4362 lines
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Entry
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- *608465 - SENATAXIN; SETX
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*608465</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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="#geneFunction">Gene Function</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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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/608465">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<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=ENSG00000107290;t=ENST00000224140" 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=23064" 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=608465" 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=ENSG00000107290;t=ENST00000224140" 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_001351527,NM_001351528,NM_015046,XM_005272172,XM_005272173,XM_011518404,XM_011518405,XM_011518406,XM_011518407,XM_011518408,XM_047423023,XM_047423024,XM_047423025" 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_015046" 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=608465" 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=07622&isoform_id=07622_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/SETX" 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/7022724,10434562,31873834,31874607,34327966,34531546,38195410,50603852,51476230,77415498,113722133,114325426,119608403,119608404,119608405,119608406,187951665,194379484,211827336,296453021,530427120,530427122,767956710,767956712,767956714,767956716,767956718,957950884,957950887,1191017961,1191017963,2217376253,2217376258,2217376260,2462623574,2462623576,2462623578,2462623580,2462623582,2462623584,2462623586,2462623588,2462623590,2462623592" 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/Q7Z333" 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=23064" 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=ENSG00000107290;t=ENST00000224140" 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=SETX" 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=SETX" 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+23064" 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/SETX" 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:23064" 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/23064" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr9&hgg_gene=ENST00000792821.1&hgg_start=132261356&hgg_end=132356744&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:445" 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://medlineplus.gov/genetics/gene/setx" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=608465[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=608465[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/SETX/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/ENSG00000107290" 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=SETX" 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=SETX" 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=SETX" 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="#mimLocusSpecificDBsFold" id="mimLocusSpecificDBsToggle" data-toggle="collapse" class="mim-tip-hint mimTriangleToggle" title="A gene-specific database of variation."><span id="mimLocusSpecificDBsToggleTriangle" class="small" style="margin-left: -0.8em;">►</span>Locus Specific DBs</div>
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<div id="mimLocusSpecificDBsFold" class="collapse">
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<div style="margin-left: 0.5em;"><a href="http://149.142.212.78/LOVD/" title="UCLA Neurogenetics SETX Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">UCLA Neurogenetics SETX Da…</a></div><div style="margin-left: 0.5em;"><a href="http://www.molgen.ua.ac.be/CMTMutations/" title="Inherited Peripheral Neuropathies Mutation Database" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Inherited Peripheral Neuro…</a></div>
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</div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=SETX&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/PA24751" 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:445" 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/FBgn0035842.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:2443480" 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/SETX#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:2443480" 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/23064/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=23064" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00016566;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-070402-1" 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:23064" 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=SETX&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 725408001, 784341001<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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608465
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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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SENATAXIN; SETX
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</span>
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<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=SETX" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">SETX</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>
|
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Cytogenetic location: <a href="/geneMap/9/594?start=-3&limit=10&highlight=594">9q34.13</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr9:132261356-132356744&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">9:132,261,356-132,356,744</a> </span>
|
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</em>
|
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</strong>
|
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<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>
|
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<br />
|
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</div>
|
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=602433,606002" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/9/594?start=-3&limit=10&highlight=594">
|
|
9q34.13
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
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|
<td>
|
|
<span class="mim-font">
|
|
Amyotrophic lateral sclerosis 4, juvenile
|
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|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/602433"> 602433 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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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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<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>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
|
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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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|
<a href="/entry/606002"> 606002 </a>
|
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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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<abbr class="mim-tip-hint" title="Autosomal recessive">AR</abbr>
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<p>SETX is an ATP-dependent helicase that is required for unwinding and resolution of RNA:DNA hybrids (R-loops) formed during transcription (<a href="#12" class="mim-tip-reference" title="Kannan, A., Cuartas, J., Gangwani, P., Branzei, D., Gangwani, L. <strong>Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4.</strong> Brain 145: 3072-3094, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35045161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35045161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35045161[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awab464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35045161">Kannan et al., 2022</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35045161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By a positional cloning strategy, <a href="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al. (2004)</a> identified the SETX gene within the interval on chromosome 9q34 associated with autosomal recessive spinocerebellar ataxia with axonal neuropathy (SCAN2; <a href="/entry/606002">606002</a>), earlier referred to as ataxia-oculomotor apraxia-2 (AOA2). The predicted 2,677-amino acid protein contains at its C terminus a classic 7-motif domain found in the superfamily 1 of helicases. <a href="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al. (2004)</a> named the gene 'senataxin' for its extensive homology to fungal Sen1p proteins. In Saccharomyces cerevisiae, Sen1p is involved in splicing and termination of tRNA, small nuclear RNA, and small nucleolar RNA, and has RNA helicase activity encoded by its C-terminal domain. Senataxin shares significant similarity with another helicase, IGHMBP2 (<a href="/entry/600502">600502</a>), which is mutant in spinal muscular atrophy with respiratory distress-1 (SMARD1, DSMA1; <a href="/entry/604320">604320</a>), a disorder of motor neurons, and in mouse neuromuscular degeneration (<a href="#8" class="mim-tip-reference" title="Cox, G. A., Mahaffey, C. L., Frankel, W. N. <strong>Identification of mouse neuromuscular degeneration gene and mapping of a second site suppressor allele.</strong> Neuron 21: 1327-1337, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9883726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9883726</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80652-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9883726">Cox et al., 1998</a>). <a href="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al. (2004)</a> suggested that senataxin may have both RNA and DNA helicase activities and that senataxin acts in the DNA repair pathway, like several other proteins defective in autosomal recessive cerebellar ataxias. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=14770181+9883726" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Chen, Y.-Z., Bennett, C. L., Huynh, H. M., Blair, I. P., Puls, I., Irobi, J., Dierick, I., Abel, A., Kennerson, M. L., Rabin, B. A., Nicholson, G. A., Auer-Grumbach, M., Wagner, K., De Jonghe, P., Griffin, J. W., Fischbeck, K. H., Timmerman, V., Cornblath, D. R., Chance, P. F. <strong>DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).</strong> Am. J. Hum. Genet. 74: 1128-1135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15106121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15106121</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15106121[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/10.1086/421054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15106121">Chen et al. (2004)</a> determined that the SETX gene encodes a 302.8-kD protein. Northern blot analysis identified 2 prominent transcripts of 11.5 and 9.0 kb in all tissues examined, including brain and spinal cord. SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 (<a href="/entry/601430">601430</a>) and IGHMBP2 (<a href="/entry/600502">600502</a>), 2 genes that encode proteins known to have roles in RNA processing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15106121" 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="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al. (2004)</a> determined that the SETX gene contains 24 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14770181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#14" class="mim-tip-reference" title="Suraweera, A., Lim, Y., Woods, R., Birrell, G. W., Nasim, T., Becherel, O. J., Lavin, M. F. <strong>Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation.</strong> Hum. Molec. Genet. 18: 3384-3396, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19515850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19515850</a>] [<a href="https://doi.org/10.1093/hmg/ddp278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19515850">Suraweera et al. (2009)</a> identified novel senataxin-interacting proteins, the majority of which are involved in transcription and RNA processing, including RNA polymerase II (see POLR2A, <a href="/entry/180660">180660</a>). Binding of RNA polymerase II to candidate genes was significantly reduced in senataxin-deficient cells, accompanied by decreased transcription of these genes, thus suggesting a role for senataxin in the regulation/modulation of transcription. RNA polymerase II-dependent transcription termination was defective in cells depleted of senataxin, in keeping with the observed interaction of senataxin with poly(A) binding proteins 1 (PABP1; <a href="/entry/604679">604679</a>) and 2 (PABP2; <a href="/entry/602279">602279</a>). Splicing efficiency of specific mRNAs and alternate splice site selection of both endogenous genes and artificial minigenes were altered in senataxin-depleted cells. <a href="#14" class="mim-tip-reference" title="Suraweera, A., Lim, Y., Woods, R., Birrell, G. W., Nasim, T., Becherel, O. J., Lavin, M. F. <strong>Functional role for senataxin, defective in ataxia oculomotor apraxia type 2, in transcriptional regulation.</strong> Hum. Molec. Genet. 18: 3384-3396, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19515850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19515850</a>] [<a href="https://doi.org/10.1093/hmg/ddp278" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19515850">Suraweera et al. (2009)</a> suggested that senataxin, similar to its yeast homolog Sen1p, may play a role in coordinating transcriptional events, in addition to its role in DNA repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19515850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="Zhao, D. Y., Gish, G., Braunschweig, U., Li, Y., Ni, Z., Schmitges, F. W., Zhong, G., Liu, K., Li, W., Moffat, J., Vedadi, M., Min, J., Pawson, T. J., Blencowe, B. J., Greenblatt, J. F. <strong>SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination.</strong> Nature 529: 48-53, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26700805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26700805</a>] [<a href="https://doi.org/10.1038/nature16469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26700805">Zhao et al. (2016)</a> showed that a carboxy-terminal domain (CTD) arginine (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires PRMT5 (<a href="/entry/604045">604045</a>) and recruits the Tudor domain of SMN (<a href="/entry/600354">600354</a>). SMN interacts with senataxin. Because POLR2A R1810me2s and SMN, like senataxin, are required for resolving RNA-DNA hybrids created by RNA polymerase II that form R-loops in transcription termination regions, <a href="#15" class="mim-tip-reference" title="Zhao, D. Y., Gish, G., Braunschweig, U., Li, Y., Ni, Z., Schmitges, F. W., Zhong, G., Liu, K., Li, W., Moffat, J., Vedadi, M., Min, J., Pawson, T. J., Blencowe, B. J., Greenblatt, J. F. <strong>SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination.</strong> Nature 529: 48-53, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26700805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26700805</a>] [<a href="https://doi.org/10.1038/nature16469" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26700805">Zhao et al. (2016)</a> proposed that R1810me2s, SMN, and senataxin are components of an R-loop resolution pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26700805" 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 in HeLa cells, <a href="#12" class="mim-tip-reference" title="Kannan, A., Cuartas, J., Gangwani, P., Branzei, D., Gangwani, L. <strong>Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4.</strong> Brain 145: 3072-3094, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35045161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35045161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35045161[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awab464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35045161">Kannan et al. (2022)</a> showed that ZPR1 (<a href="/entry/603901">603901</a>) interacted with SETX. ZPR1 also bound to R-loops to facilitate SETX recruitment for the formation of an R-loop resolution complex (RLRC) during transcription. ZPR1 colocalized with SETX in nuclear bodies in HeLa cells, and knockdown of ZPR1 resulted in downregulation of SETX and accumulation of R-loops, indicating that ZPR1 was critical for R-loop resolution. Moreover, knockdown of SETX caused disruption of ZPR1-positive subnuclear bodies, gems, and Cajal bodies and accumulation of R-loops, indicating a functional contribution of SETX in ZPR1-dependent resolution of R-loops. Analysis with fibroblasts from patients with spinal muscular atrophy (SMA; <a href="/entry/253300">253300</a>) revealed that chronic low levels of ZPR1 caused defects in RLRC assembly, which resulted in inefficient R-loop resolution and accumulation of pathogenic R-loops and DNA damage, leading to genomic instability and neurodegeneration. In contrast, ZPR1 overexpression rescued defective RLRC assembly and prevented pathogenic R-loop accumulation in SMA patient cells in vitro, and Zpr1 overexpression rescued DNA damage associated with R-loop accumulation and prevented degeneration of motor neurons in SMA mice in vivo. Further analysis of SETX mutations in ALS4 (<a href="/entry/602433">602433</a>) patient cells (see MOLECULAR GENETICS) confirmed that SETX and ZPR1 collaborate functionally to regulate R-loop resolution activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35045161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The SETX gene lies within the 9q34 region linked to ataxia-oculomotor apraxia-2 (<a href="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al., 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14770181" 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>Autosomal Recessive Spinocerebellar Ataxia with Axonal Neuropathy</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al. (2004)</a> sequenced exons 1 through 18 of the SETX gene and flanking intronic sequences in families with ataxia linked to the 9q34 region and in additional individuals with either ataxia-oculomotor apraxia or ataxia with elevated levels of alpha-fetoprotein (SCAN2; <a href="/entry/606002">606002</a>) and found 15 different disease-associated mutations in 15 families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14770181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In affected members of 10 French Canadian families with ataxia, distal amyotrophy, and peripheral neuropathy, <a href="#9" class="mim-tip-reference" title="Duquette, A., Roddier, K., McNabb-Baltar, J., Gosselin, I., St-Denis, A., Dicaire, M.-J., Loisel, L., Labuda, D., Marchand, L., Mathieu, J., Bouchard, J.-P., Brais, B. <strong>Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy.</strong> Ann. Neurol. 57: 408-414, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732101</a>] [<a href="https://doi.org/10.1002/ana.20408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732101">Duquette et al. (2005)</a> identified mutations in the SETX gene. A founder mutation, leu1976 to arg (L1976R; <a href="/entry/606465#0009">606465.0009</a>), was identified in all families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732101" 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="#11" class="mim-tip-reference" title="Fogel, B. L., Perlman, S. <strong>Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2.</strong> Neurology 67: 2083-2084, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159128</a>] [<a href="https://doi.org/10.1212/01.wnl.0000247661.19601.28" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159128">Fogel and Perlman (2006)</a> identified 6 SETX mutations, including 5 novel mutations (see, e.g., <a href="/entry/606465#0012">606465.0012</a>), in 3 unrelated patients with ataxia-oculomotor apraxia-2. Three of the mutations were in the DNA/RNA helicase functional domain, illustrating the importance of this region to the pathogenesis of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Arning, L., Schols, L., Cin, H., Souquet, M., Epplen, J. T., Timmann, D. <strong>Identification and characterisation of a large senataxin (SETX) gene duplication in ataxia with ocular apraxia type 2 (AOA2).</strong> Neurogenetics 9: 295-299, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18663494/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18663494</a>] [<a href="https://doi.org/10.1007/s10048-008-0139-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18663494">Arning et al. (2008)</a> reported a patient with ataxia-oculomotor apraxia-2 who was found to be compound heterozygous for a point mutation in the SETX gene and a large out-of-frame tandem duplication encompassing exons 7 through 10 of the SETX gene. The duplication occurred by unequal homologous recombination between AluY sequences. The authors suggested that gross deletions or duplications in the SETX gene may be an underestimated cause of the disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18663494" 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="#1" class="mim-tip-reference" title="Airoldi, G., Guidarelli, A., Cantoni, O., Panzeri, C., Vantaggiato, C., Bonato, S., Grazia D'Angelo, M., Falcone, S., De Palma, C., Tonelli, A., Crimella, C., Bondioni, S., Bresolin, N., Clementi, E., Bassi, M. T. <strong>Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin.</strong> Neurogenetics 11: 91-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19593598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19593598</a>] [<a href="https://doi.org/10.1007/s10048-009-0206-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19593598">Airoldi et al. (2010)</a> identified a homozygous in-frame deletion of leu144 in the SETX gene (L144del; <a href="#0014">608465.0014</a>) in 2 sisters with ataxia-oculumotor apraxia-2 The deletion affected an N-terminal region predicted to act as a protein-protein interaction domain. Studies of lymphoblastoid cells derived from the proband showed that the mutant protein was expressed, and that the cells were hypersensitive to DNA-damaging agents. The defect in DNA repair was corrected by silencing of the mutant protein. In contrast, cells from patients with complete lack of protein expression resulting from a nonsense mutation did not show enhanced sensitivity to DNA-damaging agents. <a href="#1" class="mim-tip-reference" title="Airoldi, G., Guidarelli, A., Cantoni, O., Panzeri, C., Vantaggiato, C., Bonato, S., Grazia D'Angelo, M., Falcone, S., De Palma, C., Tonelli, A., Crimella, C., Bondioni, S., Bresolin, N., Clementi, E., Bassi, M. T. <strong>Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin.</strong> Neurogenetics 11: 91-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19593598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19593598</a>] [<a href="https://doi.org/10.1007/s10048-009-0206-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19593598">Airoldi et al. (2010)</a> postulated that the L114del mutation caused abnormal interactions with other proteins involved in the response to oxidative damage, resulting in a toxic gain of function effect. The findings also suggested that the main function of the SETX protein is not to confer cellular protection against damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19593598" 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 gene expression profiling of fibroblasts derived from a patient with ataxia-oculomotor apraxia-2 and an unaffected heterozygous carrier, <a href="#10" class="mim-tip-reference" title="Fogel, B. L., Cho, E., Wahnich, A., Gao, F., Becherel, O. J., Wang, X., Fike, F., Chen, L., Criscuolo, C., De Michele, G., Filla, A., Collins, A., Hahn, A. F., Gatti, R. A., Konopka, G., Perlman, S., Lavin, M. F., Geschwind, D. H., Coppola, G. <strong>Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2.</strong> Hum. Molec. Genet. 23: 4758-4769, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24760770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24760770</a>] [<a href="https://doi.org/10.1093/hmg/ddu190" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24760770">Fogel et al. (2014)</a> identified a core set of genes with altered expression levels in the patient, including genes involved in neurogenesis, cell proliferation, and synaptic transmission. Overexpression of an AOA2-associated mutation (L1976R; <a href="#0009">608465.0009</a>) and an ALS4-associated mutation (R2136H; <a href="#0008">608465.0008</a>) resulted in differential gene expression patterns, suggesting that disease-specific mutations cause differential transcriptional changes within cells. However, there were some modules of overlap involving aspects of RNA processing, DNA maintenance, and transcription. The findings identified novel genes and cellular pathways related to senataxin function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24760770" 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>Juvenile Amyotrophic Lateral Sclerosis 4</em></strong></p><p>
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Juvenile amyotrophic lateral sclerosis (ALS4; <a href="/entry/602433">602433</a>) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. <a href="#7" class="mim-tip-reference" title="Chen, Y.-Z., Bennett, C. L., Huynh, H. M., Blair, I. P., Puls, I., Irobi, J., Dierick, I., Abel, A., Kennerson, M. L., Rabin, B. A., Nicholson, G. A., Auer-Grumbach, M., Wagner, K., De Jonghe, P., Griffin, J. W., Fischbeck, K. H., Timmerman, V., Cornblath, D. R., Chance, P. F. <strong>DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).</strong> Am. J. Hum. Genet. 74: 1128-1135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15106121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15106121</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15106121[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/10.1086/421054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15106121">Chen et al. (2004)</a> tested 19 genes within the ALS4 interval on 9q34 and detected 3 missense mutations (<a href="#0006">608465.0006</a>-<a href="#0008">608465.0008</a>) in the SETX gene. The observations of ALS4 suggested that mutations in SETX may cause neuronal degeneration through dysfunction of helicase activity or other steps in RNA processing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15106121" 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="#12" class="mim-tip-reference" title="Kannan, A., Cuartas, J., Gangwani, P., Branzei, D., Gangwani, L. <strong>Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4.</strong> Brain 145: 3072-3094, 2022.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35045161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35045161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35045161[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/brain/awab464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="35045161">Kannan et al. (2022)</a> found that the heterozygous L389S mutation in SETX disrupted interaction of SETX with ZPR1, leading to mislocalization of SETX and ZPR1 in ALS4 patient cells. ALS4 patient cells displayed reduced R-loop levels, because the SETX mutation altered the dynamic equilibrium of SETX dimers and caused disruption of SETX-ZPR1 complexes, likely resulting in partial impairment of the molecular brake leading to faster resolution (i.e., gain of function) and fewer R-loops in ALS4. Moreover, analysis with ALS4 patient fibroblasts revealed that SETX mutations decreased its in vivo association with R-loops. Modulation of ZPR1 levels regulated R-loop accumulation and rescued the pathogenic R-loop phenotype, suggesting that SETX and ZPR1 collaborate functionally to regulate R-loop resolution activity and that disruption of ZPR1-SETX complexes is the molecular basis for ALS4 pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=35045161" 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 3 seemingly unrelated families with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; <a href="/entry/606002">606002</a>), <a href="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al. (2004)</a> found homozygosity for a 4087C-T transition in the SETX gene, resulting in an arg1363-to-ter (R1363X) premature termination of the protein product. The 3 families originated from Portugal, Cabo Verde (once a Portuguese colony), and Spain, suggesting an Iberian founder event, although recurrent C-T changes on this CpG dinucleotide could not be formally excluded. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14770181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434377 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434377;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434377" 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=rs121434377" 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=RCV000002375" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002375" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002375</a>
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<p>In an Algerian family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; <a href="/entry/606002">606002</a>), <a href="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al. (2004)</a> found a homozygous 2602C-T transition in the SETX gene, which resulted in a gln868-to-stop (Q868X) protein truncation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14770181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28940290 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28940290;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/rs28940290?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=rs28940290" 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=rs28940290" 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=RCV000002376" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002376" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002376</a>
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<p>In a Japanese family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SETX; <a href="/entry/606002">606002</a>), <a href="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al. (2004)</a> found homozygosity for a 6638C-T transition in the SETX gene, resulting in a pro2213-to-leu (P2213L) amino acid substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14770181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776536 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776536;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776536" 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=rs587776536" 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=RCV000002377" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002377" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002377</a>
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<p>In a French family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; <a href="/entry/606002">606002</a>), <a href="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al. (2004)</a> identified compound heterozygous mutations in the SETX gene: a 5-bp deletion in exon 8, 2966_2970delGGAAA, causing a frameshift after Q988, and a 944C-T transition, resulting in an arg332-to-trp (R332W; <a href="#0005">608465.0005</a>) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14770181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs29001665 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs29001665;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/rs29001665?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=rs29001665" 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=rs29001665" 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=RCV000002378 OR RCV000269785 OR RCV004732526" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002378, RCV000269785, RCV004732526" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002378...</a>
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<p>For discussion of the arg332-to-trp (R332W) mutation in the SETX gene that was found in compound heterozygous state in affected members of a family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; <a href="/entry/606002">606002</a>) by <a href="#13" class="mim-tip-reference" title="Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others. <strong>Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2.</strong> Nature Genet. 36: 225-227, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>] [<a href="https://doi.org/10.1038/ng1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14770181">Moreira et al. (2004)</a>, see <a href="#0004">608465.0004</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14770181" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 AMYOTROPHIC LATERAL SCLEROSIS 4, JUVENILE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs29001584 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs29001584;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs29001584" 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=rs29001584" 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=RCV000002379 OR RCV000644828 OR RCV000724322 OR RCV000789615 OR RCV003233065" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002379, RCV000644828, RCV000724322, RCV000789615, RCV003233065" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002379...</a>
