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Entry
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- *118504 - CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 4; CHRNA4
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- OMIM
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</form>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*118504</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="#history">History</a>
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</li>
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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>
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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/118504">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
|
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
|
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</a>
|
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</span>
|
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</span>
|
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</div>
|
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000101204;t=ENST00000370263" 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=1137" 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=118504" 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=ENSG00000101204;t=ENST00000370263" 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_000744,NM_001256573,NR_046317" 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_000744" 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=118504" 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=00333&isoform_id=00333_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/CHRNA4" 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/755648,854159,1279459,1351848,1458114,1702912,4502827,55824648,58700664,58700666,64653281,64653285,64654445,64654852,68248536,119595675,119595676,194383068,375151585" 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/P43681" 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=1137" 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=ENSG00000101204;t=ENST00000370263" 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=CHRNA4" 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=CHRNA4" 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+1137" 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/CHRNA4" 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:1137" 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/1137" 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=chr20&hgg_gene=ENST00000370263.9&hgg_start=63343223&hgg_end=63361349&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:1958" 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=118504[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=118504[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/CHRNA4/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/ENSG00000101204" 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=CHRNA4" 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=CHRNA4" 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=CHRNA4" 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=CHRNA4&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/PA26490" 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:1958" 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/FBgn0000039.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:87888" 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/CHRNA4#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:87888" 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/1137/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=1137" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="mim#WormbaseGeneFold" id="mimWormbaseGeneToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes."><span id="mimWormbaseGeneToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Wormbase Gene</div>
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<div id="mimWormbaseGeneFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006765;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006765 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006774;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006774 </a></div><div style="margin-left: 0.5em;"><a href="https://wormbase.org/db/gene/gene?name=WBGene00006797;class=Gene" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">WBGene00006797 </a></div>
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</div>
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<div><a href="https://zfin.org/ZDB-GENE-090505-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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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:1137" 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=CHRNA4&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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118504
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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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CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 4; CHRNA4
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC, ALPHA-4 SUBUNIT
|
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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">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CHRNA4" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CHRNA4</a></em></strong>
|
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/20/470?start=-3&limit=10&highlight=470">20q13.33</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr20:63343223-63361349&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'})">20:63,343,223-63,361,349</a> </span>
|
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</em>
|
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</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">
|
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<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=188890,600513" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
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</span>
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
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<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/20/470?start=-3&limit=10&highlight=470">
|
|
20q13.33
|
|
</a>
|
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</span>
|
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</td>
|
|
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<td>
|
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<span class="mim-font">
|
|
{Nicotine addiction, susceptibility to}
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/188890"> 188890 </a>
|
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|
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</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Epilepsy, nocturnal frontal lobe, 1
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<p>The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be (hetero)pentamers composed of homologous subunits. See <a href="/entry/118508">118508</a> for additional background information on nAChRs.</p>
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<p><a href="#16" class="mim-tip-reference" title="Monteggia, L. M., Gopalakrishnan, M., Touma, E., Idler, K. B., Nash, N., Arneric, S. P., Sullivan, J. P., Giordano, T. <strong>Cloning and transient expression of genes encoding the human alpha-4 and beta-2 neuronal nicotinic acetylcholine receptor (nAChR) subunits.</strong> Gene 155: 189-193, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7721089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7721089</a>] [<a href="https://doi.org/10.1016/0378-1119(94)00914-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7721089">Monteggia et al. (1995)</a> obtained the full-length cDNA sequence for the alpha-4 neuronal nicotinic acetylcholine receptor subunit. The predicted amino acid sequence is 89% similar to the rat sequence, with most differences in the cytoplasmic domain. <a href="#6" class="mim-tip-reference" title="Elliott, K. J., Ellis, S. B., Berckhan, K. J., Urrutia, A., Chavez-Noriega, L. E., Johnson, E. C., Velicelebi, G., Harpold, M. M. <strong>Comparative structure of human neuronal alpha(2)-alpha(7) and beta(2)-beta(4) nicotinic acetylcholine receptor subunits and functional expression of the alpha(2), alpha(3), alpha(4), alpha(7), beta(2), and beta(4) subunits.</strong> J. Molec. Neurosci. 7: 217-228, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8906617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8906617</a>] [<a href="https://doi.org/10.1007/BF02736842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8906617">Elliott et al. (1996)</a> also cloned the alpha-4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8906617+7721089" 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="mim-changed mim-change"><p><a href="#24" class="mim-tip-reference" title="Steinlein, O., Weiland, S., Stoodt, J., Propping, P. <strong>Exon-intron structure of the human neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4).</strong> Genomics 32: 289-294, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8833159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8833159</a>] [<a href="https://doi.org/10.1006/geno.1996.0119" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8833159">Steinlein et al. (1996)</a> determined that the CHRNA4 gene has 6 exons distributed over approximately 17 kb of genomic DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8833159" 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></div>
