73969684;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs73969684?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs73969684" 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=rs73969684" 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=RCV000144930 OR RCV000144931 OR RCV000178871 OR RCV000331310 OR RCV000382273 OR RCV000421273 OR RCV001081785" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144930, RCV000144931, RCV000178871, RCV000331310, RCV000382273, RCV000421273, RCV001081785" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144930...</a>
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<p>In 2 unrelated patients with small fiber neuropathy (see <a href="/entry/133020">133020</a>) without autonomic dysfunction, <a href="#9" class="mim-tip-reference" title="Faber, C. G., Hoeijmakers, J. G. J., Ahn, H.-S., Cheng, X., Han, C., Choi, J.-S., Estacion, M., Lauria, G., Vanhoutte, E. K., Gerrits, M. M., Dib-Hajj, S., Drenth, J. P. H., Waxman, S. G., Merkies, I. S. J. <strong>Gain of function Na(v) 1.7 mutations in idiopathic small fiber neuropathy.</strong> Ann. Neurol. 71: 26-39, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21698661/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21698661</a>] [<a href="https://doi.org/10.1002/ana.22485" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21698661">Faber et al. (2012)</a> and <a href="#16" class="mim-tip-reference" title="Han, C., Hoeijmakers, J. G. J., Liu, S., Gerrits, M. M., te Morsche, R. H. M., Lauria, G., Dib-Hajj, S. D., Drenth, J. P. H., Faber, C. G., Merkies, I. S. J., Waxman, S. G. <strong>Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy.</strong> Brain 135: 2613-2628, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22826602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22826602</a>] [<a href="https://doi.org/10.1093/brain/aws187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22826602">Han et al. (2012)</a> identified a heterozygous c.554G-A transition in the SCN9A gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs73969684;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs73969684</a>), resulting in an arg185-to-his (R185H) substitution at a highly conserved residue in the linker region between D1/S2 and D1/S3. The variant has a heterozygote frequency of 1.2% in both the 1000 Genomes Project and Exome Variant Server databases, and a 0.4% heterozygote frequency among 1,000 European controls. In vitro functional expression assays in rat neurons showed that the R185H mutation rendered dorsal root ganglion neurons hyperexcitable and enhanced resurgent currents, but did not produce detectable changes in sympathetic neurons of the superior cervical ganglion. <a href="#16" class="mim-tip-reference" title="Han, C., Hoeijmakers, J. G. J., Liu, S., Gerrits, M. M., te Morsche, R. H. M., Lauria, G., Dib-Hajj, S. D., Drenth, J. P. H., Faber, C. G., Merkies, I. S. J., Waxman, S. G. <strong>Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy.</strong> Brain 135: 2613-2628, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22826602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22826602</a>] [<a href="https://doi.org/10.1093/brain/aws187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22826602">Han et al. (2012)</a> suggested that the lack of effect on sympathetic neurons explains the lack of autonomic features in these patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22826602+21698661" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 3-year-old girl with paroxysmal extreme pain disorder (PEXPD; <a href="/entry/167400">167400</a>), <a href="#22" class="mim-tip-reference" title="Meglic, A., Perkovic-Benedik, M., Trebusak Podkrajsek, K., Bertok, S. <strong>Painful micturition in a small child: an unusual clinical picture of paroxysmal extreme pain disorder.</strong> Pediat. Nephrol. 29: 1643-1646, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24817410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24817410</a>] [<a href="https://doi.org/10.1007/s00467-014-2819-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24817410">Meglic et al. (2014)</a> identified a heterozygous R185H mutation in the SCN9A gene. She had painful urinary voiding manifest as crying, sweating, and writhing since birth. Similar symptoms occasionally occurred when passing stool. She had no other autonomic manifestations, but had mildly delayed motor development. Treatment with carbamazepine resulted in significant clinical improvement and normal development. Family history revealed that her father occasionally had pain in the jaw while yawning, but did not remember pain attacks in his early childhood; the father was found to carry the same heterozygous SCN9A mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24817410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs182650126 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs182650126;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs182650126?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs182650126" 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=rs182650126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 3 unrelated patients with small fiber neuropathy (see <a href="/entry/133020">133020</a>) and severe autonomic dysfunction, <a href="#16" class="mim-tip-reference" title="Han, C., Hoeijmakers, J. G. J., Liu, S., Gerrits, M. M., te Morsche, R. H. M., Lauria, G., Dib-Hajj, S. D., Drenth, J. P. H., Faber, C. G., Merkies, I. S. J., Waxman, S. G. <strong>Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy.</strong> Brain 135: 2613-2628, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22826602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22826602</a>] [<a href="https://doi.org/10.1093/brain/aws187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22826602">Han et al. (2012)</a> identified a heterozygous c.2215A-G transition in exon 13 of the SCN9A gene, resulting in an ile739-to-val (I739V) substitution at a highly conserved residue in the transmembrane segment of domain II. The variant was not present in the 1000 Genomes Project database, but it was reported with a 0.5% frequency in the Exome Variant Server database and was found in 1.4% of Dutch control individuals. In vitro functional expression assays in rat neurons showed that the I739V mutation impaired channel slow inactivation in both dorsal root ganglion cells and sympathetic neurons of the superior cervical ganglion. The mutation rendered dorsal root ganglion neurons hyperexcitable and superior ganglion neurons hypoexcitable. <a href="#16" class="mim-tip-reference" title="Han, C., Hoeijmakers, J. G. J., Liu, S., Gerrits, M. M., te Morsche, R. H. M., Lauria, G., Dib-Hajj, S. D., Drenth, J. P. H., Faber, C. G., Merkies, I. S. J., Waxman, S. G. <strong>Functional profiles of SCN9A variants in dorsal root ganglion neurons and superior cervical ganglion neurons correlate with autonomic symptoms in small fibre neuropathy.</strong> Brain 135: 2613-2628, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22826602/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22826602</a>] [<a href="https://doi.org/10.1093/brain/aws187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22826602">Han et al. (2012)</a> suggested that the effects of the mutation on 2 different types of neurons correlate with the symptoms of pain and autonomic dysfunction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22826602" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Devigili, G., Eleopra, R., Pierro, T., Lombardi, R., Rinaldo, S., Lettieri, C., Faber, C. G., Merkies, I. S. J., Waxman, S. G., Lauria, G. <strong>Paroxysmal itch caused by gain-of-function Nav1.7 mutation.</strong> Pain 155: 1702-1707, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24820863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24820863</a>] [<a href="https://doi.org/10.1016/j.pain.2014.05.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24820863">Devigili et al. (2014)</a> identified a heterozygous I739V mutation in the SCN9A gene in a woman, her sister, and their mother with small fiber neuropathy manifest as paroxysmal intense neuropathic itch attacks, mainly triggered by warmth and spicy food and followed by transient burning pain. All 3 patients showed preferential involvement of the proximal arms, trunk, and neck, and all had impaired superficial sensation in the affected body area. In the 3 affected members of the family reported by <a href="#6" class="mim-tip-reference" title="Devigili, G., Eleopra, R., Pierro, T., Lombardi, R., Rinaldo, S., Lettieri, C., Faber, C. G., Merkies, I. S. J., Waxman, S. G., Lauria, G. <strong>Paroxysmal itch caused by gain-of-function Nav1.7 mutation.</strong> Pain 155: 1702-1707, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24820863/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24820863</a>] [<a href="https://doi.org/10.1016/j.pain.2014.05.006" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24820863">Devigili et al. (2014)</a>, <a href="#20" class="mim-tip-reference" title="Martinelli-Boneschi, F., Colombi, M., Castori, M., Devigili, G., Eleopra, R., Malik, R. A., Ritelli, M., Zoppi, N., Dordoni, C., Sorosina, M., Grammatico, P., Fadavi, H., and 17 others. <strong>COL6A5 variants in familial neuropathic chronic itch.</strong> Brain 140: 555-567, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28073787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28073787</a>] [<a href="https://doi.org/10.1093/brain/aww343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28073787">Martinelli-Boneschi et al. (2017)</a> identified a heterozygous missense (R2162S) variant in the COL6A5 gene (<a href="/entry/611916">611916</a>). The variant, which was found by whole-exome sequencing, segregated with the disorder in the family; it was present at a low frequency in the ExAC and gnomAD databases (2.5 x 10(-5)). Functional studies of the R2162S variant were not performed, but the authors postulated that the COL6A5 variant may have contributed to the phenotype. <a href="#20" class="mim-tip-reference" title="Martinelli-Boneschi, F., Colombi, M., Castori, M., Devigili, G., Eleopra, R., Malik, R. A., Ritelli, M., Zoppi, N., Dordoni, C., Sorosina, M., Grammatico, P., Fadavi, H., and 17 others. <strong>COL6A5 variants in familial neuropathic chronic itch.</strong> Brain 140: 555-567, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28073787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28073787</a>] [<a href="https://doi.org/10.1093/brain/aww343" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28073787">Martinelli-Boneschi et al. (2017)</a> noted that the mother in the family developed dysautonomic symptoms, including cardiovascular and sympathetic cholinergic impairment, which may have been related to the SCN9A mutation. In addition, none demonstrated length-dependent distribution of symptoms that usually occurs in small fiber neuropathy, and 1 of the 3 patients did not have small fiber neuropathy on skin biopsy. The itch in all patients responded well to gabapentin treatment. The contribution of each variant to the phenotype was unclear. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=28073787+24820863" 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">rs606231279 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs606231279;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=rs606231279" 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=rs606231279" 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=RCV000144933 OR RCV000790201 OR RCV002267728" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000144933, RCV000790201, RCV002267728" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000144933...</a>