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<p>In the large Maryland family with an autosomal dominant form of juvenile amyotrophic lateral sclerosis described by <a href="#6" class="mim-tip-reference" title="Chance, P. F., Rabin, B. A., Ryan, S. G., Ding, Y., Scavina, M., Crain, B., Griffin, J. W., Cornblath, D. R. <strong>Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34.</strong> Am. J. Hum. Genet. 62: 633-640, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9497266/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9497266</a>] [<a href="https://doi.org/10.1086/301769" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9497266">Chance et al. (1998)</a> and others (ALS4; <a href="/entry/602433">602433</a>), <a href="#7" class="mim-tip-reference" title="Chen, Y.-Z., Bennett, C. L., Huynh, H. M., Blair, I. P., Puls, I., Irobi, J., Dierick, I., Abel, A., Kennerson, M. L., Rabin, B. A., Nicholson, G. A., Auer-Grumbach, M., Wagner, K., De Jonghe, P., Griffin, J. W., Fischbeck, K. H., Timmerman, V., Cornblath, D. R., Chance, P. F. <strong>DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).</strong> Am. J. Hum. Genet. 74: 1128-1135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15106121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15106121</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15106121[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/10.1086/421054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15106121">Chen et al. (2004)</a> found heterozygosity for a leu389-to-ser (L389S) substitution in senataxin that arose from a 1166T-C transition in the SETX gene. At the time of the report of <a href="#7" class="mim-tip-reference" title="Chen, Y.-Z., Bennett, C. L., Huynh, H. M., Blair, I. P., Puls, I., Irobi, J., Dierick, I., Abel, A., Kennerson, M. L., Rabin, B. A., Nicholson, G. A., Auer-Grumbach, M., Wagner, K., De Jonghe, P., Griffin, J. W., Fischbeck, K. H., Timmerman, V., Cornblath, D. R., Chance, P. F. <strong>DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).</strong> Am. J. Hum. Genet. 74: 1128-1135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15106121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15106121</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15106121[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/10.1086/421054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15106121">Chen et al. (2004)</a>, 55 members of this family were affected. Mean age at onset was 17 years. Approximately 10% of affected persons had minimal sensory impairment, usually limited to a slight elevation of vibratory threshold in middle-aged or elderly patients. Otherwise, affected persons had no overt clinical signs of sensory nerve impairment. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15106121+9497266" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0007 AMYOTROPHIC LATERAL SCLEROSIS 4, JUVENILE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28941475 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28941475;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs28941475" 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=rs28941475" 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=RCV000002380 OR RCV000414273 OR RCV000789614" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002380, RCV000414273, RCV000789614" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002380...</a>
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<p>In a family classified as having autosomal dominant juvenile amyotrophic lateral sclerosis-4 (ALS4; <a href="/entry/602433">602433</a>), <a href="#7" class="mim-tip-reference" title="Chen, Y.-Z., Bennett, C. L., Huynh, H. M., Blair, I. P., Puls, I., Irobi, J., Dierick, I., Abel, A., Kennerson, M. L., Rabin, B. A., Nicholson, G. A., Auer-Grumbach, M., Wagner, K., De Jonghe, P., Griffin, J. W., Fischbeck, K. H., Timmerman, V., Cornblath, D. R., Chance, P. F. <strong>DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).</strong> Am. J. Hum. Genet. 74: 1128-1135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15106121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15106121</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15106121[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/10.1086/421054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15106121">Chen et al. (2004)</a> found a heterozygous 8C-T transition in exon 3 of the SETX gene (exons 1 and 2 are noncoding) leading to a thr3-to-ile (T3I) substitution. The mean age of onset was 8 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15106121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 AMYOTROPHIC LATERAL SCLEROSIS 4, JUVENILE</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434378 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434378;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434378" 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=rs121434378" 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=RCV000002381 OR RCV000789616 OR RCV005051731" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002381, RCV000789616, RCV005051731" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002381...</a>
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<p>In a Belgian family, <a href="#7" class="mim-tip-reference" title="Chen, Y.-Z., Bennett, C. L., Huynh, H. M., Blair, I. P., Puls, I., Irobi, J., Dierick, I., Abel, A., Kennerson, M. L., Rabin, B. A., Nicholson, G. A., Auer-Grumbach, M., Wagner, K., De Jonghe, P., Griffin, J. W., Fischbeck, K. H., Timmerman, V., Cornblath, D. R., Chance, P. F. <strong>DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4).</strong> Am. J. Hum. Genet. 74: 1128-1135, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15106121/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15106121</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15106121[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/10.1086/421054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15106121">Chen et al. (2004)</a> found that autosomal dominant amyotrophic lateral sclerosis-4 (ALS4; <a href="/entry/602433">602433</a>) was associated with an arg2136-to-his (R2136H) substitution in the SETX gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15106121" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0009" class="mim-anchor"></a>
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<strong>.0009 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
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SETX, LEU1976ARG
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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> rs121434379 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434379;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/rs121434379?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=rs121434379" 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=rs121434379" 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=RCV000002382 OR RCV001781169" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002382, RCV001781169" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002382...</a>
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<p>In affected members of 7 unrelated French Canadian families with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; <a href="/entry/606002">606002</a>), <a href="#9" class="mim-tip-reference" title="Duquette, A., Roddier, K., McNabb-Baltar, J., Gosselin, I., St-Denis, A., Dicaire, M.-J., Loisel, L., Labuda, D., Marchand, L., Mathieu, J., Bouchard, J.-P., Brais, B. <strong>Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy.</strong> Ann. Neurol. 57: 408-414, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732101</a>] [<a href="https://doi.org/10.1002/ana.20408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732101">Duquette et al. (2005)</a> identified a homozygous 5927T-G transversion in the SETX gene, resulting in a leu1976-to-arg (L1976R) substitution in the helicase domain of the protein. Affected members from 3 additional families had the L1986R mutation in compound heterozygosity with another disease-causing SETX mutation. The carrier rate for the L1986R mutation was estimated at 3.5% for Quebecois of Anglo-Norman descent and 2.1% in the French Canadian population of Gaspesie. All patients had a similar phenotype characterized by progressive ataxia, distal amyotrophy, and sensory impairment, but without oculomotor apraxia as strictly defined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with SCAN2, <a href="#11" class="mim-tip-reference" title="Fogel, B. L., Perlman, S. <strong>Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2.</strong> Neurology 67: 2083-2084, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159128</a>] [<a href="https://doi.org/10.1212/01.wnl.0000247661.19601.28" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159128">Fogel and Perlman (2006)</a> identified compound heterozygosity for 2 mutations in the SETX gene: L1976R and L1977F (<a href="#0012">608465.0012</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0010" class="mim-anchor"></a>
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<strong>.0010 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
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SETX, ASN603ASP AND GLN653LYS
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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> rs116205032 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116205032;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/rs116205032?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=rs116205032" 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=rs116205032" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs116333061 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs116333061;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/rs116333061?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=rs116333061" 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=rs116333061" 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=RCV000002383 OR RCV000644848 OR RCV000644849 OR RCV001085644 OR RCV001541751 OR RCV001848883 OR RCV001848884 OR RCV003233660 OR RCV003233661 OR RCV003233662 OR RCV003233663" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002383, RCV000644848, RCV000644849, RCV001085644, RCV001541751, RCV001848883, RCV001848884, RCV003233660, RCV003233661, RCV003233662, RCV003233663" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002383...</a>
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<p>In an African American mother and daughter with a restricted form of autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; <a href="/entry/606002">606002</a>), <a href="#5" class="mim-tip-reference" title="Bassuk, A. G., Chen, Y. Z., Batish, S. D., Nagan, N., Opal, P., Chance, P. F., Bennett, C. L. <strong>In cis autosomal dominant mutation of senataxin associated with tremor/ataxia syndrome.</strong> Neurogenetics 8: 45-49, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17096168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17096168</a>] [<a href="https://doi.org/10.1007/s10048-006-0067-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17096168">Bassuk et al. (2007)</a> identified 2 mutations in cis in the SETX gene: a 1807A-G transition, resulting in an asn603-to-asp (N603D) substitution, and a 1957C-A transversion, resulting in a gln653-to-lys (Q653K) substitution. The mutations occurred in a region adjacent to a putative N-terminal protein interaction domain. Detailed analysis confirmed that the 2 mutations were on the same allele and were part of the same haplotype. Although both mother and daughter had frequent falls, oculomotor deficits, and tremor, neither had peripheral neuropathy or 'head thrusting' associated with horizontal gaze, both of which are classic findings in SCAN2. <a href="#5" class="mim-tip-reference" title="Bassuk, A. G., Chen, Y. Z., Batish, S. D., Nagan, N., Opal, P., Chance, P. F., Bennett, C. L. <strong>In cis autosomal dominant mutation of senataxin associated with tremor/ataxia syndrome.</strong> Neurogenetics 8: 45-49, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17096168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17096168</a>] [<a href="https://doi.org/10.1007/s10048-006-0067-8" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17096168">Bassuk et al. (2007)</a> postulated that the 2 mutations acted synergistically, leading to a dominant-negative mutant protein with partial function and an incomplete phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17096168" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0011" class="mim-anchor"></a>