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<p>By genomic Southern blot analysis of hamster/human somatic cell hybrid DNAs, <a href="#1" class="mim-tip-reference" title="Anand, R., Lindstrom, J. <strong>Chromosomal localization of seven neuronal nicotinic acetylcholine receptor subunit genes in humans.</strong> Genomics 13: 962-967, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1505988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1505988</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90008-g" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1505988">Anand and Lindstrom (1992)</a> mapped the gene encoding the alpha-4 subunit of the human neuronal nicotinic acetylcholine receptor to chromosome 20. <a href="#18" class="mim-tip-reference" title="Pilz, A. J., Willer, E., Povey, S., Abbott, C. M. <strong>The genes coding for phosphoenolpyruvate carboxykinase-1 (PCK1) and neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4) map to human chromosome 20, extending the known region of homology with mouse chromosome 2.</strong> Ann. Hum. Genet. 56: 289-293, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1492743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1492743</a>] [<a href="https://doi.org/10.1111/j.1469-1809.1992.tb01155.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1492743">Pilz et al. (1992)</a> likewise mapped the gene to human chromosome 20 by Southern blot analysis of human/rodent somatic cell hybrids. The corresponding gene is located on chromosome 2 in the mouse (<a href="#3" class="mim-tip-reference" title="Bessis, A., Simon-Chazottes, D., Devillers-Thiery, A., Guenet, J.-L., Changeux, J.-P. <strong>Chromosomal localization of the mouse genes coding for alpha-2, alpha-3, alpha-4 and beta-2 subunits of neuronal nicotinic acetylcholine receptor.</strong> FEBS Lett. 264: 48-52, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2338144/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2338144</a>] [<a href="https://doi.org/10.1016/0014-5793(90)80761-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2338144">Bessis et al., 1990</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1505988+1492743+2338144" 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 fluorescent in situ hybridization, <a href="#23" class="mim-tip-reference" title="Steinlein, O., Smigrodzki, R., Lindstrom, J., Anand, R., Kohler, M., Tocharoentanaphol, C., Vogel, F. <strong>Refinement of the localization of the gene for neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4) to human chromosome 20q13.2-q13.3.</strong> Genomics 22: 493-495, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7806245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7806245</a>] [<a href="https://doi.org/10.1006/geno.1994.1420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7806245">Steinlein et al. (1994)</a> positioned CHRNA4 on a contig between D20S24 and D20S20 on chromosome 20q13.2-q13.3. The 2 markers were separated by 160 kb. <a href="#23" class="mim-tip-reference" title="Steinlein, O., Smigrodzki, R., Lindstrom, J., Anand, R., Kohler, M., Tocharoentanaphol, C., Vogel, F. <strong>Refinement of the localization of the gene for neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4) to human chromosome 20q13.2-q13.3.</strong> Genomics 22: 493-495, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7806245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7806245</a>] [<a href="https://doi.org/10.1006/geno.1994.1420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7806245">Steinlein et al. (1994)</a> suggested that the location of CHRNA4 made it a possible candidate gene for either benign neonatal familial convulsions (EBN1; <a href="/entry/121200">121200</a>) or the electroencephalographic variant pattern 1 (EEGV1; <a href="/entry/130180">130180</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7806245" 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="#16" class="mim-tip-reference" title="Monteggia, L. M., Gopalakrishnan, M., Touma, E., Idler, K. B., Nash, N., Arneric, S. P., Sullivan, J. P., Giordano, T. <strong>Cloning and transient expression of genes encoding the human alpha-4 and beta-2 neuronal nicotinic acetylcholine receptor (nAChR) subunits.</strong> Gene 155: 189-193, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7721089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7721089</a>] [<a href="https://doi.org/10.1016/0378-1119(94)00914-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7721089">Monteggia et al. (1995)</a> found that transfection of expression vectors for the alpha-4 and beta-2 (CHRNB2; <a href="/entry/118507">118507</a>) nAChR subunits into HEK293 cells resulted in the formation of binding sites with the expected high affinity for cytosine. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7721089" 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="Elliott, K. J., Ellis, S. B., Berckhan, K. J., Urrutia, A., Chavez-Noriega, L. E., Johnson, E. C., Velicelebi, G., Harpold, M. M. <strong>Comparative structure of human neuronal alpha(2)-alpha(7) and beta(2)-beta(4) nicotinic acetylcholine receptor subunits and functional expression of the alpha(2), alpha(3), alpha(4), alpha(7), beta(2), and beta(4) subunits.</strong> J. Molec. Neurosci. 7: 217-228, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8906617/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8906617</a>] [<a href="https://doi.org/10.1007/BF02736842" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8906617">Elliott et al. (1996)</a> demonstrated that human alpha-4 encodes a functional receptor when expressed in combination with human beta-2 or beta-4 (CHRNB4; <a href="/entry/118509">118509</a>) in Xenopus oocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8906617" 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 immunoprecipitation analysis of mouse striatal extracts, <a href="#4" class="mim-tip-reference" title="Champtiaux, N., Gotti, C., Cordero-Erausquin, M., David, D. J., Przybylski, C., Lena, C., Clementi, F., Moretti, M., Rossi, F. M., Le Novere, N., McIntosh, J. M., Gardier, A. M., Changeux, J.-P. <strong>Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice.</strong> J. Neurosci. 23: 7820-7829, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12944511/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12944511</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12944511[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.23-21-07820.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12944511">Champtiaux et al. (2003)</a> identified 3 main types of heteromeric nAChRs: alpha-4/beta-2, alpha-6 (CHRNA6; <a href="/entry/606888">606888</a>)/beta-2, and alpha-4/alpha-6/beta-2. Alpha-6/beta-2 nAChRs were mainly located on dopamine (DA) nerve terminals and were the direct target of alpha-conotoxin MII inhibition. A combination of alpha-6/beta-2 and alpha-4/beta-2 nAChRs mediated endogenous cholinergic modulation of DA release induced by systemic nicotine administration at nerve terminals. Alpha-4/beta-2 nAChRs appeared to represent the majority of nAChRs on DA neuron soma and contributed to nicotine reinforcement. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12944511" 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="#27" class="mim-tip-reference" title="Xiu, X., Puskar, N. L., Shanata, J. A. P., Lester, H. A., Dougherty, D. A. <strong>Nicotine binding to brain receptors requires a strong cation-pi interaction.</strong> Nature 458: 534-537, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19252481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19252481</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19252481[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/nature07768" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19252481">Xiu et al. (2009)</a> showed that at the brain acetylcholine receptors alpha-4 (CHRNA4)-beta-2 (CHRNB2) thought to underlie nicotine addiction, the high affinity for nicotine is the result of a strong cation-pi interaction to a specific aromatic amino acid of the receptor, TrpB. In contrast, the low affinity for nicotine at the muscle-type acetylcholine receptor is largely due to the absence of this key interaction, even though the immediate binding site residues, including the key amino acid TrpB, are identical in the brain and muscle receptors. At the same time a hydrogen bond from nicotine to the backbone carbonyl of TrpB is enhanced in the neuronal receptor relative to the muscle type. A point mutation near TrpB that differentiates alpha-4-beta-2 and muscle-type receptors seems to influence the shape of the binding site, allowing nicotine to interact more strongly with TrpB in the neuronal receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19252481" 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>Cryoelectron Microscopy</em></strong></p><p>
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<a href="#26" class="mim-tip-reference" title="Walsh, R. M., Jr., Roh, S.-H., Gharpure, A., Morales-Perez, C. L., Teng, J., Hibbs, R. E. <strong>Structural principles of distinct assemblies of the human alpha-4-beta-2 nicotinic receptor.</strong> Nature 557: 261-265, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29720657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29720657</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29720657[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/s41586-018-0081-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29720657">Walsh et al. (2018)</a> used cryoelectron microscopy to obtain structures for the alpha-4-beta-2 nicotinic acetylcholine receptor in both the 2-alpha-to-3-beta and 3-alpha-to-2-beta stoichiometries from a single sample. The antibody fragments specific to beta-2 were used to break symmetry during particle alignment and to obtain high-resolution reconstructions of receptors of both stoichiometries in complex with nicotine. The results revealed principles of subunit assembly and the structural basis of the distinctive biophysical and pharmacologic properties of the 2 different stoichiometries of this receptor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29720657" 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>Nocturnal Frontal Lobe Epilepsy 1</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Steinlein, O. K., Mulley, J. C., Propping, P., Wallace, R. H., Phillips, H. A., Sutherland, G. R., Scheffer, I. E., Berkovic, S. F. <strong>A missense mutation in the neuronal nicotinic acetylcholine receptor alpha-4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.</strong> Nature Genet. 11: 201-203, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550350</a>] [<a href="https://doi.org/10.1038/ng1095-201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550350">Steinlein et al. (1995)</a> demonstrated a missense mutation in the CHRNA4 gene (S252F; <a href="#0002">118504.0002</a>) associated with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; <a href="/entry/600513">600513</a>), which had previously been mapped to 20q. The mutation was sought because CHRNA4 maps to the candidate region of 20q and the gene is expressed in all layers of the frontal cortex. Mutations in the CHRNA4 gene appear to account for only a small proportion of the cases of nocturnal frontal lobe epilepsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550350" 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 with Other Disorders</em></strong></p><p>