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<p>In 3 Japanese patients from 2 unrelated families with hereditary sensory and autonomic neuropathy type IID (HSAN2D; see <a href="/entry/243000">243000</a>), <a href="#36" class="mim-tip-reference" title="Yuan, J., Matsuura, E., Higuchi, Y., Hashiguchi, A., Nakamura, T., Nozuma, S., Sakiyama, Y., Yoshimura, A., Izumo, S., Takashima, H. <strong>Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation.</strong> Neurology 80: 1641-1649, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23596073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23596073</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182904fdd" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23596073">Yuan et al. (2013)</a> identified a homozygous 1-bp deletion/2-bp insertion (c.3993delGinsTT) in exon 22 of the SCN9A gene, resulting in a frameshift and premature termination. The mutation was predicted to result in nonsense-mediated mRNA decay and loss of SCN9A function in nociceptive neurons. The mutation, which was found by sequencing of HSAN-related genes in 2 probands, segregated with the disorder in both families, and was not found in the 1000 Genomes Project database or in 100 Japanese control individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23596073" 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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Alves, R. M., Uva, P., Veiga, M. F., Oppo, M., Zschaber, F. C. R., Porcu, G., Porto, H. P., Persico, I., Onano, S., Cuccuru, G., Atzeni, R., Vieira, L. C. N., Pires, M. V. A., Cucca, F., Toralles, M. B. P., Angius, A., Crisponi, L.
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<strong>Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report.</strong>
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BMC Med. Genet. 20: 16, 2019. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30642272/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30642272</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30642272[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=30642272" 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.pain.2014.05.006" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/brain/awh514" target="_blank">Full Text</a>]
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Weiss, J., Pyrski, M., Jacobi, E., Bufe, B., Willnecker, V., Schick, B., Zizzari, P., Gossage, S. J., Greer, C. A., Leinders-Zufall, T., Woods, C. G., Wood, J. N., Zufall, F.
|
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<strong>Loss-of-function mutations in sodium channel NaV1.7 cause anosmia.</strong>
|
|
Nature 472: 186-190, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441906</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21441906[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=21441906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature09975" 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="35" class="mim-anchor"></a>
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<a id="Yang2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yang, Y., Wang, Y., Li, S., Xu, Z., Li, H., Ma, L., Fan, J., Bu, D., Liu, B., Fan, Z., Wu, G., Jin, J., Ding, B., Zhu, X., Shen, Y.
|
|
<strong>Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia.</strong>
|
|
J. Med. Genet. 41: 171-174, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14985375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14985375</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14985375" 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/10.1136/jmg.2003.012153" 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="36" class="mim-anchor"></a>
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<a id="Yuan2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yuan, J., Matsuura, E., Higuchi, Y., Hashiguchi, A., Nakamura, T., Nozuma, S., Sakiyama, Y., Yoshimura, A., Izumo, S., Takashima, H.
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|
<strong>Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation.</strong>
|
|
Neurology 80: 1641-1649, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23596073/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23596073</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23596073" 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.0b013e3182904fdd" target="_blank">Full Text</a>]
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</p>
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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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<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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Bao Lige - updated : 03/04/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Hilary J. Vernon - updated : 06/26/2023<br>Carol A. Bocchini - updated : 02/05/2021<br>Cassandra L. Kniffin - updated : 05/19/2020<br>Ada Hamosh - updated : 08/27/2019<br>Bao Lige - updated : 03/19/2019<br>Cassandra L. Kniffin - updated : 10/28/2014<br>Ada Hamosh - updated : 2/27/2012<br>Cassandra L. Kniffin - updated : 12/5/2011<br>Ada Hamosh - updated : 6/7/2011<br>Cassandra L. Kniffin - updated : 3/15/2010<br>Cassandra L. Kniffin - updated : 9/22/2009<br>Cassandra L. Kniffin - updated : 9/10/2007<br>Cassandra L. Kniffin - updated : 8/3/2007<br>Cassandra L. Kniffin - updated : 7/6/2007<br>Ada Hamosh - updated : 3/13/2007<br>Victor A. McKusick - updated : 12/20/2006<br>Cassandra L. Kniffin - updated : 10/19/2006<br>Cassandra L. Kniffin - updated : 6/8/2006<br>Patricia A. Hartz - updated : 12/13/2005<br>Cassandra L. Kniffin - updated : 8/18/2005<br>Natalie E. Krasikov - updated : 5/11/2004
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</span>
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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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Jennifer P. Macke : 1/11/1999
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</span>
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</div>
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</div>
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</div>
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<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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mgross : 03/04/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 07/07/2023<br>carol : 06/26/2023<br>carol : 01/01/2023<br>carol : 12/28/2022<br>carol : 12/25/2022<br>carol : 09/08/2022<br>carol : 02/08/2021<br>carol : 02/05/2021<br>carol : 09/01/2020<br>alopez : 05/26/2020<br>ckniffin : 05/19/2020<br>alopez : 08/27/2019<br>mgross : 03/19/2019<br>carol : 10/20/2017<br>carol : 09/26/2016<br>carol : 11/10/2014<br>mcolton : 10/30/2014<br>ckniffin : 10/28/2014<br>terry : 8/3/2012<br>terry : 7/5/2012<br>alopez : 2/29/2012<br>terry : 2/27/2012<br>carol : 1/20/2012<br>carol : 12/5/2011<br>ckniffin : 12/5/2011<br>alopez : 6/9/2011<br>terry : 6/7/2011<br>carol : 4/18/2011<br>ckniffin : 4/12/2011<br>ckniffin : 2/10/2011<br>wwang : 12/7/2010<br>wwang : 3/23/2010<br>ckniffin : 3/15/2010<br>wwang : 10/12/2009<br>ckniffin : 9/22/2009<br>carol : 9/13/2007<br>wwang : 9/12/2007<br>ckniffin : 9/10/2007<br>wwang : 8/17/2007<br>ckniffin : 8/3/2007<br>wwang : 7/12/2007<br>ckniffin : 7/6/2007<br>alopez : 3/13/2007<br>carol : 12/22/2006<br>terry : 12/20/2006<br>wwang : 10/25/2006<br>ckniffin : 10/19/2006<br>carol : 10/4/2006<br>carol : 6/22/2006<br>ckniffin : 6/8/2006<br>wwang : 12/20/2005<br>wwang : 12/13/2005<br>wwang : 8/19/2005<br>ckniffin : 8/18/2005<br>carol : 5/11/2004<br>kayiaros : 7/8/1999<br>alopez : 1/11/1999
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</span>
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</div>
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 603415
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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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SODIUM VOLTAGE-GATED CHANNEL, ALPHA SUBUNIT 9; SCN9A
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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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SODIUM CHANNEL, VOLTAGE-GATED, TYPE IX, ALPHA SUBUNIT<br />
|
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NAV1.7<br />
|
|
NEUROENDOCRINE SODIUM CHANNEL; NENA<br />
|
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PERIPHERAL SODIUM CHANNEL 1; PN1
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SCN9A</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> 403390002, 699190008, 709489006;
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</span>
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</p>
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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: 2q24.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:166,195,185-166,375,987 </span>
|
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</em>
|