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<strong>.0011 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
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SETX, MET274ILE AND ARG1294CYS
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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> rs267607044 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607044;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/rs267607044?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=rs267607044" 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=rs267607044" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div> <div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs997473183 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs997473183;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs997473183" 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=rs997473183" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 2 Japanese sibs, born of consanguineous parents, with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; <a href="/entry/606002">606002</a>), <a href="#4" class="mim-tip-reference" title="Asaka, T., Yokoji, H., Ito, J., Yamaguchi, K., Matsushima, A. <strong>Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX.</strong> Neurology 66: 1580-1581, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16717225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16717225</a>] [<a href="https://doi.org/10.1212/01.wnl.0000216135.59699.9b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16717225">Asaka et al. (2006)</a> identified homozygosity for 2 mutations in the SETX gene: met274-to-ile (M274I) and arg1294-to-cys (R1294C). Both had late-teenage onset of severe cerebellar ataxia with rapid progression, peripheral neuropathy, increased serum AFP, and distal muscle atrophy. Oculomotor apraxia was unclear. The mutations affected conserved residues and were not identified in 400 control chromosomes. Three unaffected sibs were heterozygous for the 2 mutations, and all had normal serum AFP. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16717225" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0012 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121434380 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434380;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/rs121434380?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=rs121434380" 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=rs121434380" 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=RCV000002385 OR RCV001288413 OR RCV003764517" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002385, RCV001288413, RCV003764517" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002385...</a>
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<p>In a 22-year-old man with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; <a href="/entry/606002">606002</a>), <a href="#11" class="mim-tip-reference" title="Fogel, B. L., Perlman, S. <strong>Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2.</strong> Neurology 67: 2083-2084, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159128</a>] [<a href="https://doi.org/10.1212/01.wnl.0000247661.19601.28" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17159128">Fogel and Perlman (2006)</a> identified compound heterozygosity for 2 mutations in the SETX gene: leu1977-to-phe (L1977F) and L1976R (<a href="#0009">608465.0009</a>). Both mutations lie in the conserved DNA/RNA helicase domain of the protein. The patient had onset of progressive gait and limb ataxia at age 16. Other features included oculomotor apraxia, dysarthria, axonal peripheral sensory neuropathy, and tremor. Each unaffected parent was heterozygous for 1 of the mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0013 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434381 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434381;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121434381" 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=rs121434381" 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=RCV000002386" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002386" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002386</a>
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<p>In 4 sibs, born of consanguineous Algerian parents, with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; <a href="/entry/606002">606002</a>), <a href="#2" class="mim-tip-reference" title="Anheim, M., Fleury, M.-C., Franques, J., Moreira, M.-C., Delaunoy, J.-P., Stoppa-Lyonnet, D., Koenig, M., Tranchant, C. <strong>Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families.</strong> Arch. Neurol. 65: 958-962, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18625865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18625865</a>] [<a href="https://doi.org/10.1001/archneur.65.7.958" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18625865">Anheim et al. (2008)</a> identified a homozygous 1027G-T transversion in exon 7 of the SETX gene, resulting in a glu343-to-ter (E343X) substitution. All had teenage onset of progressive cerebellar ataxia and areflexia. The unaffected parents were heterozygous for the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18625865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0014 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776537 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776537;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs587776537" 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=rs587776537" 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=RCV000002387 OR RCV000624514" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000002387, RCV000624514" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000002387...</a>
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<p>In 2 sisters with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; <a href="/entry/606002">606002</a>), who were born of consanguineous parents, <a href="#1" class="mim-tip-reference" title="Airoldi, G., Guidarelli, A., Cantoni, O., Panzeri, C., Vantaggiato, C., Bonato, S., Grazia D'Angelo, M., Falcone, S., De Palma, C., Tonelli, A., Crimella, C., Bondioni, S., Bresolin, N., Clementi, E., Bassi, M. T. <strong>Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin.</strong> Neurogenetics 11: 91-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19593598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19593598</a>] [<a href="https://doi.org/10.1007/s10048-009-0206-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19593598">Airoldi et al. (2010)</a> identified a homozygous 3-bp deletion (340_342delCTT) in the SETX gene, resulting in an in-frame deletion of leu144 (L144del) in an N-terminal region predicted to act as a protein-protein interaction domain. The deletion was outside of the putative helicase region. Both sisters had onset in their twenties of progressive cerebellar ataxia resulting in wheelchair-dependence in their forties. Other features included tremor, dysarthria, ocular motor deficits, and severe distal muscular atrophy. Studies of lymphoblastoid cells derived from the proband showed that the mutant protein was expressed, and that the cells were hypersensitive to DNA-damaging agents. The defect in DNA repair was corrected by silencing of the mutant protein. In contrast, cells from patients with complete lack of protein expression resulting from a nonsense mutation did not show enhanced sensitivity to DNA-damaging agents. <a href="#1" class="mim-tip-reference" title="Airoldi, G., Guidarelli, A., Cantoni, O., Panzeri, C., Vantaggiato, C., Bonato, S., Grazia D'Angelo, M., Falcone, S., De Palma, C., Tonelli, A., Crimella, C., Bondioni, S., Bresolin, N., Clementi, E., Bassi, M. T. <strong>Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin.</strong> Neurogenetics 11: 91-100, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19593598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19593598</a>] [<a href="https://doi.org/10.1007/s10048-009-0206-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19593598">Airoldi et al. (2010)</a> postulated that the L114del mutation caused abnormal interactions with other proteins involved in the response to oxidative damage, resulting in a toxic gain of function effect. The findings also suggested that the main function of the SETX protein is not to confer cellular protection against damage. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19593598" 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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Airoldi, G., Guidarelli, A., Cantoni, O., Panzeri, C., Vantaggiato, C., Bonato, S., Grazia D'Angelo, M., Falcone, S., De Palma, C., Tonelli, A., Crimella, C., Bondioni, S., Bresolin, N., Clementi, E., Bassi, M. T.
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<strong>Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin.</strong>
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Neurogenetics 11: 91-100, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19593598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19593598</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19593598" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families.</strong>
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Arch. Neurol. 65: 958-962, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18625865/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18625865</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18625865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s10048-008-0139-z" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000216135.59699.9b" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1007/s10048-006-0067-8" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/301769" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1086/421054" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0896-6273(00)80652-2" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732101</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ana.20408" target="_blank">Full Text</a>]
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<strong>Mutation of senataxin alters disease-specific transcriptional networks in patients with ataxia with oculomotor apraxia type 2.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24760770/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24760770</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24760770" 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/ddu190" target="_blank">Full Text</a>]
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<strong>Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17159128/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17159128</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17159128" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/01.wnl.0000247661.19601.28" target="_blank">Full Text</a>]
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Kannan, A., Cuartas, J., Gangwani, P., Branzei, D., Gangwani, L.