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Nicotine is the major addictive substance in cigarettes, and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction (<a href="/entry/188890">188890</a>). <a href="#8" class="mim-tip-reference" title="Feng, Y., Niu, T., Xing, H., Xu, X., Chen, C., Peng, S., Wang, L., Laird, N., Xu, X. <strong>A common haplotype of the nicotine acetylcholine receptor alpha-4 subunit gene is associated with vulnerability to nicotine addiction in men.</strong> Am. J. Hum. Genet. 75: 112-121, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15154117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15154117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15154117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/422194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15154117">Feng et al. (2004)</a> studied 6 single-nucleotide polymorphisms (SNPs) in the CHRNA4 gene and 4 SNPs in the CHRNB2 gene (<a href="/entry/118507">118507</a>) in relation to nicotine dependence in a collection of 901 subjects (815 sibs and 86 parents) from 222 nuclear families with multiple nicotine-addicted sibs. They found 2 SNPs in exon 5 of the CHRNA4 gene to be significantly associated with a protective effect against nicotine addiction. Furthermore, a common (22.5%) CHRNA4 haplotype was significantly associated with a protective effect against nicotine addiction. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15154117" 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="Li, M. D., Beuten, J., Ma, J. Z., Payne, T. J., Lou, X.-Y., Garcia, V., Duenes, A. S., Crews, K. M., Elston, R. C. <strong>Ethnic- and gender-specific association of the nicotinic acetylcholine receptor alpha-4 subunit gene (CHRNA4) with nicotine dependence.</strong> Hum. Molec. Genet. 14: 1211-1219, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15790597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15790597</a>] [<a href="https://doi.org/10.1093/hmg/ddi132" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15790597">Li et al. (2005)</a> analyzed 6 SNPs within CHRNA4 for association with nicotine dependence (ND). In a sample of European American families, SNPs <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2273504;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2273504</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1044396;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1044396</a> (<a href="#0005">118504.0005</a>) were significantly associated with the adjusted smoking quantity and Fagerstrom test for ND score, respectively. In the African American families, SNPs <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs3787137;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs3787137</a> and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2236196;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2236196</a> were each significantly associated with at least 2 adjusted ND measures. Haplotype analysis of <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2273505;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2273505</a>, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2273504;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2273504</a>, and <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2236196;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2236196</a> showed significant association after Bonferroni correction of a C-G-G haplotype (53.4%) with 3 adjusted ND measures in samples from the African American females. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15790597" 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>For a possible association between variation in the CHRNA4 gene and the psychologic trait of harm avoidance, see <a href="/entry/607834">607834</a>.</p>
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<p>Benign familial neonatal seizures 1 (BFNS1; <a href="/entry/121200">121200</a>) was shown to be caused by mutations in the KCNQ2 gene (<a href="/entry/602235">602235</a>), which also maps to chromosome 20q13 (<a href="#20" class="mim-tip-reference" title="Singh, N. A., Charlier, C., Stauffer, D., DuPont, B. R., Leach, R. J., Melis, R., Ronen, G. M., Bjerre, I., Quattlebaum, T., Murphy, J. V., McHarg, M. L., Gagnon, D., Rosales, T. O., Peiffer, A., Anderson, V. E., Leppert, M. <strong>A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.</strong> Nature Genet. 18: 25-29, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9425895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9425895</a>] [<a href="https://doi.org/10.1038/ng0198-25" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9425895">Singh et al., 1998</a>). The finding of a presumed mutation (<a href="#2" class="mim-tip-reference" title="Beck, C., Moulard, B., Steinlein, O., Guipponi, M., Vallee, L., Montpied, P., Baldy-Moulnier, M., Malafosse, A. <strong>A nonsense mutation in the alpha-4 subunit of the nicotinic acetylcholine receptor (CHRNA4) cosegregates with 20q-linked benign neonatal familial convulsions (EBN1).</strong> Neurobiol. Dis. 1: 95-99, 1994. Note: Erratum: Neurobiol. Dis. 2: 189 only, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9216991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9216991</a>] [<a href="https://doi.org/10.1006/nbdi.1994.0012" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9216991">Beck et al., 1994</a>) in the CHRNA4 gene, which maps to the same region, in 1 of 20 families, was presumably an error. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9425895+9216991" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#15" class="mim-tip-reference" title="Marubio, L. M., del Mar Arroyo-Jimenez, M., Cordero-Erausquin, M., Lena, C., Le Novere, N., de Kerchove d'Exaerde, A., Huchet, M., Damaj, M. I., Changeux, J.-P. <strong>Reduced antinociception in mice lacking neuronal nicotinic receptor subunits.</strong> Nature 398: 805-810, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10235262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10235262</a>] [<a href="https://doi.org/10.1038/19756" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10235262">Marubio et al. (1999)</a> disrupted the alpha-4 subunit of the neuronal nicotinic acetylcholine receptor by homologous recombination and studied homozygous alpha-4-null mice and mice lacking the beta-2 subunit of the nAChR. The homozygous alpha-4 -/- mice no longer expressed high-affinity nicotine binding sites throughout the brain. In addition, both types of mutant mice displayed a reduced antinociceptive effect of nicotine on the hot-plate test and diminished sensitivity to nicotine in the tail-flick test. Patch-clamp recordings revealed that raphe magnus and thalamic neurons no longer responded to nicotine. <a href="#15" class="mim-tip-reference" title="Marubio, L. M., del Mar Arroyo-Jimenez, M., Cordero-Erausquin, M., Lena, C., Le Novere, N., de Kerchove d'Exaerde, A., Huchet, M., Damaj, M. I., Changeux, J.-P. <strong>Reduced antinociception in mice lacking neuronal nicotinic receptor subunits.</strong> Nature 398: 805-810, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10235262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10235262</a>] [<a href="https://doi.org/10.1038/19756" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10235262">Marubio et al. (1999)</a> stated that the alpha-4 nAChR subunit, thought to associate with the beta-2 nAChR subunit, is therefore crucial for nicotine-elicited antinociception. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10235262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The electroconvulsive threshold (ECT) test has been used extensively to determine the protection conferred by antiepileptic drug candidates against induced seizures in rodents. <a href="#28" class="mim-tip-reference" title="Yang, Y., Beyer, B. J., Otto, J. F., O'Brien, T. P., Letts, V. A., White, H. S., Frankel, W. N. <strong>Spontaneous deletion of epilepsy gene orthologs in a mutant mouse with a low electroconvulsive threshold.</strong> Hum. Molec. Genet. 12: 975-984, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700166</a>] [<a href="https://doi.org/10.1093/hmg/ddg118" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12700166">Yang et al. (2003)</a> adopted the ECT test to screen the progeny of ethylnitrosourea-treated male C57BL/6J mice. In a small-scale screen, several mutant lines conferring a low threshold to ECT minimal clonic seizures were mapped to the telomeric region of mouse chromosome 2 in independent founder families. Genetic and physical mapping data indicated that several lines shared a single mutation, Szt1 (seizure threshold-1), consisting of a 300-kb deletion of genomic DNA involving 3 known genes. Two of these genes, Kcnq2 and Chrna4, are known to be mutated in human epilepsy families. Szt1 homozygotes and heterozygotes displayed similar phenotypes to those found in the respective Kcnq2 knockout mutant mice, suggesting that Kcnq2 haploinsufficiency may lie at the root of the Szt1 seizure sensitivity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12700166" 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="#25" class="mim-tip-reference" title="Tapper, A. R., McKinney, S. L., Nashmi, R., Schwarz, J., Deshpande, P., Labarca, C., Whiteaker, P., Marks, M. J., Collins, A. C., Lester, H. A. <strong>Nicotine activation of alpha-4* receptors: sufficient for reward, tolerance, and sensitization.</strong> Science 306: 1029-1032, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15528443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15528443</a>] [<a href="https://doi.org/10.1126/science.1099420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15528443">Tapper et al. (2004)</a> generated mutant mice with alpha-4 nicotinic subunits containing a single point mutation, leu9-prime to ala, in the pore-forming M2 domain, rendering alpha-4 mutant receptors hypersensitive to nicotine. Selective activation of alpha-4 mutant nicotinic acetylcholine receptors with low doses of agonist recapitulated nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. <a href="#25" class="mim-tip-reference" title="Tapper, A. R., McKinney, S. L., Nashmi, R., Schwarz, J., Deshpande, P., Labarca, C., Whiteaker, P., Marks, M. J., Collins, A. C., Lester, H. A. <strong>Nicotine activation of alpha-4* receptors: sufficient for reward, tolerance, and sensitization.</strong> Science 306: 1029-1032, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15528443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15528443</a>] [<a href="https://doi.org/10.1126/science.1099420" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15528443">Tapper et al. (2004)</a> concluded that activation of alpha-4 mutant receptors is sufficient for nicotine-induced reward, tolerance, and sensitization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15528443" 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="#13" class="mim-tip-reference" title="Klaassen, A., Glykys, J., Maguire, J., Labarca, C., Mody, I., Boulter, J. <strong>Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy.</strong> Proc. Nat. Acad. Sci. 103: 19152-19157, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17146052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17146052</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17146052[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.0608215103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17146052">Klaassen et al. (2006)</a> generated 2 mouse models of autosomal dominant nocturnal frontal lobe epilepsy by introducing an S252F (<a href="#0002">118504.0002</a>) mutation or a leu264 insertion in the Chrna4 gene, respectively. Mice heterozygous for the S252F mutation or the leu264 insertion showed abnormal cortical EEGs with prominent delta and theta frequencies, frequent spontaneous seizures, and increased sensitivity to the proconvulsant action of nicotine. Voltage-clamp studies showed that a considerable fraction of mutant Chrna4-containing nAChRs were located on presynaptic terminals of cortical GABAergic interneurons and that activation of these receptors resulted in elevated presynaptic calcium levels. The results were consistent with a model of epileptogenesis in which acetylcholine significantly enhances cortical GABAergic transmission, which contributes to epileptogenesis through inhibitory resetting and synchronization of neural networks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17146052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In affected members of a large Australian kindred with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; <a href="/entry/600513">600513</a>) reported by <a href="#17" class="mim-tip-reference" title="Phillips, H. A., Scheffer, I. E., Berkovic, S. F., Hollway, G. E., Sutherland, G. R., Mulley, J. C. <strong>Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2.</strong> Nature Genet. 10: 117-118, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7647781/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7647781</a>] [<a href="https://doi.org/10.1038/ng0595-117" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7647781">Phillips et al. (1995)</a>, <a href="#22" class="mim-tip-reference" title="Steinlein, O. K., Mulley, J. C., Propping, P., Wallace, R. H., Phillips, H. A., Sutherland, G. R., Scheffer, I. E., Berkovic, S. F. <strong>A missense mutation in the neuronal nicotinic acetylcholine receptor alpha-4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.</strong> Nature Genet. 11: 201-203, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550350</a>] [<a href="https://doi.org/10.1038/ng1095-201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550350">Steinlein et al. (1995)</a> used single-strand conformation analysis to identify a C-to-T transition in exon 5 of the CHRNA4 gene, resulting in ser248-to-phe (SER248PHE) substitution in the sixth amino acid position of transmembrane domain 2 (M2) and reduced receptor function. Their numbering was based on the Torpedo californica Chrna4 sequence. <a href="#19" class="mim-tip-reference" title="Saenz, A., Galan, J., Caloustian, C., Lorenzo, F., Marquez, C., Rodriguez, N., Jimenez, M. D., Poza, J. J., Cobo, A. M., Grid, D., Prud'homme, J. F., de Munain, A. L. <strong>Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a ser252phe mutation in the CHRNA4 gene.</strong> Arch. Neurol. 56: 1004-1009, 1999. Note: Erratum: Arch. Neurol. 57: 1150 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10448807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10448807</a>] [<a href="https://doi.org/10.1001/archneur.56.8.1004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10448807">Saenz et al. (1999)</a> noted that in the human sequence codon 252 is homologous to the Torpedo codon 248, and they referred to the mutation as ser252 to phe (S252F). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10448807+7647781+7550350" 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="Forman, S. A., Yellen, G., Thiele, E. A. <strong>Alternative mechanism for pathogenesis of an inherited epilepsy by a nicotinic AChR mutation. (Letter)</strong> Nature Genet. 13: 396-397, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696332</a>] [<a href="https://doi.org/10.1038/ng0896-396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696332">Forman et al. (1996)</a> suggested an alternative mechanism for pathogenesis of epilepsy associated with this CHRNA4 mutation. From studies of the mouse muscle alpha-1 nicotinic receptor (<a href="/entry/100690">100690</a>) noted in <a href="#9" class="mim-tip-reference" title="Forman, S. A., Miller, K. W., Yellen, G. <strong>A discrete site for general anesthetics on a postsynaptic receptor.</strong> Molec. Pharm. 48: 574-581, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7476881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7476881</a>]" pmid="7476881">Forman et al. (1995)</a>, <a href="#10" class="mim-tip-reference" title="Forman, S. A., Yellen, G., Thiele, E. A. <strong>Alternative mechanism for pathogenesis of an inherited epilepsy by a nicotinic AChR mutation. (Letter)</strong> Nature Genet. 13: 396-397, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696332/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696332</a>] [<a href="https://doi.org/10.1038/ng0896-396" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696332">Forman et al. (1996)</a> speculated that the mutation in CHRNA4 may cause receptor hyperactivity that could lead to epileptic activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7476881+8696332" 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 11 affected members of a large Spanish family with nocturnal frontal lobe epilepsy, <a href="#19" class="mim-tip-reference" title="Saenz, A., Galan, J., Caloustian, C., Lorenzo, F., Marquez, C., Rodriguez, N., Jimenez, M. D., Poza, J. J., Cobo, A. M., Grid, D., Prud'homme, J. F., de Munain, A. L. <strong>Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a ser252phe mutation in the CHRNA4 gene.</strong> Arch. Neurol. 56: 1004-1009, 1999. Note: Erratum: Arch. Neurol. 57: 1150 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10448807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10448807</a>] [<a href="https://doi.org/10.1001/archneur.56.8.1004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10448807">Saenz et al. (1999)</a> identified the S252F mutation. <a href="#19" class="mim-tip-reference" title="Saenz, A., Galan, J., Caloustian, C., Lorenzo, F., Marquez, C., Rodriguez, N., Jimenez, M. D., Poza, J. J., Cobo, A. M., Grid, D., Prud'homme, J. F., de Munain, A. L. <strong>Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a ser252phe mutation in the CHRNA4 gene.</strong> Arch. Neurol. 56: 1004-1009, 1999. Note: Erratum: Arch. Neurol. 57: 1150 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10448807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10448807</a>] [<a href="https://doi.org/10.1001/archneur.56.8.1004" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10448807">Saenz et al. (1999)</a> noted that the clinical features were similar to those reported by <a href="#22" class="mim-tip-reference" title="Steinlein, O. K., Mulley, J. C., Propping, P., Wallace, R. H., Phillips, H. A., Sutherland, G. R., Scheffer, I. E., Berkovic, S. F. <strong>A missense mutation in the neuronal nicotinic acetylcholine receptor alpha-4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.</strong> Nature Genet. 11: 201-203, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550350</a>] [<a href="https://doi.org/10.1038/ng1095-201" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550350">Steinlein et al. (1995)</a>. This same residue is affected in the S252L mutation (<a href="#0004">118504.0004</a>) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10448807+7550350" 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 PET scans, <a href="#7" class="mim-tip-reference" title="Fedi, M., Berkovic, S. F., Scheffer, I. E., O'Keefe, G., Marini, C., Mulligan, R., Gong, S., Tochon-Danguy, H., Reutens, D. C. <strong>Reduced striatal D(1) receptor binding in autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 71: 795-798, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18685138/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18685138</a>] [<a href="https://doi.org/10.1212/01.wnl.0000316192.52731.77" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18685138">Fedi et al. (2008)</a> observed decreased striatal D1 receptor (DRD1; <a href="/entry/126449">126449</a>) binding, particularly in the right putamen, in 12 individuals with autosomal dominant nocturnal frontal lobe epilepsy and the S252L mutation compared to controls. Decreased D1 receptor binding was postulated to represent receptor downregulation from increased extracellular levels of dopamine. Increased dopamine release may result from a gain-of-function in nAChRs with the mutant CHRNA4 subunit, since nAChRs regulate dopamine release. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18685138" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a Norwegian family with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; <a href="/entry/600513">600513</a>), <a href="#21" class="mim-tip-reference" title="Steinlein, O. K., Magnusson, A., Stoodt, J., Bertrand, S., Weiland, S., Berkovic, S. F., Nakken, K. O., Propping, P., Bertrand, D. <strong>An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy.</strong> Hum. Molec. Genet. 6: 943-947, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9175743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9175743</a>] [<a href="https://doi.org/10.1093/hmg/6.6.943" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9175743">Steinlein et al. (1997)</a> identified a 3-bp (GCT) insertion at nucleotide position 776 into the region of the CHRNA4 gene coding for the C-terminal end of the M2 domain. Physiologic investigations of the receptor reconstituted with the mutated CHRNA4 subunit revealed that this insertion does not prevent the receptor function but increases its apparent affinity for acetylcholine. In addition, this mutant receptor showed a significantly lower calcium permeability that, at the cellular level, may correspond to a loss of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9175743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; <a href="/entry/600513">600513</a>), <a href="#11" class="mim-tip-reference" title="Hirose, S., Iwata, H., Akiyoshi, H., Kobayashi, K., Ito, M., Wada, K., Kaneko, S., Mitsudome, A. <strong>A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 53: 1749-1753, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10563623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10563623</a>] [<a href="https://doi.org/10.1212/wnl.53.8.1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10563623">Hirose et al. (1999)</a> identified a 755C-T transition in exon 5 of the CHRNA4 gene, causing a ser252-to-leu (S252L) substitution. The mutation was not found in 200 alleles of healthy volunteers. Based on analysis of the amino acid sequence, <a href="#11" class="mim-tip-reference" title="Hirose, S., Iwata, H., Akiyoshi, H., Kobayashi, K., Ito, M., Wada, K., Kaneko, S., Mitsudome, A. <strong>A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 53: 1749-1753, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10563623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10563623</a>] [<a href="https://doi.org/10.1212/wnl.53.8.1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10563623">Hirose et al. (1999)</a> suggested that the serine-to-leucine change undermines the channel function considerably. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10563623" 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 Korean family in which 9 members in 3 generations were affected with ENFL1, <a href="#5" class="mim-tip-reference" title="Cho, Y.-W., Motamedi, G. K., Laufenberg, I., Sohn, S.-I., Lim, J.-G., Lee, H., Yi, S.