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</strong>
|
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<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>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>
|
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="5">
|
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<span class="mim-font">
|
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2q24.3
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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Erythermalgia, primary
|
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</span>
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</td>
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<td>
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<span class="mim-font">
|
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133020
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
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Autosomal dominant
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
|
Insensitivity to pain, congenital
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
243000
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
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Autosomal recessive
|
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</span>
|
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</td>
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<td>
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<span class="mim-font">
|
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3
|
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</span>
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Neuropathy, hereditary sensory and autonomic, type IID
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
243000
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
Autosomal recessive
|
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</span>
|
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</td>
|
|
<td>
|
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<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>
|
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<span class="mim-font">
|
|
Paroxysmal extreme pain disorder
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
167400
|
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</span>
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
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3
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Small fiber neuropathy
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
133020
|
|
</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
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<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>
|
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<h4>
|
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<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>SCN9A is a voltage-gated sodium channel that is enriched in nociceptive and sympathetic neurons of the peripheral nervous system. It is also expressed in subcortical structures of brain (summary by McDermott et al., 2019). </p>
|
|
</span>
|
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<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cloning and Expression</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<span class="mim-text-font">
|
|
<p>Klugbauer et al. (1995) cloned a novel voltage-gated sodium channel, which they termed NENA, from a human medullary thyroid carcinoma cell cDNA library. Sequence analysis revealed that the cDNA encodes a 1,977-amino acid polypeptide (Nav1.7) composed of 4 domains, each with 6 transmembrane domains and 2 highly conserved pore-forming segments. The sequence is highly similar to brain and skeletal muscle voltage-gated sodium channels; the authors stated that this channel represents an evolutionary link between sodium channels found in brain and skeletal muscle. Northern blot analysis detected 9.4- and 7.0-kb NENA transcripts in a human C-cell carcinoma cell line. </p><p>By RT-PCR, Sangameswaran et al. (1997) determined that NENA, which they designated NE for neuroendocrine channel, was expressed in the same tissues as rat PN1 (peripheral sodium channel-1), including dorsal root ganglia, adrenal, and thyroid tissue. Neither rat PN1 nor human NE was expressed in skeletal muscle. Sangameswaran et al. (1997) stated that NE is the human ortholog of the rat PN1 sodium channel. </p><p>By electrophysiologic and inhibitor studies and quantitative RT-PCR analysis, Jo et al. (2004) found that SCN9A was the major sodium channel expressed in smooth muscle cells cultured from normal human bronchus, main pulmonary artery, and large coronary artery. </p><p>McDermott et al. (2019) found that endogenous epitope-tagged SCN9A was highly expressed in human induced pluripotent stem cell (iPSC) nociceptors and was trafficked appropriately to polarized neuronal compartments, such as soma membrane, axon, axon terminals, and nodes of Ranvier. </p>
|
|
</span>
|
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<div>
|
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<br />
|
|
</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The SCN9A gene contains 26 exons (Michiels et al., 2005). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The SCN9A gene maps to chromosome 2q24.3 (Michiels et al., 2005). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By RT-PCR analysis, Fu et al. (2024) showed that Nav1.7 was expressed in human chondrocytes and was upregulated in human osteoarthritic (OA) cartilage, which they confirmed electrophysiologically. Analysis of mice with Nav1.7 deletion in neurons, chondrocytes, or both revealed that loss of Nav1.7 in chondrocytes protected mice from OA, as Nav1.7 expressed in chondrocytes modulated OA progression and resultant OA-associated pain behavior, whereas Nav1.7 expressed by neurons contributed to OA-associated pain without affecting OA progression. Pharmacologic inhibition of Nav1.7 protected mice against OA, and treatment with carbamazepine, a clinically used Na channel inhibitor that acts on Nav1.7, reduced cartilage loss and pain from OA. HSP70 (see 140550) and midkine (MDK; 162096) were important for maintaining the protective effects of Nav1.7 inhibition against OA, and blockade of Nav1.7 regulated human chondrocyte biology by enhancing HSP70 and midkine secretion in chondrocytes. Moreover, intracellular Ca(2+) signals were essential for enhanced secretion of HSP70 and midkine following Nav1.7 blockade, and Nav1.7 blockade altered chondrocyte Ca(2+). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
|
|
Shen et al. (2019) reported the cryoelectron microscopy structures of the human Nav1.7-beta1-beta2 complex bound to 2 combinations of pore blockers and gating modifier toxins, tetrodotoxin with protoxin-II and saxitoxin with huwentoxin-IV, both determined at overall resolutions of 3.2 angstroms. The 2 structures were nearly identical except for minor shifts of voltage-sensing domain II, whose S3-S4 linker accommodates the 2 gating modifier toxins in a similar manner. One additional protoxin-II sits on top of the S3-S4 linker in voltage sensing domain IV. The structures may represent an inactivated state with all 4 voltage-sensing domains 'up' and the intracellular gate closed. The structures illuminated the path toward mechanistic understanding of the function and disease of Nav1.7 and established the foundation for structure-aided development of analgesics. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Primary Erythermalgia</em></strong></p><p>
|
|
In affected members of a Chinese family with primary erythermalgia (133020) linked to chromosome 2q and in a sporadic patient, Yang et al. (2004) identified mutations in the SCN9A gene (603415.0001-603415.0002). </p><p>In 5 affected members of a Flemish family with primary erythermalgia, Michiels et al. (2005) identified a heterozygous mutation in the SCN9A gene (603415.0003). </p><p><strong><em>Small Fiber Neuropathy</em></strong></p><p>
|
|
In 8 (28.6%) of 28 unrelated Dutch Caucasian patients with biopsy-confirmed small fiber neuropathy (SFNP; see 133020), Faber et al. (2012) identified 7 different heterozygous gain-of-function mutations in the SCN9A gene (see, e.g., 603415.0023-603415.0025). The patients presented with adult-onset pain, most commonly a burning sensation in the extremities, although 2 patients had generalized bodily pain. Seven of 8 complained of autonomic symptoms, such as dry eyes or mouth, orthostatic dizziness, or gastrointestinal problems. All had significantly decreased intraepithelial fiber densities compared to controls, and all had distally impaired sensation to warmth and/or cold. Three had family members with a similar condition. In vitro functional expression studies in HEK293 cells and dorsal root ganglion neurons showed that all the mutations caused hyperexcitability of dorsal root ganglion neurons, either by impairing slow inactivation, depolarizing slow and fast inactivation, or causing enhanced resurgent currents and increasing the number of action potentials evoked by depolarization. Faber et al. (2012) postulated that increased sodium channel activity may also trigger axonal degeneration via calcium-importing reverse sodium-calcium exchange. The findings expanded the phenotype associated with SCN9A mutations. </p><p><strong><em>Channelopathy-Associated Insensitivity to Pain</em></strong></p><p>
|
|