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<strong>Mutation in senataxin alters the mechanism of R-loop resolution in amyotrophic lateral sclerosis 4.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/35045161/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">35045161</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=35045161[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=35045161" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/brain/awab464" target="_blank">Full Text</a>]
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Moreira, M.-C., Klur, S., Watanabe, M., Nemeth, A. H., Le Ber, I., Moniz, J.-C., Tranchant, C., Aubourg, P., Tazir, M., Schols, L., Pandolfo, P., Schulz, J. B., and 22 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14770181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14770181</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14770181" 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/ng1303" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19515850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19515850</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19515850" 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/ddp278" target="_blank">Full Text</a>]
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<a id="Zhao2016" class="mim-anchor"></a>
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Zhao, D. Y., Gish, G., Braunschweig, U., Li, Y., Ni, Z., Schmitges, F. W., Zhong, G., Liu, K., Li, W., Moffat, J., Vedadi, M., Min, J., Pawson, T. J., Blencowe, B. J., Greenblatt, J. F.
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Nature 529: 48-53, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26700805/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26700805</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26700805" 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/nature16469" target="_blank">Full Text</a>]
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Bao Lige - updated : 03/01/2023
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Ada Hamosh - updated : 07/07/2016<br>Cassandra L. Kniffin - updated : 9/29/2014<br>George E. Tiller - updated : 7/7/2010<br>Cassandra L. Kniffin - updated : 3/1/2010<br>Cassandra L. Kniffin - updated : 10/28/2008<br>Cassandra L. Kniffin - updated : 10/16/2008<br>Cassandra L. Kniffin - updated : 11/6/2007<br>Cassandra L. Kniffin - updated : 8/7/2007<br>Cassandra L. Kniffin - updated : 2/27/2007<br>Cassandra L. Kniffin - updated : 5/11/2005<br>Victor A. McKusick - updated : 5/20/2004
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Victor A. McKusick : 2/13/2004
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carol : 04/16/2019<br>carol : 04/15/2019<br>carol : 10/18/2017<br>alopez : 07/07/2016<br>carol : 7/22/2015<br>mcolton : 7/21/2015<br>carol : 3/10/2015<br>carol : 9/29/2014<br>ckniffin : 9/29/2014<br>carol : 2/21/2014<br>carol : 2/19/2014<br>alopez : 7/20/2010<br>terry : 7/7/2010<br>wwang : 3/3/2010<br>ckniffin : 3/1/2010<br>wwang : 11/7/2008<br>ckniffin : 10/28/2008<br>wwang : 10/17/2008<br>ckniffin : 10/16/2008<br>wwang : 11/12/2007<br>ckniffin : 11/6/2007<br>wwang : 8/22/2007<br>ckniffin : 8/7/2007<br>ckniffin : 8/7/2007<br>wwang : 3/5/2007<br>ckniffin : 2/27/2007<br>tkritzer : 5/16/2005<br>ckniffin : 5/11/2005<br>alopez : 5/24/2004<br>terry : 5/20/2004<br>alopez : 3/1/2004<br>alopez : 2/16/2004<br>alopez : 2/13/2004<br>alopez : 2/13/2004
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</span>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 608465
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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SENATAXIN; SETX
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</span>
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</h3>
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</div>
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<br />
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: SETX</em></strong>
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</span>
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</p>
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</div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 725408001, 784341001;
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</span>
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</p>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 9q34.13
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Genomic coordinates <span class="small">(GRCh38)</span> : 9:132,261,356-132,356,744 </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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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</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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9q34.13
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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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Amyotrophic lateral sclerosis 4, juvenile
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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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602433
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</td>
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<td>
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<span class="mim-font">
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3
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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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Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
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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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606002
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal recessive
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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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</tr>
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</tbody>
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</table>
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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>SETX is an ATP-dependent helicase that is required for unwinding and resolution of RNA:DNA hybrids (R-loops) formed during transcription (Kannan et al., 2022). </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>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>By a positional cloning strategy, Moreira et al. (2004) identified the SETX gene within the interval on chromosome 9q34 associated with autosomal recessive spinocerebellar ataxia with axonal neuropathy (SCAN2; 606002), earlier referred to as ataxia-oculomotor apraxia-2 (AOA2). The predicted 2,677-amino acid protein contains at its C terminus a classic 7-motif domain found in the superfamily 1 of helicases. Moreira et al. (2004) named the gene 'senataxin' for its extensive homology to fungal Sen1p proteins. In Saccharomyces cerevisiae, Sen1p is involved in splicing and termination of tRNA, small nuclear RNA, and small nucleolar RNA, and has RNA helicase activity encoded by its C-terminal domain. Senataxin shares significant similarity with another helicase, IGHMBP2 (600502), which is mutant in spinal muscular atrophy with respiratory distress-1 (SMARD1, DSMA1; 604320), a disorder of motor neurons, and in mouse neuromuscular degeneration (Cox et al., 1998). Moreira et al. (2004) suggested that senataxin may have both RNA and DNA helicase activities and that senataxin acts in the DNA repair pathway, like several other proteins defective in autosomal recessive cerebellar ataxias. </p><p>Chen et al. (2004) determined that the SETX gene encodes a 302.8-kD protein. Northern blot analysis identified 2 prominent transcripts of 11.5 and 9.0 kb in all tissues examined, including brain and spinal cord. SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 (601430) and IGHMBP2 (600502), 2 genes that encode proteins known to have roles in RNA processing. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Moreira et al. (2004) determined that the SETX gene contains 24 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Suraweera et al. (2009) identified novel senataxin-interacting proteins, the majority of which are involved in transcription and RNA processing, including RNA polymerase II (see POLR2A, 180660). Binding of RNA polymerase II to candidate genes was significantly reduced in senataxin-deficient cells, accompanied by decreased transcription of these genes, thus suggesting a role for senataxin in the regulation/modulation of transcription. RNA polymerase II-dependent transcription termination was defective in cells depleted of senataxin, in keeping with the observed interaction of senataxin with poly(A) binding proteins 1 (PABP1; 604679) and 2 (PABP2; 602279). Splicing efficiency of specific mRNAs and alternate splice site selection of both endogenous genes and artificial minigenes were altered in senataxin-depleted cells. Suraweera et al. (2009) suggested that senataxin, similar to its yeast homolog Sen1p, may play a role in coordinating transcriptional events, in addition to its role in DNA repair. </p><p>Zhao et al. (2016) showed that a carboxy-terminal domain (CTD) arginine (R1810 in human) that is conserved across vertebrates is symmetrically dimethylated (me2s). This R1810me2s modification requires PRMT5 (604045) and recruits the Tudor domain of SMN (600354). SMN interacts with senataxin. Because POLR2A R1810me2s and SMN, like senataxin, are required for resolving RNA-DNA hybrids created by RNA polymerase II that form R-loops in transcription termination regions, Zhao et al. (2016) proposed that R1810me2s, SMN, and senataxin are components of an R-loop resolution pathway. </p><p>By immunoprecipitation analysis in HeLa cells, Kannan et al. (2022) showed that ZPR1 (603901) interacted with SETX. ZPR1 also bound to R-loops to facilitate SETX recruitment for the formation of an R-loop resolution complex (RLRC) during transcription. ZPR1 colocalized with SETX in nuclear bodies in HeLa cells, and knockdown of ZPR1 resulted in downregulation of SETX and accumulation of R-loops, indicating that ZPR1 was critical for R-loop resolution. Moreover, knockdown of SETX caused disruption of ZPR1-positive subnuclear bodies, gems, and Cajal bodies and accumulation of R-loops, indicating a functional contribution of SETX in ZPR1-dependent resolution of R-loops. Analysis with fibroblasts from patients with spinal muscular atrophy (SMA; 253300) revealed that chronic low levels of ZPR1 caused defects in RLRC assembly, which resulted in inefficient R-loop resolution and accumulation of pathogenic R-loops and DNA damage, leading to genomic instability and neurodegeneration. In contrast, ZPR1 overexpression rescued defective RLRC assembly and prevented pathogenic R-loop accumulation in SMA patient cells in vitro, and Zpr1 overexpression rescued DNA damage associated with R-loop accumulation and prevented degeneration of motor neurons in SMA mice in vivo. Further analysis of SETX mutations in ALS4 (602433) patient cells (see MOLECULAR GENETICS) confirmed that SETX and ZPR1 collaborate functionally to regulate R-loop resolution activity. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The SETX gene lies within the 9q34 region linked to ataxia-oculomotor apraxia-2 (Moreira et al., 2004). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Autosomal Recessive Spinocerebellar Ataxia with Axonal Neuropathy</em></strong></p><p>