-D., Lee, J.-H., Kim, D.-K., Reba, R., Gaillard, W. D., Theodore, W. H., Lesser, R. P., Steinlein, O. K. <strong>A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation.</strong> Arch. Neurol. 60: 1625-1632, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14623738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14623738</a>] [<a href="https://doi.org/10.1001/archneur.60.11.1625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14623738">Cho et al. (2003)</a> identified the S252L mutation. <a href="#5" class="mim-tip-reference" title="Cho, Y.-W., Motamedi, G. K., Laufenberg, I., Sohn, S.-I., Lim, J.-G., Lee, H., Yi, S.-D., Lee, J.-H., Kim, D.-K., Reba, R., Gaillard, W. D., Theodore, W. H., Lesser, R. P., Steinlein, O. K. <strong>A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation.</strong> Arch. Neurol. 60: 1625-1632, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14623738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14623738</a>] [<a href="https://doi.org/10.1001/archneur.60.11.1625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14623738">Cho et al. (2003)</a> noted that the clinical phenotype in the Korean family was similar to that reported by <a href="#11" class="mim-tip-reference" title="Hirose, S., Iwata, H., Akiyoshi, H., Kobayashi, K., Ito, M., Wada, K., Kaneko, S., Mitsudome, A. <strong>A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 53: 1749-1753, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10563623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10563623</a>] [<a href="https://doi.org/10.1212/wnl.53.8.1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10563623">Hirose et al. (1999)</a> in the Japanese family with the same mutation. Shared features included mental retardation and drug resistance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14623738+10563623" 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>This same residue is affected in the S252F mutation (<a href="#0002">118504.0002</a>).</p><p>By haplotype analysis, <a href="#12" class="mim-tip-reference" title="Hwang, S.-K., Makita, Y., Kurahashi, H., Cho, Y.-W., Hirose, S. <strong>Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 ser285leu mutation.</strong> J. Hum. Genet. 56: 609-612, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753767</a>] [<a href="https://doi.org/10.1038/jhg.2011.69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753767">Hwang et al. (2011)</a> determined that the common mutation identified by <a href="#11" class="mim-tip-reference" title="Hirose, S., Iwata, H., Akiyoshi, H., Kobayashi, K., Ito, M., Wada, K., Kaneko, S., Mitsudome, A. <strong>A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy.</strong> Neurology 53: 1749-1753, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10563623/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10563623</a>] [<a href="https://doi.org/10.1212/wnl.53.8.1749" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10563623">Hirose et al. (1999)</a> and <a href="#5" class="mim-tip-reference" title="Cho, Y.-W., Motamedi, G. K., Laufenberg, I., Sohn, S.-I., Lim, J.-G., Lee, H., Yi, S.-D., Lee, J.-H., Kim, D.-K., Reba, R., Gaillard, W. D., Theodore, W. H., Lesser, R. P., Steinlein, O. K. <strong>A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation.</strong> Arch. Neurol. 60: 1625-1632, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14623738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14623738</a>] [<a href="https://doi.org/10.1001/archneur.60.11.1625" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14623738">Cho et al. (2003)</a>, which <a href="#12" class="mim-tip-reference" title="Hwang, S.-K., Makita, Y., Kurahashi, H., Cho, Y.-W., Hirose, S. <strong>Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 ser285leu mutation.</strong> J. Hum. Genet. 56: 609-612, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21753767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21753767</a>] [<a href="https://doi.org/10.1038/jhg.2011.69" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21753767">Hwang et al. (2011)</a> referred to as ser284-to-leu (S284L), did not arise from a common founder, but rather occurred independently. The mutation was associated with a CpG hypermutable site. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21753767+10563623+14623738" 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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CHRNA4, EX5, C-T (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1044396;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1044396</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> rs1044396 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1044396;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/rs1044396?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=rs1044396" 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=rs1044396" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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CHRNA4, EX5, G-A (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1044397;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1044397</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> rs1044397 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1044397;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/rs1044397?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=rs1044397" 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=rs1044397" 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=RCV000019054 OR RCV000079314 OR RCV000576716 OR RCV001521000 OR RCV001578891 OR RCV002311569" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000019054, RCV000079314, RCV000576716, RCV001521000, RCV001578891, RCV002311569" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000019054...</a>
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<p><a href="#8" class="mim-tip-reference" title="Feng, Y., Niu, T., Xing, H., Xu, X., Chen, C., Peng, S., Wang, L., Laird, N., Xu, X. <strong>A common haplotype of the nicotine acetylcholine receptor alpha-4 subunit gene is associated with vulnerability to nicotine addiction in men.</strong> Am. J. Hum. Genet. 75: 112-121, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15154117/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15154117</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15154117[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/422194" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15154117">Feng et al. (2004)</a> found a single-nucleotide polymorphism in exon 5 of the CHRNA4 gene, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1044397;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs1044397</a>, to be significantly associated with a protective effect against nicotine addiction (<a href="/entry/188890">188890</a>). The G-to-A transition is synonymous (ala-ala). The variant A allele is the protective allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15154117" 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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Anand, R., Lindstrom, J.
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<strong>Chromosomal localization of seven neuronal nicotinic acetylcholine receptor subunit genes in humans.</strong>
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Genomics 13: 962-967, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1505988/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1505988</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1505988" 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/10.1016/0888-7543(92)90008-g" target="_blank">Full Text</a>]
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Beck, C., Moulard, B., Steinlein, O., Guipponi, M., Vallee, L., Montpied, P., Baldy-Moulnier, M., Malafosse, A.
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<strong>A nonsense mutation in the alpha-4 subunit of the nicotinic acetylcholine receptor (CHRNA4) cosegregates with 20q-linked benign neonatal familial convulsions (EBN1).</strong>
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Neurobiol. Dis. 1: 95-99, 1994. Note: Erratum: Neurobiol. Dis. 2: 189 only, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9216991/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9216991</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9216991" 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/10.1006/nbdi.1994.0012" target="_blank">Full Text</a>]
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<strong>Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a ser252phe mutation in the CHRNA4 gene.</strong>
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Arch. Neurol. 56: 1004-1009, 1999. Note: Erratum: Arch. Neurol. 57: 1150 only, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10448807/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10448807</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10448807" 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/10.1001/archneur.56.8.1004" target="_blank">Full Text</a>]
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</p>
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<a id="20" class="mim-anchor"></a>
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<a id="Singh1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Singh, N. A., Charlier, C., Stauffer, D., DuPont, B. R., Leach, R. J., Melis, R., Ronen, G. M., Bjerre, I., Quattlebaum, T., Murphy, J. V., McHarg, M. L., Gagnon, D., Rosales, T. O., Peiffer, A., Anderson, V. E., Leppert, M.
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<strong>A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns.</strong>
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Nature Genet. 18: 25-29, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9425895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9425895</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9425895" 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/ng0198-25" target="_blank">Full Text</a>]
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</p>
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<a id="21" class="mim-anchor"></a>
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<a id="Steinlein1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Steinlein, O. K., Magnusson, A., Stoodt, J., Bertrand, S., Weiland, S., Berkovic, S. F., Nakken, K. O., Propping, P., Bertrand, D.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9175743/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9175743</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9175743" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/6.6.943" target="_blank">Full Text</a>]
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<a id="22" class="mim-anchor"></a>
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<a id="Steinlein1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Steinlein, O. K., Mulley, J. C., Propping, P., Wallace, R. H., Phillips, H. A., Sutherland, G. R., Scheffer, I. E., Berkovic, S. F.