In affected members of 3 consanguineous northern Pakistani families with autosomal recessive 'channelopathy-associated insensitivity to pain' (243000) mapping to chromosome 2q24.3, Cox et al. (2006) identified 3 distinct homozygous mutations in the SCN9A gene: S459X (603415.0005), I767X (603415.0006), and W897X (603415.0007). By coexpression of wildtype or mutant human Nav1.7 with sodium channel beta-1 (SCN1B; 600235) and beta-2 (SCN2B; 601327) in cultured cells, they showed that these mutations cause loss of function of Nav1.7. In cells expressing mutant Nav1.7, the currents were no greater than background. Cox et al. (2006) noted that the autosomal dominant pain disorder primary erythermalgia, and the autosomal recessive pain disorder channelopathy-associated insensitivity to pain, are the result, respectively, of gain-of-function and loss-of-function mutations in the SCN9A gene. </p><p>Goldberg et al. (2007) identified 10 different mutations in the SCN9A gene (see, e.g., 603415.0014-603415.0015), 9 of which were truncating mutations, in affected members of 9 different families with congenital insensitivity to pain. The families were from various countries in Europe as well as Canada, the U.S., and Argentina. </p><p>Weiss et al. (2011) reported 3 additional individuals with channelopathy-associated insensitivity to pain. All of them were compound heterozygous for nonsense and frameshift mutations leading to complete loss of function. Interestingly, Weiss et al. (2011) found that, in addition to insensitivity to pain, these people had congenital and complete anosmia, although none were aware. </p><p>McDermott et al. (2019) heterologously expressed several NaV1.7 mutants associated with congenital insensitivity to pain in HEK293T cells and showed that all resulted in loss of NaV1.7 channel function. Both iPSC nociceptors derived from patients and NaV1.7-knockout iPSC lines exhibited inability to respond to depolarizing stimuli, demonstrating that NaV1.7 is a key regulator of excitability. The authors also showed that NaV1.7-knockout iPSC lines could be used for analgesic drug screening. </p><p><strong><em>Hereditary Sensory and Autonomic Neuropathy, Type IID</em></strong></p><p>
|
|
In 3 Japanese patients from 2 unrelated families with hereditary sensory and autonomic neuropathy type IID (HSAN2D; see 243000), Yuan et al. (2013) identified a homozygous truncating mutation in the SCN9A gene (603415.0028). The mutation was predicted to result in nonsense-mediated mRNA decay and loss of SCN9A function in nociceptive neurons. The patients had early childhood onset of insensitivity to pain and temperature limited to the distal parts of the body, as well as variable autonomic nervous system dysfunction. </p><p><strong><em>Paroxysmal Extreme Pain Disorder</em></strong></p><p>
|
|
In affected members of 8 of 13 families with paroxysmal extreme pain disorder (PEXPD; 167400), Fertleman et al. (2006) identified 8 missense mutations in the SCN9A gene. Three were located in the inactivation gate itself, 3 in the S4-S5 loop in domain III, and 1 in the S4-S5 loop in domain IV (Catterall and Yu, 2006). Functional analysis in vitro of 3 of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. </p><p>Catterall and Yu (2006) noted that SCN9A mutations that result in primary erythermalgia enhance the activation of sodium channels, while those resulting in paroxysmal extreme pain disorder impair inactivation of Na(v)1.7 channels. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
|
|
For discussion of a possible association between generalized epilepsy with febrile seizures plus, type 7 (GEFSP7; see 613863) and variation in the SCN9A gene, see 603415.0018 and 603415.0019.</p><p>For discussion of a possible association between isolated febrile seizures (FEB3B; see 613863) and variation in the SCN9A gene, see 603415.0020 and 603415.0021.</p><p>Singh et al. (2009) presented preliminary evidence that mutation in the SCN9A gene may act as a genetic modifier of Dravet syndrome when found in conjunction with an SCN1A mutation (182389). They identified a mutation in the SCN9A gene in 9 (8%) of 109 patients with Dravet syndrome, including 6 with SCN1A mutation. The authors noted that 'additional proconvulsive genes may act in concert with SCN9A' in the 3 patients without a mutation in SCN1A. </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">
|
|
<strong>Evolution</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>St. John Smith et al. (2011) described a species-specific variant of the nociceptor sodium channel NaV1.7, which is potently blocked by protons and can account for acid insensitivity in the naked mole rat. They concluded that evolutionary pressure has selected for an NaV1.7 gene variant that tips the balance from proton-induced excitation to inhibition of action potential initiation to abolish acid nociception. </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>Weiss et al. (2011) developed conditional NaV1.7-null mice in which NaV1.7 was removed from olfactory sensory neurons. In the absence of NaV1.7, these neurons still produced odor-evoked action potentials but failed to initiate synaptic signaling from their axon terminals at the first synapse in the olfactory system. The mutant mice no longer displayed vital, odor-guided behaviors such as innate odor recognition and avoidance, short-term odor learning, and maternal pup retrieval. Weiss et al. (2011) concluded that their study created a mouse model of congenital general anosmia and provided new strategies to explore the genetic basis of the human sense of smell. </p><p>Middleton et al. (2022) found that SCN9A mRNA was expressed in C-low threshold mechanoreceptors (C-LTMRs), peptidergic nociceptors, and myelinated fibers in mice. Selective knockout of SCN9A in C-LTMRs resulted in smaller sodium currents, decreased sensitivity to punctate mechanical stimuli, and reduced sensitivity to cooling. Similar findings were seen with pharmacologic inhibition of SCN9A. </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>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>28 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">
|
|
<strong>.0001 ERYTHERMALGIA, PRIMARY</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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|
|
SCN9A, LEU858HIS
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<br />
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|
|
SNP: rs80356475,
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|
|
ClinVar: RCV000006721, RCV002512849
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In all affected members of a Chinese family with autosomal dominant primary erythermalgia (133020), Yang et al. (2004) identified heterozygosity for a 2573T-A transversion in the SCN9A gene, resulting in a leu858-to-his (L858H) substitution. The mutation was not found in unaffected members of the family or in 400 alleles from normal Chinese controls. </p><p>Using functional expression studies, Cummins et al. (2004) showed that the L858H mutant SCN9A channel was activated at more negative potentials and had approximately 10-fold slower inactivation kinetics than wildtype channels. The findings indicated that the mutant channel confers hyperexcitability to peripheral sensory and sympathetic neurons, contributing to symptom production in erythermalgia. </p><p>Rush et al. (2006) found that expression of the L858H mutant SCN9A channel in rat dorsal root ganglion (DRG) neurons and sympathetic ganglion neurons in vitro resulted in a depolarization of the resting membrane potential by about 5 mV compared to wildtype cells. In DRG neurons, the current threshold was reduced by approximately 40%, resulting in hyperexcitability and enhanced repetitive firing. By contrast, in sympathetic ganglion cells, the current threshold was increased by approximately 88%, resulting in hypoexcitability and attenuated repetitive firing. In DRG, the action potential overshoot was unchanged; in sympathetic neurons, there was a 50% attenuation of the action potential overshoot. Expression studies showed that DRG neurons, but not sympathetic neurons, also expressed SCN10A channels (604427), which presumably accounted for the opposing effects. The findings indicated that a single ion channel mutation can result in opposing phenotypes in different cell types. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 ERYTHERMALGIA, PRIMARY</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
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<span class="mim-text-font">
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|
|
|
SCN9A, ILE848THR
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|
|
<br />
|
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|
|
SNP: rs80356474,
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|
|
|
|
|
|
ClinVar: RCV000006722, RCV001004018, RCV001067998, RCV001270748, RCV001781194
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a sporadic patient with primary erythermalgia (133020), Yang et al. (2004) identified heterozygosity for a 2543T-C transition in the SCN9A gene, resulting in an ile848-to-thr (I848T) substitution. The mutation was not found in his unaffected parents or in 400 alleles from normal Chinese controls. </p><p>Using functional expression studies, Cummins et al. (2004) showed that the I848T mutant SCN9A channel was activated at more negative potentials and had approximately 3-fold slower inactivation kinetics than wildtype channels. The findings indicated that the mutant channel confers hyperexcitability to peripheral sensory and sympathetic neurons, contributing to symptom production in erythermalgia. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
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|
</div>
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 ERYTHERMALGIA, PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN9A, SER241THR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs80356470,
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|
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|
|
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|
|
ClinVar: RCV000006723
|
|
|
|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 5 affected members of a Flemish family with primary erythermalgia (133020), Michiels et al. (2005) identified a heterozygous 721T-A transversion in exon 6 of the SCN9A gene, resulting in a ser241-to-thr (S241T) substitution. The mutation occurs in a highly conserved residue within the sodium ion transport-associated domain that determines ion selectivity and is central to channel function. </p>
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|
</span>
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|
</div>
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<div>
|
|
<br />
|
|
</div>
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</div>
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<div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 ERYTHERMALGIA, PRIMARY</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
SCN9A, PHE1449VAL
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|
|
|
|
|
<br />
|
|
|
|
SNP: rs80356478,
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|
|
|
|
|
|
|
ClinVar: RCV000006724
