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Entry
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- *601517 - ATAXIN 2; ATXN2
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- OMIM
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<p>
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<span class="h4">*601517</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#animalModel">Animal Model</a>
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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/601517">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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<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-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=ENSG00000204842;t=ENST00000673436" 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=6311" 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=601517" 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 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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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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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=ENSG00000204842;t=ENST00000673436" 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_001310121,NM_001310123,NM_001372574,NM_002973,NR_132311" 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_001372574" 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=601517" 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=03307&isoform_id=03307_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/ATXN2" 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/1679684,1770390,34536073,85057074,90112010,119618363,119618364,119618365,119618366,209980583,209980585,209980587,209980589,209980591,209980599,209980601,209980603,209980605,209980607,215273941,858437822,858437832,1622996232,1734272048" 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/Q99700" 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=6311" 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=ENSG00000204842;t=ENST00000673436" 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=ATXN2" 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=ATXN2" 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+6311" 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/ATXN2" 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:6311" 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/6311" 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=chr12&hgg_gene=ENST00000673436.1&hgg_start=111452214&hgg_end=111599673&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 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:10555" 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/atxn2" 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=601517[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=601517[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/ATXN2/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/ENSG00000204842" 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=ATXN2" 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=ATXN2" 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=ATXN2" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ATXN2&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/PA34968" 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:10555" 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/FBgn0041188.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:1277223" 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/ATXN2#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:1277223" 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/6311/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=6311" 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=WBGene00000231;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-060526-217" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
|
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</a>
|
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</span>
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</span>
|
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:6311" 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=ATXN2&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> 715751004<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
601517
|
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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>
|
|
<span class="mim-font">
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ATAXIN 2; ATXN2
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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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ATXN2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ATXN2</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/12/813?start=-3&limit=10&highlight=813">12q24.12</a>
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:111452214-111599673&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'})">12:111,452,214-111,599,673</a> </span>
|
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</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=183090,168600,183090" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/813?start=-3&limit=10&highlight=813">
|
|
12q24.12
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Amyotrophic lateral sclerosis, susceptibility to, 13}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/183090"> 183090 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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|
|
</span>
|
|
</td>
|
|
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</tr>
|
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|
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