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<strong>A missense mutation in the neuronal nicotinic acetylcholine receptor alpha-4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.</strong>
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Nature Genet. 11: 201-203, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550350/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550350</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550350" 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/ng1095-201" target="_blank">Full Text</a>]
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</p>
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<a id="23" class="mim-anchor"></a>
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<a id="Steinlein1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Steinlein, O., Smigrodzki, R., Lindstrom, J., Anand, R., Kohler, M., Tocharoentanaphol, C., Vogel, F.
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<strong>Refinement of the localization of the gene for neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4) to human chromosome 20q13.2-q13.3.</strong>
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Genomics 22: 493-495, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7806245/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7806245</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7806245" 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/10.1006/geno.1994.1420" target="_blank">Full Text</a>]
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<a id="24" class="mim-anchor"></a>
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<a id="Steinlein1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Steinlein, O., Weiland, S., Stoodt, J., Propping, P.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8833159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8833159</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8833159" 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/10.1006/geno.1996.0119" target="_blank">Full Text</a>]
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<a id="25" class="mim-anchor"></a>
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<a id="Tapper2004" class="mim-anchor"></a>
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Tapper, A. R., McKinney, S. L., Nashmi, R., Schwarz, J., Deshpande, P., Labarca, C., Whiteaker, P., Marks, M. J., Collins, A. C., Lester, H. A.
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Science 306: 1029-1032, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15528443/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15528443</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15528443" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1099420" target="_blank">Full Text</a>]
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<a id="26" class="mim-anchor"></a>
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<a id="Walsh2018" class="mim-anchor"></a>
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Walsh, R. M., Jr., Roh, S.-H., Gharpure, A., Morales-Perez, C. L., Teng, J., Hibbs, R. E.
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<strong>Structural principles of distinct assemblies of the human alpha-4-beta-2 nicotinic receptor.</strong>
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Nature 557: 261-265, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29720657/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29720657</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29720657[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=29720657" 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/s41586-018-0081-7" target="_blank">Full Text</a>]
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<a id="Xiu2009" class="mim-anchor"></a>
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Xiu, X., Puskar, N. L., Shanata, J. A. P., Lester, H. A., Dougherty, D. A.
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<strong>Nicotine binding to brain receptors requires a strong cation-pi interaction.</strong>
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Nature 458: 534-537, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19252481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19252481</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19252481[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=19252481" 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/nature07768" target="_blank">Full Text</a>]
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<a id="28" class="mim-anchor"></a>
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<a id="Yang2003" class="mim-anchor"></a>
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Yang, Y., Beyer, B. J., Otto, J. F., O'Brien, T. P., Letts, V. A., White, H. S., Frankel, W. N.
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<strong>Spontaneous deletion of epilepsy gene orthologs in a mutant mouse with a low electroconvulsive threshold.</strong>
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Hum. Molec. Genet. 12: 975-984, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12700166/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12700166</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12700166" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/ddg118" target="_blank">Full Text</a>]
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</ol>
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<br />
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 09/08/2018
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<div class="row collapse" id="mimCollapseContributors">
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Cassandra L. Kniffin - updated : 9/19/2011<br>Patricia A. Hartz - updated : 5/19/2010<br>Ada Hamosh - updated : 4/28/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 9/15/2008<br>George E. Tiller - updated : 5/19/2008<br>Cassandra L. Kniffin - updated : 4/24/2007<br>Ada Hamosh - updated : 3/3/2005<br>George E. Tiller - updated : 12/17/2004<br>Victor A. McKusick - updated : 6/30/2004<br>Cassandra L. Kniffin - updated : 2/6/2004<br>Cassandra L. Kniffin - updated : 6/4/2002<br>Ada Hamosh - updated : 5/6/1999<br>Victor A. McKusick - updated : 10/23/1998<br>Rebekah S. Rasooly - updated : 4/27/1998<br>Victor A. McKusick - updated : 12/30/1997<br>Victor A. McKusick - updated : 6/23/1997<br>Alan F. Scott - updated : 8/4/1995
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</span>
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 8/14/1992
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carol : 02/07/2025
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<span class="mim-text-font">
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carol : 09/10/2018<br>alopez : 09/08/2018<br>carol : 12/17/2012<br>carol : 10/4/2011<br>ckniffin : 9/19/2011<br>ckniffin : 9/19/2011<br>carol : 2/10/2011<br>ckniffin : 2/10/2011<br>wwang : 8/12/2010<br>terry : 8/6/2010<br>mgross : 5/19/2010<br>mgross : 5/19/2010<br>wwang : 5/7/2010<br>ckniffin : 5/4/2010<br>alopez : 5/5/2009<br>terry : 4/28/2009<br>wwang : 4/13/2009<br>ckniffin : 4/6/2009<br>wwang : 9/17/2008<br>ckniffin : 9/15/2008<br>wwang : 5/22/2008<br>terry : 5/19/2008<br>wwang : 5/1/2007<br>ckniffin : 4/24/2007<br>alopez : 3/8/2007<br>terry : 2/23/2007<br>alopez : 10/25/2006<br>carol : 3/15/2005<br>terry : 3/14/2005<br>wwang : 3/11/2005<br>alopez : 3/4/2005<br>terry : 3/3/2005<br>tkritzer : 12/17/2004<br>alopez : 7/19/2004<br>alopez : 7/19/2004<br>terry : 6/30/2004<br>ckniffin : 2/6/2004<br>carol : 6/4/2002<br>ckniffin : 6/4/2002<br>alopez : 5/22/2001<br>carol : 4/27/2000<br>alopez : 5/6/1999<br>alopez : 5/6/1999<br>carol : 10/26/1998<br>terry : 10/23/1998<br>alopez : 4/27/1998<br>alopez : 1/7/1998<br>terry : 1/6/1998<br>joanna : 12/15/1997<br>jenny : 6/23/1997<br>terry : 6/19/1997<br>terry : 8/9/1996<br>terry : 7/31/1996<br>mark : 3/25/1996<br>terry : 3/14/1996<br>mark : 10/10/1995<br>terry : 9/7/1995<br>carol : 2/4/1993<br>carol : 8/31/1992<br>carol : 8/14/1992
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<strong>*</strong> 118504
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<h3>
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<span class="mim-font">
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CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 4; CHRNA4
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<h4>
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<span class="mim-font">
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ACETYLCHOLINE RECEPTOR, NEURONAL NICOTINIC, ALPHA-4 SUBUNIT
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<strong><em>HGNC Approved Gene Symbol: CHRNA4</em></strong>
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<strong>
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Cytogenetic location: 20q13.33
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Genomic coordinates <span class="small">(GRCh38)</span> : 20:63,343,223-63,361,349 </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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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
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<th>
|
|
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="2">
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<span class="mim-font">
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|
20q13.33
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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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{Nicotine addiction, susceptibility to}
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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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|
188890
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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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</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">
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|
Epilepsy, nocturnal frontal lobe, 1
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
600513
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
Autosomal dominant
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</span>
|
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</td>
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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|