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|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In 17 affected members of a large family with primary erythermalgia (133020) reported by Finley et al. (1992), Dib-Hajj et al. (2005) identified a heterozygous 4393T-G transversion in exon 23 of the SCN9A gene, resulting in a phe1449-to-val (F1449V) substitution in the N terminus of loop 3, which joins domains III and IV of the protein. The mutation was not identified in 5 unaffected family members or in 100 control chromosomes. In vitro functional expression studies showed that the F1449V mutant protein produced a hyperpolarizing shift in channel activation and a depolarizing shift in steady-state activation, lowering the threshold for single action potentials and high frequency firing in dorsal root ganglion neurons. The findings were consistent with a gain-of-function mutation. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
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|
</div>
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</div>
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<div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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|
|
|
SCN9A, SER459TER
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<br />
|
|
|
|
SNP: rs121908908,
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|
|
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gnomAD: rs121908908,
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|
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ClinVar: RCV000006725
|
|
|
|
|
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</span>
|
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</div>
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|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a consanguineous northern Pakistani family segregating autosomal recessive congenital insensitivity to pain (243000), Cox et al. (2006) identified homozygosity for a 1376C-G transversion in exon 10 of the SCN9A gene, resulting in a ser459-to-ter (S459X) substitution. The mutation was not found in 300 northern Pakistani control chromosomes. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED</strong>
|
|
</span>
|
|
</h4>
|
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
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SCN9A, 1-BP DEL, 2298T
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<br />
|
|
|
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SNP: rs1574856736,
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|
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ClinVar: RCV000006726
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|
|
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a consanguineous northern Pakistani family segregating autosomal recessive congenital insensitivity to pain (243000), Cox et al. (2006) identified homozygosity for a 1-bp deletion (2298delT) in exon 13 of the SCN9A gene, resulting in a frameshift and an ile767-to-ter (I767X) substitution. The mutation was not found in 300 northern Pakistani control chromosomes. </p>
|
|
</span>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
|
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SCN9A, TRP897TER
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<br />
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|
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SNP: rs121908909,
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ClinVar: RCV000006727
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a consanguineous northern Pakistani family segregating autosomal recessive congenital insensitivity to pain (243000), Cox et al. (2006) identified homozygosity for a 2691G-A transition in exon 15 of the SCN9A gene, resulting in a trp897-to-ter (W897X) substitution. The mutation was not found in 300 northern Pakistani control chromosomes. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0008 PAROXYSMAL EXTREME PAIN DISORDER</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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SCN9A, ARG996CYS
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<br />
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SNP: rs121908910,
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gnomAD: rs121908910,
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ClinVar: RCV000006728, RCV000559164, RCV001559739
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 families segregating paroxysmal extreme pain disorder (PEXPD; 167400), Fertleman et al. (2006) identified a C-to-T transition in exon 16 of the SCN9A gene resulting in an arginine-to-cysteine substitution at codon 996 (R996C). Affected members of 1 family who carried this mutation in heterozygosity had a less severe phenotype not requiring medication. In another family, the R996C mutation was found in the proband in compound heterozygosity with a V1298D mutation (603415.0009) and in his affected father in heterozygosity. The proband was more severely affected than his father. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0009 PAROXYSMAL EXTREME PAIN DISORDER</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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SCN9A, VAL1298ASP
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<br />
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SNP: rs121908911,
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ClinVar: RCV000006729
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an individual with paroxysmal extreme pain disorder (PEXPD; 167400) who inherited an R996C (603415.0008) mutation from his affected father, Fertleman et al. (2006) found a de novo T-to-A transversion in exon 21 of the SCN9A gene, which resulted in a valine-to-aspartic acid substitution at codon 1298 (V1298D), as well. The valine at position 1298 is completely conserved through evolution and among paralogous human voltage-gated sodium channels, and is critical to inactivation of the sodium channel. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0010 PAROXYSMAL EXTREME PAIN DISORDER</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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SCN9A, VAL1298PHE
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<br />
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SNP: rs121908912,
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ClinVar: RCV000006730
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a family segregating paroxysmal extreme pain disorder (PEXPD; 167400), Fertleman et al. (2006) identified a heterozygous G-to-T transversion in exon 21 of the SCN9A gene, resulting in a valine-to-phenylalanine substitution at codon 1298 (V1298F). The valine at position 1298 is completely conserved through evolution and among paralogous human voltage-gated sodium channels, and is critical to inactivation of the sodium channel. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0011 PAROXYSMAL EXTREME PAIN DISORDER</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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SCN9A, VAL1299PHE
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<br />
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SNP: rs121908913,
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ClinVar: RCV000006731, RCV000691966, RCV001090456
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a large 5-generation family segregating autosomal dominant paroxysmal extreme pain disorder (PEXPD; 167400), Fertleman et al. (2006) identified a heterozygous G-to-T transversion in exon 21 of the SCN9A gene, resulting in a valine-to-phenylalanine substitution at codon 1299 (V1299F). The valine at codon 1299 is completely conserved through evolution and among paralogous human voltage-gated sodium channels. It occurs in the loop between domain III S4-S5 and is believed to interact with domain III-IV inactivation motif. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0012 PAROXYSMAL EXTREME PAIN DISORDER</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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SCN9A, ILE1461THR
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<br />
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SNP: rs121908914,
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ClinVar: RCV000006732, RCV002512850
|
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|
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family segregating paroxysmal extreme pain disorder (PEXPD; 167400), Fertleman et al. (2006) identified a heterozygous T-to-C transition in exon 24 of the SCN9A gene, resulting in an isoleucine-to-threonine substitution at codon 1461 (I1461T). Functional analysis of this mutation showed that there was altered inactivation with persistent currents which were maintained for more than several hundred milliseconds. In vitro assessment showed that Na(v)1.7 channels carrying this mutant were sensitive to carbamazepine, as was seen in the patients. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 PAROXYSMAL EXTREME PAIN DISORDER</strong>
|
|
</span>
|
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</h4>
|
|
</div>
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<div>
|
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<span class="mim-text-font">
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|
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SCN9A, THR1464ILE
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<br />
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|
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SNP: rs121908915,
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ClinVar: RCV000006733
|
|
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</span>
|
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</div>
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family segregating paroxysmal extreme pain disorder (PXPD; 167400), Fertleman et al. (2006) identified a heterozygous C-to-T transition in exon 24 of the SCN9A gene that resulted in a threonine-to-isoleucine substitution at codon 1464 (T1464I). This mutation occurred in the domain III-IV linker region and was shown in in vitro assays to result in altered inactivation with associated persistent currents. In the presence of carbamazepine this current was reduced in a concentration-dependent manner. </p>