{Parkinson disease, late-onset, susceptibility to}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/168600"> 168600 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Multifactorial">Mu</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia 2
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/183090"> 183090 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
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<p>Ataxin-2, the protein encoded by the ATXN2 gene, contains a polyglutamine tract, long expansions (greater than 33 repeats) of which result in spinocerebellar ataxia-2 (SCA2; <a href="/entry/183090">183090</a>), an autosomal dominant form of olivopontocerebellar atrophy. Intermediate-length expansions (27-33 glutamines) contribute to susceptibility to amyotrophic lateral sclerosis (ALS13; see <a href="/entry/183090">183090</a>).</p>
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<p>Using a monoclonal antibody that recognizes expanded polyglutamine stretches in TATA box-binding protein (<a href="/entry/600075">600075</a>), mutant huntingtin (<a href="/entry/613004">613004</a>), mutant ataxin-1 (<a href="/entry/164400">164400</a>), and glutamine expanded proteins in patients with SCA3 (<a href="/entry/109150">109150</a>), <a href="#31" class="mim-tip-reference" title="Trottier, Y., Lutz, Y., Stevanin, G., Imbert, G., Devys, D., Cancel, G., Saudou, F., Weber, C., David, G., Tora, L., Agid, Y., Brice, A., Mandel, J.-L. <strong>Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias.</strong> Nature 378: 403-406, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7477379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7477379</a>] [<a href="https://doi.org/10.1038/378403a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7477379">Trottier et al. (1995)</a> used Western blotting to detect a 150-kD protein in a patient with SCA2, but not his normal relative. By analogy to other disorders associated with anticipation in expanded triplet repeats, they suggested that this may be the protein encoded by the mutant gene responsible for this disorder. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7477379" 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="#23" class="mim-tip-reference" title="Pulst, S.-M., Nechiporuk, A., Nechiporuk, T., Gispert, S., Chen, X.-N., Lopes-Cendes, I., Pearlman, S., Starkman, S., Orozco-Diaz, G., Lunkes, A., DeJong, P., Rouleau, G. A., Auburger, G., Korenberg, J. R., Figueroa, C., Sahba, S. <strong>Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2.</strong> Nature Genet. 14: 269-276, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896555</a>] [<a href="https://doi.org/10.1038/ng1196-269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896555">Pulst et al. (1996)</a> isolated the ATXN2 gene through a positional cloning approach. They assembled a 1.1-Mb contig in the 12q24.1 region where the disease SCA2 had been mapped, and then identified a genomic clone that contained CAG repeats. By screening human adult and human fetal brain libraries, <a href="#23" class="mim-tip-reference" title="Pulst, S.-M., Nechiporuk, A., Nechiporuk, T., Gispert, S., Chen, X.-N., Lopes-Cendes, I., Pearlman, S., Starkman, S., Orozco-Diaz, G., Lunkes, A., DeJong, P., Rouleau, G. A., Auburger, G., Korenberg, J. R., Figueroa, C., Sahba, S. <strong>Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2.</strong> Nature Genet. 14: 269-276, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896555</a>] [<a href="https://doi.org/10.1038/ng1196-269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896555">Pulst et al. (1996)</a> identified a cDNA clone with a 3,936-kb open reading frame (ORF) that encodes a 1,312-amino acid polypeptide with a molecular mass of 140 kD. The (CAG)n repeat (<a href="#0001">601517.0001</a>) is located in the 5-prime end of the coding region of the ATXN2 gene, which they also referred to as the ataxin-2 gene. The ataxin-2 gene showed no homology with genes of known function. ATXN2 did, however, show homology with cDNAs in an EST database, and <a href="#23" class="mim-tip-reference" title="Pulst, S.-M., Nechiporuk, A., Nechiporuk, T., Gispert, S., Chen, X.-N., Lopes-Cendes, I., Pearlman, S., Starkman, S., Orozco-Diaz, G., Lunkes, A., DeJong, P., Rouleau, G. A., Auburger, G., Korenberg, J. R., Figueroa, C., Sahba, S. <strong>Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2.</strong> Nature Genet. 14: 269-276, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896555</a>] [<a href="https://doi.org/10.1038/ng1196-269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896555">Pulst et al. (1996)</a> cloned a related human cDNA they called ataxin-2-related protein (A2RP; GenBank <a href="https://www.ncbi.nlm.nih.gov/search/all/?term=U70671" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'GENBANK\', \'domain\': \'ncbi.nlm.nih.gov\'})">U70671</a>) and a cDNA for a mouse gene homologous to ATXN2. These 2 genes, however, lacked the polyglutamine repeat region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Sanpei, K., Takano, H., Igarashi, S., Sato, T., Oyake, M., Sasaki, H., Wakisaka, A., Tashiro, K., Ishida, Y., Ikeuchi, T., Koide, R., Saito, M., Sato, A., Tanaka, T., Hanyu, S., Takiyama, Y., Nishizawa, M., Shimizu, N., Nomura, Y., Segawa, M., Iwabuchi, K., Eguchi, I., Tanaka, H., Takahashi, H., Tsuji, S. <strong>Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT.</strong> Nature Genet. 