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Moreira et al. (2004) sequenced exons 1 through 18 of the SETX gene and flanking intronic sequences in families with ataxia linked to the 9q34 region and in additional individuals with either ataxia-oculomotor apraxia or ataxia with elevated levels of alpha-fetoprotein (SCAN2; 606002) and found 15 different disease-associated mutations in 15 families. </p><p>In affected members of 10 French Canadian families with ataxia, distal amyotrophy, and peripheral neuropathy, Duquette et al. (2005) identified mutations in the SETX gene. A founder mutation, leu1976 to arg (L1976R; 606465.0009), was identified in all families. </p><p>Fogel and Perlman (2006) identified 6 SETX mutations, including 5 novel mutations (see, e.g., 606465.0012), in 3 unrelated patients with ataxia-oculomotor apraxia-2. Three of the mutations were in the DNA/RNA helicase functional domain, illustrating the importance of this region to the pathogenesis of the disorder. </p><p>Arning et al. (2008) reported a patient with ataxia-oculomotor apraxia-2 who was found to be compound heterozygous for a point mutation in the SETX gene and a large out-of-frame tandem duplication encompassing exons 7 through 10 of the SETX gene. The duplication occurred by unequal homologous recombination between AluY sequences. The authors suggested that gross deletions or duplications in the SETX gene may be an underestimated cause of the disorder. </p><p>Airoldi et al. (2010) identified a homozygous in-frame deletion of leu144 in the SETX gene (L144del; 608465.0014) in 2 sisters with ataxia-oculumotor apraxia-2 The deletion affected an N-terminal region predicted to act as a protein-protein interaction domain. Studies of lymphoblastoid cells derived from the proband showed that the mutant protein was expressed, and that the cells were hypersensitive to DNA-damaging agents. The defect in DNA repair was corrected by silencing of the mutant protein. In contrast, cells from patients with complete lack of protein expression resulting from a nonsense mutation did not show enhanced sensitivity to DNA-damaging agents. Airoldi et al. (2010) postulated that the L114del mutation caused abnormal interactions with other proteins involved in the response to oxidative damage, resulting in a toxic gain of function effect. The findings also suggested that the main function of the SETX protein is not to confer cellular protection against damage. </p><p>By gene expression profiling of fibroblasts derived from a patient with ataxia-oculomotor apraxia-2 and an unaffected heterozygous carrier, Fogel et al. (2014) identified a core set of genes with altered expression levels in the patient, including genes involved in neurogenesis, cell proliferation, and synaptic transmission. Overexpression of an AOA2-associated mutation (L1976R; 608465.0009) and an ALS4-associated mutation (R2136H; 608465.0008) resulted in differential gene expression patterns, suggesting that disease-specific mutations cause differential transcriptional changes within cells. However, there were some modules of overlap involving aspects of RNA processing, DNA maintenance, and transcription. The findings identified novel genes and cellular pathways related to senataxin function. </p><p><strong><em>Juvenile Amyotrophic Lateral Sclerosis 4</em></strong></p><p>
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Juvenile amyotrophic lateral sclerosis (ALS4; 602433) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Chen et al. (2004) tested 19 genes within the ALS4 interval on 9q34 and detected 3 missense mutations (608465.0006-608465.0008) in the SETX gene. The observations of ALS4 suggested that mutations in SETX may cause neuronal degeneration through dysfunction of helicase activity or other steps in RNA processing. </p><p>Kannan et al. (2022) found that the heterozygous L389S mutation in SETX disrupted interaction of SETX with ZPR1, leading to mislocalization of SETX and ZPR1 in ALS4 patient cells. ALS4 patient cells displayed reduced R-loop levels, because the SETX mutation altered the dynamic equilibrium of SETX dimers and caused disruption of SETX-ZPR1 complexes, likely resulting in partial impairment of the molecular brake leading to faster resolution (i.e., gain of function) and fewer R-loops in ALS4. Moreover, analysis with ALS4 patient fibroblasts revealed that SETX mutations decreased its in vivo association with R-loops. Modulation of ZPR1 levels regulated R-loop accumulation and rescued the pathogenic R-loop phenotype, suggesting that SETX and ZPR1 collaborate functionally to regulate R-loop resolution activity and that disruption of ZPR1-SETX complexes is the molecular basis for ALS4 pathogenesis. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>14 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</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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SETX, ARG1363TER
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<br />
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SNP: rs121434376,
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gnomAD: rs121434376,
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ClinVar: RCV000002374, RCV000622386, RCV002247241, RCV004732525
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 seemingly unrelated families with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Moreira et al. (2004) found homozygosity for a 4087C-T transition in the SETX gene, resulting in an arg1363-to-ter (R1363X) premature termination of the protein product. The 3 families originated from Portugal, Cabo Verde (once a Portuguese colony), and Spain, suggesting an Iberian founder event, although recurrent C-T changes on this CpG dinucleotide could not be formally excluded. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</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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SETX, GLN868TER
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<br />
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SNP: rs121434377,
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ClinVar: RCV000002375
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an Algerian family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Moreira et al. (2004) found a homozygous 2602C-T transition in the SETX gene, which resulted in a gln868-to-stop (Q868X) protein truncation. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</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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SETX, PRO2213LEU
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<br />
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SNP: rs28940290,
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gnomAD: rs28940290,
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ClinVar: RCV000002376
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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 recessive spinocerebellar ataxia with axonal neuropathy-2 (SETX; 606002), Moreira et al. (2004) found homozygosity for a 6638C-T transition in the SETX gene, resulting in a pro2213-to-leu (P2213L) amino acid substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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|
<strong>.0004 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</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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SETX, 5-BP DEL, NT2966
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|
<br />
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|
SNP: rs587776536,
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ClinVar: RCV000002377
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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 French family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Moreira et al. (2004) identified compound heterozygous mutations in the SETX gene: a 5-bp deletion in exon 8, 2966_2970delGGAAA, causing a frameshift after Q988, and a 944C-T transition, resulting in an arg332-to-trp (R332W; 608465.0005) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0005 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</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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SETX, ARG332TRP
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<br />
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SNP: rs29001665,
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gnomAD: rs29001665,
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ClinVar: RCV000002378, RCV000269785, RCV004732526
|
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>For discussion of the arg332-to-trp (R332W) mutation in the SETX gene that was found in compound heterozygous state in affected members of a family with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002) by Moreira et al. (2004), see 608465.0004. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 AMYOTROPHIC LATERAL SCLEROSIS 4, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
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|
SETX, LEU389SER
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<br />
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|
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|