|
|
</span>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN9A, ARG277TER
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|
|
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|
|
<br />
|
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|
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SNP: rs121908916,
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|
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|
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gnomAD: rs121908916,
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|
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ClinVar: RCV000006734, RCV001383702, RCV002426494
|
|
|
|
|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 2 unrelated Swiss families with congenital insensitivity to pain (243000), Goldberg et al. (2007) identified a homozygous 829C-T transition in exon 6 of the SCN9A gene, resulting in an arg277-to-ter (R277X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
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|
|
<div>
|
|
<br />
|
|
</div>
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|
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</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 INSENSITIVITY TO PAIN, CHANNELOPATHY-ASSOCIATED</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN9A, TYR328TER
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|
|
<br />
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|
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SNP: rs121908917,
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|
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|
|
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gnomAD: rs121908917,
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|
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|
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ClinVar: RCV000006735, RCV002281698
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large Canadian family with congenital insensitivity to pain (243000), Goldberg et al. (2007) identified a homozygous 984C-A transversion in exon 8 of the SCN9A gene, resulting in a tyr328-to-ter (Y328X) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
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|
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|
|
<div>
|
|
<br />
|
|
</div>
|
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 ERYTHERMALGIA, PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN9A, LEU858PHE
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|
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|
|
<br />
|
|
|
|
SNP: rs80356476,
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|
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|
|
|
|
|
ClinVar: RCV000006736
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Chinese brothers with primary erythermalgia (133020), Han et al. (2006) identified a 2572C-T transition in exon 15 of the SCN9A gene, resulting in a leu858-to-phe (L858F) substitution in the linker region between transmembrane segments 4 and 5 in domain 2. The asymptomatic father was found to be a somatic mosaic for the mutation, which was present in 13% of his leukocytes. In vitro functional expression studies showed that the L858F protein caused a hyperpolarizing shift in channel activation, a depolarizing shift of inactivation, and an 18-fold increase in deactivation time compared to wildtype. In addition, the mean ramp current amplitude in response to slow depolarization was higher in L858F-mutant channels. The mutation was not identified in 200 alleles from Chinese controls. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
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|
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</div>
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|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0017 ERYTHERMALGIA, PRIMARY</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN9A, PHE216SER
|
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|
|
<br />
|
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|
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SNP: rs80356469,
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|
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|
|
ClinVar: RCV000006737
|
|
|
|
|
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</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a father and daughter with primary erythermalgia (133020), Drenth et al. (2005) identified heterozygosity for a 647T-C transition in exon 5 of the SCN9A gene, resulting in a phe216-to-ser (F216S) substitution within the S4 membrane-spanning segment of the first domain. </p><p>Choi et al. (2006) noted that the phe216 residue is strictly conserved in all known voltage-gated sodium channels. By patch-clamp studies in HEK293 cells, Choi et al. (2006) found that the F216S-mutant protein hyperpolarized the voltage dependence of activation by 10 mV, accelerated activation, slowed deactivation, and enhanced the response to slow, small depolarizations. These changes were predicted to increase excitability of nociceptive dorsal root ganglion neurons in which the mutant channel is present, thus contributing to pain. In an accompanying editorial, Schorge and Ptacek (2006) noted that the F216S mutation involves a noncharged aromatic amino acid being replaced by a noncharged slightly polar amino acid, which may not have been predicted to have major biophysical effects. </p>
|
|
</span>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
SCN9A, ASN641TYR
|
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|
|
<br />
|
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|
|
SNP: rs121908918,
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|
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|
|
|
gnomAD: rs121908918,
|
|
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|
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ClinVar: RCV000006738, RCV000557785, RCV001535456, RCV002408454
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, previously titled GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 7, has been reclassified based on the report by Fasham et al. (2020), which found that the N641Y variant was present at high frequency in the Amish involving hundreds of variant carriers with no history of seizure phenotypes. In addition, Fasham et al. (2020) stated that the overall frequency of N641Y in the European population in the gnomAD database (v2.1.1), 1.4x10(-5), confirms that it represents a low frequency variant in the European population. </p><p>In affected members of a large Utah family with generalized epilepsy with febrile seizures plus, Singh et al. (2009) identified a heterozygous 1921A-T transversion in exon 11 of the SCN9A gene, resulting in an asn641-to-tyr (N641Y) substitution in the large intracellular loop between domains I and II. The mutation was not found in 586 control chromosomes. The was only 1 unaffected mutation carrier, indicating about 95% penetrance. The phenotype in this family, which was originally reported by Peiffer et al. (1999), showed a broad clinical spectrum: 11 individuals experienced only febrile seizures before age 6 years, whereas 10 additional individuals later developed afebrile seizures. In 8 of the 10, seizures remitted by age 16 years. The remaining 2 affected individuals developed intractable epilepsy: 1 had complex-partial seizures associated with left mesial temporal sclerosis, and the other had afebrile generalized convulsive seizures requiring the placement of a vagal nerve stimulator. The phenotype was consistent with GEFS+ (Moulard et al., 2000; Scheffer et al., 2000). Singh et al. (2009) reported that mice targeted with the N641Y mutation had reduced seizure thresholds and increased corneal kindling acquisition rates, indicating that the mutant channel had functional effects. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
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</div>
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<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0019 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
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|
SCN9A, LYS655ARG ({dbSNP rs121908919})
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<br />
|
|
|
|
SNP: rs121908919,
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|
|
gnomAD: rs121908919,
|
|
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|
|
|
ClinVar: RCV000006739, RCV000153918, RCV000415152, RCV000488281, RCV001083774, RCV001133028, RCV001133029, RCV001133030, RCV002415403, RCV004532301
|
|
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>This variant, previously titled GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 7, has been reclassified based on the report by Fasham et al. (2020), which noted that the K655R variant has a high frequency (0.2%) and is present in homozygous state in the gnomAD database, inconsistent with it being causative of a monogenic seizure disorder. </p><p>In a patient with a phenotype consistent with GEFS+, Singh et al. (2009) identified a heterozygous 1964A-G transition in the SCN9A gene, resulting in a lys655-to-arg (K655R) substitution in a highly conserved residue in the large intracellular loop between domains I and II. The mutation was not identified in 562 control chromosomes. The patient had febrile seizures, idiopathic generalized epilepsy, and generalized spike-wave patterns on EEG. Singh et al. (2009) found this mutation in 2 patients diagnosed with Dravet syndrome (607208), one of whom also had a mutation in the SCN1A gene (182389). Singh et al. (2009) suggested that SCN9A mutations may have a modifier effect in partner with SCN1A mutations. </p><p>In 2 sisters from a nonconsanguineous Brazilian family with GEFS+, Alves et al. (2019) identified the K655R mutation in the SCN9A gene. The mutation, which was found by whole-exome sequencing, was also present in their unaffected father. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<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>.0020 RECLASSIFIED - 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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SCN9A, ILE62VAL
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<br />