<p>The nicotinic acetylcholine receptors (nAChRs) are members of a superfamily of ligand-gated ion channels that mediate fast signal transmission at synapses. The nAChRs are thought to be (hetero)pentamers composed of homologous subunits. See 118508 for additional background information on nAChRs.</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>Cloning and Expression</strong>
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</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
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<p>Monteggia et al. (1995) obtained the full-length cDNA sequence for the alpha-4 neuronal nicotinic acetylcholine receptor subunit. The predicted amino acid sequence is 89% similar to the rat sequence, with most differences in the cytoplasmic domain. Elliott et al. (1996) also cloned the alpha-4 gene. </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>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>Steinlein et al. (1996) determined that the CHRNA4 gene has 6 exons distributed over approximately 17 kb of genomic DNA. </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">
|
|
<p>By genomic Southern blot analysis of hamster/human somatic cell hybrid DNAs, Anand and Lindstrom (1992) mapped the gene encoding the alpha-4 subunit of the human neuronal nicotinic acetylcholine receptor to chromosome 20. Pilz et al. (1992) likewise mapped the gene to human chromosome 20 by Southern blot analysis of human/rodent somatic cell hybrids. The corresponding gene is located on chromosome 2 in the mouse (Bessis et al., 1990). </p><p>By fluorescent in situ hybridization, Steinlein et al. (1994) positioned CHRNA4 on a contig between D20S24 and D20S20 on chromosome 20q13.2-q13.3. The 2 markers were separated by 160 kb. Steinlein et al. (1994) suggested that the location of CHRNA4 made it a possible candidate gene for either benign neonatal familial convulsions (EBN1; 121200) or the electroencephalographic variant pattern 1 (EEGV1; 130180). </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>Gene Function</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<span class="mim-text-font">
|
|
<p>Monteggia et al. (1995) found that transfection of expression vectors for the alpha-4 and beta-2 (CHRNB2; 118507) nAChR subunits into HEK293 cells resulted in the formation of binding sites with the expected high affinity for cytosine. </p><p>Elliott et al. (1996) demonstrated that human alpha-4 encodes a functional receptor when expressed in combination with human beta-2 or beta-4 (CHRNB4; 118509) in Xenopus oocytes. </p><p>By immunoprecipitation analysis of mouse striatal extracts, Champtiaux et al. (2003) identified 3 main types of heteromeric nAChRs: alpha-4/beta-2, alpha-6 (CHRNA6; 606888)/beta-2, and alpha-4/alpha-6/beta-2. Alpha-6/beta-2 nAChRs were mainly located on dopamine (DA) nerve terminals and were the direct target of alpha-conotoxin MII inhibition. A combination of alpha-6/beta-2 and alpha-4/beta-2 nAChRs mediated endogenous cholinergic modulation of DA release induced by systemic nicotine administration at nerve terminals. Alpha-4/beta-2 nAChRs appeared to represent the majority of nAChRs on DA neuron soma and contributed to nicotine reinforcement. </p>
|
|
</span>
|
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<div>
|
|
<br />
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|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Biochemical Features</strong>
|
|
</span>
|
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</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Crystal Structure</em></strong></p><p>
|
|
Xiu et al. (2009) showed that at the brain acetylcholine receptors alpha-4 (CHRNA4)-beta-2 (CHRNB2) thought to underlie nicotine addiction, the high affinity for nicotine is the result of a strong cation-pi interaction to a specific aromatic amino acid of the receptor, TrpB. In contrast, the low affinity for nicotine at the muscle-type acetylcholine receptor is largely due to the absence of this key interaction, even though the immediate binding site residues, including the key amino acid TrpB, are identical in the brain and muscle receptors. At the same time a hydrogen bond from nicotine to the backbone carbonyl of TrpB is enhanced in the neuronal receptor relative to the muscle type. A point mutation near TrpB that differentiates alpha-4-beta-2 and muscle-type receptors seems to influence the shape of the binding site, allowing nicotine to interact more strongly with TrpB in the neuronal receptor. </p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
|
|
Walsh et al. (2018) used cryoelectron microscopy to obtain structures for the alpha-4-beta-2 nicotinic acetylcholine receptor in both the 2-alpha-to-3-beta and 3-alpha-to-2-beta stoichiometries from a single sample. The antibody fragments specific to beta-2 were used to break symmetry during particle alignment and to obtain high-resolution reconstructions of receptors of both stoichiometries in complex with nicotine. The results revealed principles of subunit assembly and the structural basis of the distinctive biophysical and pharmacologic properties of the 2 different stoichiometries of this receptor. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Nocturnal Frontal Lobe Epilepsy 1</em></strong></p><p>
|
|
Steinlein et al. (1995) demonstrated a missense mutation in the CHRNA4 gene (S252F; 118504.0002) associated with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513), which had previously been mapped to 20q. The mutation was sought because CHRNA4 maps to the candidate region of 20q and the gene is expressed in all layers of the frontal cortex. Mutations in the CHRNA4 gene appear to account for only a small proportion of the cases of nocturnal frontal lobe epilepsy. </p><p><strong><em>Associations with Other Disorders</em></strong></p><p>
|
|
Nicotine is the major addictive substance in cigarettes, and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction (188890). Feng et al. (2004) studied 6 single-nucleotide polymorphisms (SNPs) in the CHRNA4 gene and 4 SNPs in the CHRNB2 gene (118507) in relation to nicotine dependence in a collection of 901 subjects (815 sibs and 86 parents) from 222 nuclear families with multiple nicotine-addicted sibs. They found 2 SNPs in exon 5 of the CHRNA4 gene to be significantly associated with a protective effect against nicotine addiction. Furthermore, a common (22.5%) CHRNA4 haplotype was significantly associated with a protective effect against nicotine addiction. </p><p>Li et al. (2005) analyzed 6 SNPs within CHRNA4 for association with nicotine dependence (ND). In a sample of European American families, SNPs rs2273504 and rs1044396 (118504.0005) were significantly associated with the adjusted smoking quantity and Fagerstrom test for ND score, respectively. In the African American families, SNPs rs3787137 and rs2236196 were each significantly associated with at least 2 adjusted ND measures. Haplotype analysis of rs2273505, rs2273504, and rs2236196 showed significant association after Bonferroni correction of a C-G-G haplotype (53.4%) with 3 adjusted ND measures in samples from the African American females. </p><p>For a possible association between variation in the CHRNA4 gene and the psychologic trait of harm avoidance, see 607834.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>History</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Benign familial neonatal seizures 1 (BFNS1; 121200) was shown to be caused by mutations in the KCNQ2 gene (602235), which also maps to chromosome 20q13 (Singh et al., 1998). The finding of a presumed mutation (Beck et al., 1994) in the CHRNA4 gene, which maps to the same region, in 1 of 20 families, was presumably an error. </p>
|
|
</span>
|
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<div>
|
|
<br />
|
|
</div>
|
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|
|
|
|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Marubio et al. (1999) disrupted the alpha-4 subunit of the neuronal nicotinic acetylcholine receptor by homologous recombination and studied homozygous alpha-4-null mice and mice lacking the beta-2 subunit of the nAChR. The homozygous alpha-4 -/- mice no longer expressed high-affinity nicotine binding sites throughout the brain. In addition, both types of mutant mice displayed a reduced antinociceptive effect of nicotine on the hot-plate test and diminished sensitivity to nicotine in the tail-flick test. Patch-clamp recordings revealed that raphe magnus and thalamic neurons no longer responded to nicotine. Marubio et al. (1999) stated that the alpha-4 nAChR subunit, thought to associate with the beta-2 nAChR subunit, is therefore crucial for nicotine-elicited antinociception. </p><p>The electroconvulsive threshold (ECT) test has been used extensively to determine the protection conferred by antiepileptic drug candidates against induced seizures in rodents. Yang et al. (2003) adopted the ECT test to screen the progeny of ethylnitrosourea-treated male C57BL/6J mice. In a small-scale screen, several mutant lines conferring a low threshold to ECT minimal clonic seizures were mapped to the telomeric region of mouse chromosome 2 in independent founder families. Genetic and physical mapping data indicated that several lines shared a single mutation, Szt1 (seizure threshold-1), consisting of a 300-kb deletion of genomic DNA involving 3 known genes. Two of these genes, Kcnq2 and Chrna4, are known to be mutated in human epilepsy families. Szt1 homozygotes and heterozygotes displayed similar phenotypes to those found in the respective Kcnq2 knockout mutant mice, suggesting that Kcnq2 haploinsufficiency may lie at the root of the Szt1 seizure sensitivity. </p><p>Tapper et al. (2004) generated mutant mice with alpha-4 nicotinic subunits containing a single point mutation, leu9-prime to ala, in the pore-forming M2 domain, rendering alpha-4 mutant receptors hypersensitive to nicotine. Selective activation of alpha-4 mutant nicotinic acetylcholine receptors with low doses of agonist recapitulated nicotine effects thought to be important in dependence, including reinforcement in response to acute nicotine administration, as well as tolerance and sensitization elicited by chronic nicotine administration. Tapper et al. (2004) concluded that activation of alpha-4 mutant receptors is sufficient for nicotine-induced reward, tolerance, and sensitization. </p><p>Klaassen et al. (2006) generated 2 mouse models of autosomal dominant nocturnal frontal lobe epilepsy by introducing an S252F (118504.0002) mutation or a leu264 insertion in the Chrna4 gene, respectively. Mice heterozygous for the S252F mutation or the leu264 insertion showed abnormal cortical EEGs with prominent delta and theta frequencies, frequent spontaneous seizures, and increased sensitivity to the proconvulsant action of nicotine. Voltage-clamp studies showed that a considerable fraction of mutant Chrna4-containing nAChRs were located on presynaptic terminals of cortical GABAergic interneurons and that activation of these receptors resulted in elevated presynaptic calcium levels. The results were consistent with a model of epileptogenesis in which acetylcholine significantly enhances cortical GABAergic transmission, which contributes to epileptogenesis through inhibitory resetting and synchronization of neural networks. </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>6 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</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 REMOVED FROM DATABASE</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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<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 EPILEPSY, NOCTURNAL FRONTAL LOBE, TYPE 1</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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|