SNP: rs29001584,
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|
ClinVar: RCV000002379, RCV000644828, RCV000724322, RCV000789615, RCV003233065
|
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|
|
</span>
|
|
</div>
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<div>
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|
<span class="mim-text-font">
|
|
<p>In the large Maryland family with an autosomal dominant form of juvenile amyotrophic lateral sclerosis described by Chance et al. (1998) and others (ALS4; 602433), Chen et al. (2004) found heterozygosity for a leu389-to-ser (L389S) substitution in senataxin that arose from a 1166T-C transition in the SETX gene. At the time of the report of Chen et al. (2004), 55 members of this family were affected. Mean age at onset was 17 years. Approximately 10% of affected persons had minimal sensory impairment, usually limited to a slight elevation of vibratory threshold in middle-aged or elderly patients. Otherwise, affected persons had no overt clinical signs of sensory nerve impairment. </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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 AMYOTROPHIC LATERAL SCLEROSIS 4, JUVENILE</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
|
SETX, THR3ILE
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|
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<br />
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|
|
SNP: rs28941475,
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|
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|
|
ClinVar: RCV000002380, RCV000414273, RCV000789614
|
|
|
|
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a family classified as having autosomal dominant juvenile amyotrophic lateral sclerosis-4 (ALS4; 602433), Chen et al. (2004) found a heterozygous 8C-T transition in exon 3 of the SETX gene (exons 1 and 2 are noncoding) leading to a thr3-to-ile (T3I) substitution. The mean age of onset was 8 years. </p>
|
|
</span>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
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|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 AMYOTROPHIC LATERAL SCLEROSIS 4, JUVENILE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
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|
|
|
SETX, ARG2136HIS
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|
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|
|
|
<br />
|
|
|
|
SNP: rs121434378,
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|
|
|
|
|
|
|
ClinVar: RCV000002381, RCV000789616, RCV005051731
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a Belgian family, Chen et al. (2004) found that autosomal dominant amyotrophic lateral sclerosis-4 (ALS4; 602433) was associated with an arg2136-to-his (R2136H) substitution in the SETX gene. </p>
|
|
</span>
|
|
</div>
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SETX, LEU1976ARG
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121434379,
|
|
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|
|
|
gnomAD: rs121434379,
|
|
|
|
|
|
ClinVar: RCV000002382, RCV001781169
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of 7 unrelated French Canadian families with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Duquette et al. (2005) identified a homozygous 5927T-G transversion in the SETX gene, resulting in a leu1976-to-arg (L1976R) substitution in the helicase domain of the protein. Affected members from 3 additional families had the L1986R mutation in compound heterozygosity with another disease-causing SETX mutation. The carrier rate for the L1986R mutation was estimated at 3.5% for Quebecois of Anglo-Norman descent and 2.1% in the French Canadian population of Gaspesie. All patients had a similar phenotype characterized by progressive ataxia, distal amyotrophy, and sensory impairment, but without oculomotor apraxia as strictly defined. </p><p>In a patient with SCAN2, Fogel and Perlman (2006) identified compound heterozygosity for 2 mutations in the SETX gene: L1976R and L1977F (608465.0012). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SETX, ASN603ASP AND GLN653LYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs116205032, rs116333061,
|
|
|
|
|
|
gnomAD: rs116205032, rs116333061,
|
|
|
|
|
|
ClinVar: RCV000002383, RCV000644848, RCV000644849, RCV001085644, RCV001541751, RCV001848883, RCV001848884, RCV003233660, RCV003233661, RCV003233662, RCV003233663
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an African American mother and daughter with a restricted form of autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Bassuk et al. (2007) identified 2 mutations in cis in the SETX gene: a 1807A-G transition, resulting in an asn603-to-asp (N603D) substitution, and a 1957C-A transversion, resulting in a gln653-to-lys (Q653K) substitution. The mutations occurred in a region adjacent to a putative N-terminal protein interaction domain. Detailed analysis confirmed that the 2 mutations were on the same allele and were part of the same haplotype. Although both mother and daughter had frequent falls, oculomotor deficits, and tremor, neither had peripheral neuropathy or 'head thrusting' associated with horizontal gaze, both of which are classic findings in SCAN2. Bassuk et al. (2007) postulated that the 2 mutations acted synergistically, leading to a dominant-negative mutant protein with partial function and an incomplete phenotype. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SETX, MET274ILE AND ARG1294CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607044, rs997473183,
|
|
|
|
|
|
gnomAD: rs267607044,
|
|
|
|
|
|
ClinVar: RCV000002384, RCV000790202, RCV001755758
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 Japanese sibs, born of consanguineous parents, with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Asaka et al. (2006) identified homozygosity for 2 mutations in the SETX gene: met274-to-ile (M274I) and arg1294-to-cys (R1294C). Both had late-teenage onset of severe cerebellar ataxia with rapid progression, peripheral neuropathy, increased serum AFP, and distal muscle atrophy. Oculomotor apraxia was unclear. The mutations affected conserved residues and were not identified in 400 control chromosomes. Three unaffected sibs were heterozygous for the 2 mutations, and all had normal serum AFP. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SETX, LEU1977PHE
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121434380,
|
|
|
|
|
|
gnomAD: rs121434380,
|
|
|
|
|
|
ClinVar: RCV000002385, RCV001288413, RCV003764517
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 22-year-old man with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Fogel and Perlman (2006) identified compound heterozygosity for 2 mutations in the SETX gene: leu1977-to-phe (L1977F) and L1976R (608465.0009). Both mutations lie in the conserved DNA/RNA helicase domain of the protein. The patient had onset of progressive gait and limb ataxia at age 16. Other features included oculomotor apraxia, dysarthria, axonal peripheral sensory neuropathy, and tremor. Each unaffected parent was heterozygous for 1 of the mutations. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SETX, GLU343TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121434381,
|
|
|
|
|
|
|
|
ClinVar: RCV000002386
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 4 sibs, born of consanguineous Algerian parents, with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), Anheim et al. (2008) identified a homozygous 1027G-T transversion in exon 7 of the SETX gene, resulting in a glu343-to-ter (E343X) substitution. All had teenage onset of progressive cerebellar ataxia and areflexia. The unaffected parents were heterozygous for the mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 SPINOCEREBELLAR ATAXIA, AUTOSOMAL RECESSIVE, WITH AXONAL NEUROPATHY 2</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
SETX, 3-BP DEL, 340CTT
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776537,
|
|
|
|
|
|
|
|
ClinVar: RCV000002387, RCV000624514
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 sisters with autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2; 606002), who were born of consanguineous parents, Airoldi et al. (2010) identified a homozygous 3-bp deletion (340_342delCTT) in the SETX gene, resulting in an in-frame deletion of leu144 (L144del) in an N-terminal region predicted to act as a protein-protein interaction domain. The deletion was outside of the putative helicase region. Both sisters had onset in their twenties of progressive cerebellar ataxia resulting in wheelchair-dependence in their forties. Other features included tremor, dysarthria, ocular motor deficits, and severe distal muscular atrophy. Studies of lymphoblastoid cells derived from the proband showed that the mutant protein was expressed, and that the cells were hypersensitive to DNA-damaging agents. The defect in DNA repair was corrected by silencing of the mutant protein. In contrast, cells from patients with complete lack of protein expression resulting from a nonsense mutation did not show enhanced sensitivity to DNA-damaging agents. Airoldi et al. (2010) postulated that the L114del mutation caused abnormal interactions with other proteins involved in the response to oxidative damage, resulting in a toxic gain of function effect. The findings also suggested that the main function of the SETX protein is not to confer cellular protection against damage. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Airoldi, G., Guidarelli, A., Cantoni, O., Panzeri, C., Vantaggiato, C., Bonato, S., Grazia D'Angelo, M., Falcone, S., De Palma, C., Tonelli, A., Crimella, C., Bondioni, S., Bresolin, N., Clementi, E., Bassi, M. T.
|
|
<strong>Characterization of two novel SETX mutations in AOA2 patients reveals aspects of the pathophysiological role of senataxin.</strong>
|
|
Neurogenetics 11: 91-100, 2010.
|
|
|
|
|
|
[PubMed: 19593598]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s10048-009-0206-0]
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Anheim, M., Fleury, M.-C., Franques, J., Moreira, M.-C., Delaunoy, J.-P., Stoppa-Lyonnet, D., Koenig, M., Tranchant, C.
|
|
<strong>Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families.</strong>
|
|
Arch. Neurol. 65: 958-962, 2008.
|
|
|
|
|
|
[PubMed: 18625865]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1001/archneur.65.7.958]
|
|
|
|
|
|
</p>
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