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SNP: rs121908920,
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gnomAD: rs121908920,
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ClinVar: RCV000006740, RCV000215091, RCV000555200, RCV000765531, RCV002408455, RCV004525845
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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, previously titled FEBRILE SEIZURES, FAMILIAL, 3B, has been reclassified because its pathogenicity has not been confirmed.</p><p>From a panel of 92 unrelated patients with childhood seizures occurring in the setting of febrile seizures (see 613863), Singh et al. (2009) identified a Hispanic patient who was heterozygous for a 184A-G transition in the SCN9A gene, resulting in an ile62-to-val (I62V) substitution at a highly conserved residue in the N-terminal region. The mutation was not identified in 276 ethnically matched control chromosomes. The authors did not find a mutation in the SCNA1 gene in this patient. </p><p>Fasham et al. (2020) noted the lack of segregation studies for this variant in the report by Singh et al. (2009). </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>.0021 RECLASSIFIED - 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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SCN9A, PRO149GLN
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<br />
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SNP: rs121908921,
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gnomAD: rs121908921,
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ClinVar: RCV000006741
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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, previously titled FEBRILE SEIZURES, FAMILIAL, 3B, has been reclassified because its pathogenicity has not been confirmed.</p><p>From a panel of 92 unrelated patients with childhood seizures occurring in the setting of febrile seizures (see 613863), Singh et al. (2009) identified a Caucasian patient with a heterozygous 446C-A transversion in the SCN9A gene, resulting in a pro149-to-gln (P149Q) substitution in a highly conserved residue in domain I. The mutation was not identified in 562 ethnically matched control chromosomes. </p><p>Fasham et al. (2020) noted the lack of segregation studies for this variant in the report by Singh et al. (2009). </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>.0022 ERYTHERMALGIA, PRIMARY</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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SCN9A, GLN10ARG
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<br />
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SNP: rs267607030,
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gnomAD: rs267607030,
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ClinVar: RCV000006742, RCV000302710, RCV000309032, RCV000402111, RCV000532835
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Chinese boy with relatively late onset of primary erythermalgia (133020) of the lower extremities at age 14 years, Han et al. (2009) identified a heterozygous 29A-G transition in exon 1 of the SCN9A gene, resulting in a gln10-to-arg (Q10R) substitution in the cytoplasmic N terminus of the channel. Neither unaffected parent carried the mutation, and it was not present in 200 Chinese control alleles. In vitro patch-clamp studies showed that the Q10R mutation caused a hyperpolarizing shift of -5.3 mV for the midpoint of activation, which is smaller than that seen in other SCN9A mutations causing early-onset erythromelalgia mutations. The Q10R mutation also caused a faster rate of activation and slower deactivation compared to wildtype. Expression of Q10R-mutant protein induced hyperexcitability in DRG neurons, but the increase was smaller than that produced by I848T (603415.0002), an early-onset erythromelalgia mutation. The findings suggested a genotype-phenotype correlation, such that mutations resulting in smaller effects on sodium channel activation are associated with a smaller degree of neuron excitability and later onset of clinical signs. </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>.0023 NEUROPATHY, SMALL FIBER</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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SCN9A, ILE720LYS
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<br />
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SNP: rs200945460,
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gnomAD: rs200945460,
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ClinVar: RCV000023302, RCV000118297, RCV000191125, RCV000311897, RCV000393721, RCV000476046, RCV001546748, RCV002415425
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 39-year-old Dutch Caucasian man with small fiber neuropathy (SFNP; see 133020), Faber et al. (2012) identified a heterozygous 2159T-A transversion in the SCN9A gene, resulting in an ile720-to-lys (I720K) substitution in the cytoplasmic linker-1 region between domains I and II. The mutation was not found in 200 control chromosomes. The patient developed stabbing pain in the whole body at age 37 years. Two months later, he also had burning pain in the feet and lower legs, followed by pain in the lower arms. He also had numbness and hyperhidrosis in the feet. He had distally impaired warmth sensation and decreased intraepithelial nerve fiber density compared to controls. In vitro functional expression and electrophysiologic studies in HEK293 and dorsal root ganglion neurons showed that the mutant I720K protein resulted in impaired slow inactivation and hyperexcitability of dorsal root ganglion cells. I720K caused a depolarizing shift in the resting membrane potential and an increase in the number of action potentials evoked by a depolarizing stimulus compared to control. Activation, fast-inactivation, and ramp currents were similar 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>.0024 NEUROPATHY, SMALL FIBER</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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SCN9A, ASP623ASN
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<br />
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SNP: rs200398202,
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gnomAD: rs200398202,
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ClinVar: RCV000023303, RCV002513185
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 63-year-old Dutch Caucasian woman with small fiber neuropathy (see 133020), Faber et al. (2012) identified a heterozygous 1867G-A transition in the SCN9A gene, resulting in an asp623-to-asn (D623N) substitution in the cytoplasmic linker-1 region between domains I and II. The mutation was not found in 200 control chromosomes. The patient had onset of muscle pain at age 22 years. At age 58, she had severe burning pain in the soles, which progressed to involve other parts of the feet and the hands. She later developed patchy skin redness, dry eyes, dry mouth, and orthostatic dizziness, as well as tenderness and burning in other areas, such as the scalp, lips, mouth, and trunk. She had impaired cold sensation in the feet and decreased intraepithelial nerve fiber density compared to controls. A sister reportedly had similar complaints. In vitro functional expression and electrophysiologic studies in HEK293 and dorsal root ganglion neurons showed that the mutant D623N protein resulted in impaired fast and slow inactivation and hyperexcitability of dorsal root ganglion cells. D623N caused a depolarizing shift in the resting membrane potential, an increase in the number of action potentials evoked by a depolarizing stimulus, and an increase in the proportion of spontaneously firing cells compared to control. Current densities, activation, and ramp currents were not significantly different from control. </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>.0025 NEUROPATHY, SMALL FIBER</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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SCN9A, MET932LEU AND VAL991LEU
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<br />
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SNP: rs12478318, rs4369876,
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gnomAD: rs12478318, rs4369876,
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ClinVar: RCV000023304, RCV000080038, RCV000080039, RCV000284177, RCV000375717, RCV000389941, RCV000399125, RCV000461431, RCV000469131, RCV000490436, RCV000986924, RCV000992914, RCV000992915, RCV001129274, RCV001129275, RCV003313935
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 22-year-old Dutch Caucasian man with small fiber neuropathy (see 133020), Faber et al. (2012) identified a heterozygous complex allele with 2 mutations in cis in the SCN9A gene: a 2794A-C transversion resulting in a met932-to-leu (M932L) substitution, and a 2971G-T transversion resulting in a val991-to-leu (V991L) substitution in the cytoplasmic linker-2 region between domains II and III. Neither mutation was found in 200 control chromosomes. The patient presented at age 16 years with burning pain in the feet and lower legs. The pain increased with exercise and interfered with standing. He also had autonomic symptoms, including orthostatic dizziness, dry mouth and eyes, and constipation. The symptoms were aggravated by warmth. He had impaired warmth sensation in the left foot and decreased intraepithelial nerve fiber density compared to controls. In vitro functional expression and electrophysiologic studies in HEK293 and dorsal root ganglion neurons showed that the mutant protein increased the generation of resurgent currents, but did not affect activation, fast or slow inactivation, ramp currents, or deactivation. The change in resurgent currents would produce repetitive neuronal firing. The mutant protein made dorsal root ganglion cells hyperexcitable, with a depolarizing shift in the resting membrane potential, an increase in the number of action potentials evoked by a depolarizing stimulus, and a trend toward an increase in the proportion of spontaneously firing cells compared to control. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0026 NEUROPATHY, SMALL FIBER</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">
|
|
PAROXYSMAL EXTREME PAIN DISORDER, INCLUDED
|