CHRNA4, SER252PHE
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<br />
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|
|
SNP: rs121909580,
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|
|
ClinVar: RCV000019050, RCV000487099, RCV001206285
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</span>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a large Australian kindred with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513) reported by Phillips et al. (1995), Steinlein et al. (1995) used single-strand conformation analysis to identify a C-to-T transition in exon 5 of the CHRNA4 gene, resulting in ser248-to-phe (SER248PHE) substitution in the sixth amino acid position of transmembrane domain 2 (M2) and reduced receptor function. Their numbering was based on the Torpedo californica Chrna4 sequence. Saenz et al. (1999) noted that in the human sequence codon 252 is homologous to the Torpedo codon 248, and they referred to the mutation as ser252 to phe (S252F). </p><p>Forman et al. (1996) suggested an alternative mechanism for pathogenesis of epilepsy associated with this CHRNA4 mutation. From studies of the mouse muscle alpha-1 nicotinic receptor (100690) noted in Forman et al. (1995), Forman et al. (1996) speculated that the mutation in CHRNA4 may cause receptor hyperactivity that could lead to epileptic activity. </p><p>In 11 affected members of a large Spanish family with nocturnal frontal lobe epilepsy, Saenz et al. (1999) identified the S252F mutation. Saenz et al. (1999) noted that the clinical features were similar to those reported by Steinlein et al. (1995). This same residue is affected in the S252L mutation (118504.0004) </p><p>Using PET scans, Fedi et al. (2008) observed decreased striatal D1 receptor (DRD1; 126449) binding, particularly in the right putamen, in 12 individuals with autosomal dominant nocturnal frontal lobe epilepsy and the S252L mutation compared to controls. Decreased D1 receptor binding was postulated to represent receptor downregulation from increased extracellular levels of dopamine. Increased dopamine release may result from a gain-of-function in nAChRs with the mutant CHRNA4 subunit, since nAChRs regulate dopamine release. </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>.0003 EPILEPSY, NOCTURNAL FRONTAL LOBE, TYPE 1</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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|
|
CHRNA4, 3-BP INS, 776GCT
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<br />
|
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|
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SNP: rs281865067,
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|
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ClinVar: RCV000033927
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</span>
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</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Norwegian family with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513), Steinlein et al. (1997) identified a 3-bp (GCT) insertion at nucleotide position 776 into the region of the CHRNA4 gene coding for the C-terminal end of the M2 domain. Physiologic investigations of the receptor reconstituted with the mutated CHRNA4 subunit revealed that this insertion does not prevent the receptor function but increases its apparent affinity for acetylcholine. In addition, this mutant receptor showed a significantly lower calcium permeability that, at the cellular level, may correspond to a loss of function. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 EPILEPSY, NOCTURNAL FRONTAL LOBE, TYPE 1</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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CHRNA4, SER252LEU
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|
|
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<br />
|
|
|
|
SNP: rs28931591,
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|
|
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ClinVar: RCV000019052, RCV000186931, RCV000692832, RCV002316197
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ENFL1; 600513), Hirose et al. (1999) identified a 755C-T transition in exon 5 of the CHRNA4 gene, causing a ser252-to-leu (S252L) substitution. The mutation was not found in 200 alleles of healthy volunteers. Based on analysis of the amino acid sequence, Hirose et al. (1999) suggested that the serine-to-leucine change undermines the channel function considerably. </p><p>In a Korean family in which 9 members in 3 generations were affected with ENFL1, Cho et al. (2003) identified the S252L mutation. Cho et al. (2003) noted that the clinical phenotype in the Korean family was similar to that reported by Hirose et al. (1999) in the Japanese family with the same mutation. Shared features included mental retardation and drug resistance. </p><p>This same residue is affected in the S252F mutation (118504.0002).</p><p>By haplotype analysis, Hwang et al. (2011) determined that the common mutation identified by Hirose et al. (1999) and Cho et al. (2003), which Hwang et al. (2011) referred to as ser284-to-leu (S284L), did not arise from a common founder, but rather occurred independently. The mutation was associated with a CpG hypermutable site. </p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0005 NICOTINE ADDICTION, PROTECTION AGAINST</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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CHRNA4, EX5, C-T ({dbSNP rs1044396})
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<br />
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SNP: rs1044396,
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gnomAD: rs1044396,
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ClinVar: RCV000019053, RCV000079313, RCV000576445, RCV001517150, RCV001578892, RCV002311568
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</span>
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</div>
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<span class="mim-text-font">
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<p>Feng et al. (2004) found a single-nucleotide polymorphism in exon 5 of the CHRNA4 gene, rs1044396, to be significantly associated with a protective effect against nicotine addiction (188890). The C-to-T transition is synonymous (ser-ser). The variant T allele is the protective allele. </p>
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</span>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0006 NICOTINE ADDICTION, PROTECTION AGAINST</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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CHRNA4, EX5, G-A ({dbSNP rs1044397})
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<br />
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SNP: rs1044397,
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gnomAD: rs1044397,
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ClinVar: RCV000019054, RCV000079314, RCV000576716, RCV001521000, RCV001578891, RCV002311569
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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>Feng et al. (2004) found a single-nucleotide polymorphism in exon 5 of the CHRNA4 gene, rs1044397, to be significantly associated with a protective effect against nicotine addiction (188890). The G-to-A transition is synonymous (ala-ala). The variant A allele is the protective allele. </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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<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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<strong>A missense mutation in the neuronal nicotinic acetylcholine receptor alpha-4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy.</strong>
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<strong>Refinement of the localization of the gene for neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4) to human chromosome 20q13.2-q13.3.</strong>
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Steinlein, O., Weiland, S., Stoodt, J., Propping, P.
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<strong>Exon-intron structure of the human neuronal nicotinic acetylcholine receptor alpha-4 subunit (CHRNA4).</strong>
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Ada Hamosh - updated : 09/08/2018<br>Cassandra L. Kniffin - updated : 9/19/2011<br>Patricia A. Hartz - updated : 5/19/2010<br>Ada Hamosh - updated : 4/28/2009<br>Cassandra L. Kniffin - updated : 4/6/2009<br>Cassandra L. Kniffin - updated : 9/15/2008<br>George E. Tiller - updated : 5/19/2008<br>Cassandra L. Kniffin - updated : 4/24/2007<br>Ada Hamosh - updated : 3/3/2005<br>George E. Tiller - updated : 12/17/2004<br>Victor A. McKusick - updated : 6/30/2004<br>Cassandra L. Kniffin - updated : 2/6/2004<br>Cassandra L. Kniffin - updated : 6/4/2002<br>Ada Hamosh - updated : 5/6/1999<br>Victor A. McKusick - updated : 10/23/1998<br>Rebekah S. Rasooly - updated : 4/27/1998<br>Victor A. McKusick - updated : 12/30/1997<br>Victor A. McKusick - updated : 6/23/1997<br>Alan F. Scott - updated : 8/4/1995
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Victor A. McKusick : 8/14/1992
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