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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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SCN9A, ARG185HIS ({dbSNP rs73969684})
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<br />
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SNP: rs73969684,
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gnomAD: rs73969684,
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ClinVar: RCV000144930, RCV000144931, RCV000178871, RCV000331310, RCV000382273, RCV000421273, RCV001081785
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 2 unrelated patients with small fiber neuropathy (see 133020) without autonomic dysfunction, Faber et al. (2012) and Han et al. (2012) identified a heterozygous c.554G-A transition in the SCN9A gene (rs73969684), resulting in an arg185-to-his (R185H) substitution at a highly conserved residue in the linker region between D1/S2 and D1/S3. The variant has a heterozygote frequency of 1.2% in both the 1000 Genomes Project and Exome Variant Server databases, and a 0.4% heterozygote frequency among 1,000 European controls. In vitro functional expression assays in rat neurons showed that the R185H mutation rendered dorsal root ganglion neurons hyperexcitable and enhanced resurgent currents, but did not produce detectable changes in sympathetic neurons of the superior cervical ganglion. Han et al. (2012) suggested that the lack of effect on sympathetic neurons explains the lack of autonomic features in these patients. </p><p>In a 3-year-old girl with paroxysmal extreme pain disorder (PEXPD; 167400), Meglic et al. (2014) identified a heterozygous R185H mutation in the SCN9A gene. She had painful urinary voiding manifest as crying, sweating, and writhing since birth. Similar symptoms occasionally occurred when passing stool. She had no other autonomic manifestations, but had mildly delayed motor development. Treatment with carbamazepine resulted in significant clinical improvement and normal development. Family history revealed that her father occasionally had pain in the jaw while yawning, but did not remember pain attacks in his early childhood; the father was found to carry the same heterozygous SCN9A mutation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0027 NEUROPATHY, SMALL FIBER</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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SCN9A, ILE739VAL
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<br />
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SNP: rs182650126,
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gnomAD: rs182650126,
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ClinVar: RCV000144932, RCV000218739, RCV000281545, RCV000284837, RCV000398464, RCV000416064, RCV000986925, RCV001083229, RCV001094589, RCV002415629, RCV004532638
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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 unrelated patients with small fiber neuropathy (see 133020) and severe autonomic dysfunction, Han et al. (2012) identified a heterozygous c.2215A-G transition in exon 13 of the SCN9A gene, resulting in an ile739-to-val (I739V) substitution at a highly conserved residue in the transmembrane segment of domain II. The variant was not present in the 1000 Genomes Project database, but it was reported with a 0.5% frequency in the Exome Variant Server database and was found in 1.4% of Dutch control individuals. In vitro functional expression assays in rat neurons showed that the I739V mutation impaired channel slow inactivation in both dorsal root ganglion cells and sympathetic neurons of the superior cervical ganglion. The mutation rendered dorsal root ganglion neurons hyperexcitable and superior ganglion neurons hypoexcitable. Han et al. (2012) suggested that the effects of the mutation on 2 different types of neurons correlate with the symptoms of pain and autonomic dysfunction. </p><p>Devigili et al. (2014) identified a heterozygous I739V mutation in the SCN9A gene in a woman, her sister, and their mother with small fiber neuropathy manifest as paroxysmal intense neuropathic itch attacks, mainly triggered by warmth and spicy food and followed by transient burning pain. All 3 patients showed preferential involvement of the proximal arms, trunk, and neck, and all had impaired superficial sensation in the affected body area. In the 3 affected members of the family reported by Devigili et al. (2014), Martinelli-Boneschi et al. (2017) identified a heterozygous missense (R2162S) variant in the COL6A5 gene (611916). The variant, which was found by whole-exome sequencing, segregated with the disorder in the family; it was present at a low frequency in the ExAC and gnomAD databases (2.5 x 10(-5)). Functional studies of the R2162S variant were not performed, but the authors postulated that the COL6A5 variant may have contributed to the phenotype. Martinelli-Boneschi et al. (2017) noted that the mother in the family developed dysautonomic symptoms, including cardiovascular and sympathetic cholinergic impairment, which may have been related to the SCN9A mutation. In addition, none demonstrated length-dependent distribution of symptoms that usually occurs in small fiber neuropathy, and 1 of the 3 patients did not have small fiber neuropathy on skin biopsy. The itch in all patients responded well to gabapentin treatment. The contribution of each variant to the phenotype was unclear. </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>.0028 NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IID</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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SCN9A, 1-BP DEL/2-BP INS, NT3993
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<br />
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SNP: rs606231279,
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ClinVar: RCV000144933, RCV000790201, RCV002267728
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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 Japanese patients from 2 unrelated families with hereditary sensory and autonomic neuropathy type IID (HSAN2D; see 243000), Yuan et al. (2013) identified a homozygous 1-bp deletion/2-bp insertion (c.3993delGinsTT) in exon 22 of the SCN9A gene, resulting in a frameshift and premature termination. The mutation was predicted to result in nonsense-mediated mRNA decay and loss of SCN9A function in nociceptive neurons. The mutation, which was found by sequencing of HSAN-related genes in 2 probands, segregated with the disorder in both families, and was not found in the 1000 Genomes Project database or in 100 Japanese control individuals. </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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Alves, R. M., Uva, P., Veiga, M. F., Oppo, M., Zschaber, F. C. R., Porcu, G., Porto, H. P., Persico, I., Onano, S., Cuccuru, G., Atzeni, R., Vieira, L. C. N., Pires, M. V. A., Cucca, F., Toralles, M. B. P., Angius, A., Crisponi, L.
|
|
<strong>Novel ANKRD11 gene mutation in an individual with a mild phenotype of KBG syndrome associated to a GEFS+ phenotypic spectrum: a case report.</strong>
|
|
BMC Med. Genet. 20: 16, 2019. Note: Electronic Article.
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[PubMed: 30642272]
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[Full Text: https://doi.org/10.1186/s12881-019-0745-7]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Catterall, W. A., Yu, F. H.
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<strong>Painful channels.</strong>
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Neuron 52: 743-749, 2006.
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[PubMed: 17145494]
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[Full Text: https://doi.org/10.1016/j.neuron.2006.11.017]
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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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<strong>Loss-of-function mutations in sodium channel NaV1.7 cause anosmia.</strong>
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Nature 472: 186-190, 2011.
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[PubMed: 21441906]
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[Full Text: https://doi.org/10.1038/nature09975]
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Yang, Y., Wang, Y., Li, S., Xu, Z., Li, H., Ma, L., Fan, J., Bu, D., Liu, B., Fan, Z., Wu, G., Jin, J., Ding, B., Zhu, X., Shen, Y.
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<strong>Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia.</strong>
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[Full Text: https://doi.org/10.1136/jmg.2003.012153]
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Yuan, J., Matsuura, E., Higuchi, Y., Hashiguchi, A., Nakamura, T., Nozuma, S., Sakiyama, Y., Yoshimura, A., Izumo, S., Takashima, H.
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<strong>Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation.</strong>
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Neurology 80: 1641-1649, 2013.
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[PubMed: 23596073]
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[Full Text: https://doi.org/10.1212/WNL.0b013e3182904fdd]
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Bao Lige - updated : 03/04/2024<br>Hilary J. Vernon - updated : 06/26/2023<br>Carol A. Bocchini - updated : 02/05/2021<br>Cassandra L. Kniffin - updated : 05/19/2020<br>Ada Hamosh - updated : 08/27/2019<br>Bao Lige - updated : 03/19/2019<br>Cassandra L. Kniffin - updated : 10/28/2014<br>Ada Hamosh - updated : 2/27/2012<br>Cassandra L. Kniffin - updated : 12/5/2011<br>Ada Hamosh - updated : 6/7/2011<br>Cassandra L. Kniffin - updated : 3/15/2010<br>Cassandra L. Kniffin - updated : 9/22/2009<br>Cassandra L. Kniffin - updated : 9/10/2007<br>Cassandra L. Kniffin - updated : 8/3/2007<br>Cassandra L. Kniffin - updated : 7/6/2007<br>Ada Hamosh - updated : 3/13/2007<br>Victor A. McKusick - updated : 12/20/2006<br>Cassandra L. Kniffin - updated : 10/19/2006<br>Cassandra L. Kniffin - updated : 6/8/2006<br>Patricia A. Hartz - updated : 12/13/2005<br>Cassandra L. Kniffin - updated : 8/18/2005<br>Natalie E. Krasikov - updated : 5/11/2004
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Jennifer P. Macke : 1/11/1999
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