14: 277-284, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896556</a>] [<a href="https://doi.org/10.1038/ng1196-277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896556">Sanpei et al. (1996)</a> devised a novel strategy for identification of triplet-repeat expansion genes referred to by them as DIRECT (direct identification of repeat expansion and cloning technique). This technique involved preparation of a probe with high specific radioactivity by PCR internal labeling, preparation of single-stranded probe, and detection of disease-specific expanded repeats by Southern blot hybridization under stringent conditions, followed by cloning of the genomic segment containing the pathologically expanded repeat. <a href="#27" class="mim-tip-reference" title="Sanpei, K., Takano, H., Igarashi, S., Sato, T., Oyake, M., Sasaki, H., Wakisaka, A., Tashiro, K., Ishida, Y., Ikeuchi, T., Koide, R., Saito, M., Sato, A., Tanaka, T., Hanyu, S., Takiyama, Y., Nishizawa, M., Shimizu, N., Nomura, Y., Segawa, M., Iwabuchi, K., Eguchi, I., Tanaka, H., Takahashi, H., Tsuji, S. <strong>Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT.</strong> Nature Genet. 14: 277-284, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896556</a>] [<a href="https://doi.org/10.1038/ng1196-277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896556">Sanpei et al. (1996)</a> applied this technique to the identification of expanded repeats in patients with SCA2. Southern blots of genomic DNA digested with TspEI revealed a 2.5-kb fragment which was absent from normal individuals. A genomic clone containing the expanded (CAG)n repeat was isolated and sequenced, and was predicted to encode a 1,313-amino acid polypeptide with a molecular mass of 140 kD, referred to as ataxin-2. Northern blot analysis with ataxin-2 gene sequences revealed a 4.7-kb transcript which was expressed in brain, heart, liver, muscle, pancreas, and placenta. <a href="#27" class="mim-tip-reference" title="Sanpei, K., Takano, H., Igarashi, S., Sato, T., Oyake, M., Sasaki, H., Wakisaka, A., Tashiro, K., Ishida, Y., Ikeuchi, T., Koide, R., Saito, M., Sato, A., Tanaka, T., Hanyu, S., Takiyama, Y., Nishizawa, M., Shimizu, N., Nomura, Y., Segawa, M., Iwabuchi, K., Eguchi, I., Tanaka, H., Takahashi, H., Tsuji, S. <strong>Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT.</strong> Nature Genet. 14: 277-284, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896556</a>] [<a href="https://doi.org/10.1038/ng1196-277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896556">Sanpei et al. (1996)</a> noted that there was another ATG codon 120 codons downstream of the first ATG codon and that if this was a functional initiation site, the smaller transcript would result in a predicted 124-kD polypeptide. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The gene encoding the protein that is mutant in SCA2 was also cloned by <a href="#17" class="mim-tip-reference" title="Imbert, G., Saudou, F., Yvert, G., Devys, D., Trottier, Y., Garnier, J.-M., Weber, C., Mandel, J.-L., Cancel, G., Abbas, N., Durr, A., Didierjean, O., Stevanin, G., Agid, Y., Brice, A. <strong>Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats.</strong> Nature Genet. 14: 285-291, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896557</a>] [<a href="https://doi.org/10.1038/ng1196-285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896557">Imbert et al. (1996)</a>, who screened cDNA expression libraries with an antibody specific for polyglutamine repeats. They identified 6 unreported (CAG)n repeat expansion-containing genes and designed primers from the DNA region flanking the gene associated with SCA2 patients. One genomic clone they isolated (DAN1), which corresponded to ATXN2, was fully sequenced and was found to contain a 2,745-bp ORF, a 243-bp untranslated region, and a GC-rich upstream sequence. They found a putative internal poly(A) site and presented amino acid sequences from 2 reading frames of the 2,745-bp ORF that may be related by ribosomal frameshifting. A 2.5-kb fragment of the DAN1 clone was used to probe Northern blots, from which they detected ubiquitous expression in brain, heart, skeletal muscle, and placenta. They also summarized their findings on the (CAG)n and (CAA)n repeats identified in both normal and affected individuals (see <a href="#0001">601517.0001</a>). From zoo blot analysis they found that the gene was highly conserved in 5 different mammalian species and in chicken. <a href="#17" class="mim-tip-reference" title="Imbert, G., Saudou, F., Yvert, G., Devys, D., Trottier, Y., Garnier, J.-M., Weber, C., Mandel, J.-L., Cancel, G., Abbas, N., Durr, A., Didierjean, O., Stevanin, G., Agid, Y., Brice, A. <strong>Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats.</strong> Nature Genet. 14: 285-291, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896557</a>] [<a href="https://doi.org/10.1038/ng1196-285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896557">Imbert et al. (1996)</a> reported that ATXN2 mutant protein is cytoplasmic in location and has an apparent molecular weight of 150 kD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896557" 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="#22" class="mim-tip-reference" title="Nechiporuk, T., Huynh, D. P., Figueroa, K., Sahba, S., Nechiporuk, A., Pulst, S.-M. <strong>The mouse SCA2 gene: cDNA sequence, alternative splicing and protein expression.</strong> Hum. Molec. Genet. 7: 1301-1309, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9668173/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9668173</a>] [<a href="https://doi.org/10.1093/hmg/7.8.1301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9668173">Nechiporuk et al. (1998)</a> isolated and characterized the mouse homolog of the ATXN2 gene. Sequence and amino acid analyses revealed 89% and 91% identity at the nucleotide and amino acid level, respectively. However, there was no extended polyglutamine tract in the mouse Sca2 cDNA, suggesting that the normal function of ATXN2 is not dependent on this domain. Northern blot analysis of mouse tissues indicated that the mouse gene is expressed in most tissues, but at varying levels. Alternative splicing seen in human ATXN2 was conserved in the mouse. By Northern blot analysis, ATXN2 was found to be expressed during embryogenesis as early as day 8 of gestation. Immunohistochemical staining using affinity-purified antibodies demonstrated that ataxin-2 is expressed in the cytoplasm of Purkinje cells as well as in other neurons of the CNS. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9668173" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By RT-PCR of human peripheral blood lymphocyte total RNA, <a href="#1" class="mim-tip-reference" title="Affaitati, A., de Cristofaro, T., Feliciello, A., Varrone, S. <strong>Identification of alternative splicing of spinocerebellar ataxia type 2 gene.</strong> Gene 267: 89-93, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11311558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11311558</a>] [<a href="https://doi.org/10.1016/s0378-1119(01)00402-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11311558">Affaitati et al. (2001)</a> cloned an ATXN21 splice variant lacking exon 21. In this variant, which the authors called ATXN2 type IV, exon 20 is spliced in-frame to exon 22, resulting in a deduced protein of 1,294 amino acids. RT-PCR detected both full-length ATXN2 and ATXN2 type IV in human brain, spinal cord, cerebellum, heart, and placenta. Both variants were also detected in mouse brain, heart, and liver, as well as in all stages of mouse development examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11311558" 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 genomic sequence analysis, <a href="#26" class="mim-tip-reference" title="Sahba, S., Nechiporuk, A., Figueroa, K. P., Nechiporuk, T., Pulst, S.-M. <strong>Genomic structure of the human gene for spinocerebellar ataxia type 2 (SCA2) on chromosome 12q24.1.</strong> Genomics 47: 359-364, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9480749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9480749</a>] [<a href="https://doi.org/10.1006/geno.1997.5131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9480749">Sahba et al. (1998)</a> determined that the ATXN2 gene contains 25 exons and spans approximately 130 kb. Exon sizes range from 37 to 890 bp. The CAG repeat is in exon 1. <a href="#26" class="mim-tip-reference" title="Sahba, S., Nechiporuk, A., Figueroa, K. P., Nechiporuk, T., Pulst, S.-M. <strong>Genomic structure of the human gene for spinocerebellar ataxia type 2 (SCA2) on chromosome 12q24.1.</strong> Genomics 47: 359-364, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9480749/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9480749</a>] [<a href="https://doi.org/10.1006/geno.1997.5131" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9480749">Sahba et al. (1998)</a> also identified an isoform resulting from alternative splicing in exon 10, predicted to encode a protein truncated by 70 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9480749" 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="#27" class="mim-tip-reference" title="Sanpei, K., Takano, H., Igarashi, S., Sato, T., Oyake, M., Sasaki, H., Wakisaka, A., Tashiro, K., Ishida, Y., Ikeuchi, T., Koide, R., Saito, M., Sato, A., Tanaka, T., Hanyu, S., Takiyama, Y., Nishizawa, M., Shimizu, N., Nomura, Y., Segawa, M., Iwabuchi, K., Eguchi, I., Tanaka, H., Takahashi, H., Tsuji, S. <strong>Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT.</strong> Nature Genet. 14: 277-284, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896556</a>] [<a href="https://doi.org/10.1038/ng1196-277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896556">Sanpei et al. (1996)</a> reported that ataxin-2 contained a consensus cleavage site (amino acids DXXD) for apopain (<a href="/entry/600636">600636</a>) at amino acid residues 397-400. They noted that apopain is the human counterpart of the nematode cysteine protease death-gene product CED3 and that apopain may be involved in the processing of huntingtin (<a href="/entry/613004">613004</a>). Furthermore, <a href="#11" class="mim-tip-reference" title="Goldberg, Y. P., Nicholson, D. W., Rasper, D. M., Kalchman, M. A., Koide, H. B., Graham, R. K., Bromm, M., Kazemi-Esfarjani, P., Thornberry, N. A., Vaillancourt, J. P., Hayden, M. R. <strong>Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract.</strong> Nature Genet. 13: 442-449, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696339</a>] [<a href="https://doi.org/10.1038/ng0896-442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8696339">Goldberg et al. (1996)</a> reported that the rate of cleavage increases with the length of the polyglutamine repeat and suggested that the truncated protein products may be toxic to neuronal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8696339+8896556" 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="Huynh, D. P., Del Bigio, M. R., Ho, D. H., Pulst, S. M. <strong>Expression of ataxin-2 in brains from normal individuals and patients with Alzheimer's disease and spinocerebellar ataxia 2.</strong> Ann. Neurol. 45: 232-241, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9989626/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9989626</a>] [<a href="https://doi.org/10.1002/1531-8249(199902)45:2<232::aid-ana14>3.0.co;2-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9989626">Huynh et al. (1999)</a> used antibodies to study the distribution of ataxin-2 in normal individuals and patients with SCA2. The staining was cytoplasmic. Highest levels were observed in the ependyma and choroid plexus. High levels were present in cerebellar Purkinje cells, large neurons of the substantia nigra, and the trochlear nuclei. Moderate staining was observed in apical cytoplasm of hippocampal and cortical pyramidal neurons, olivary nuclei, inferior colliculus, globus pallidus, and amygdala. Glial cells in the superficial molecular area of the cerebral cortex, granule cells in cortical layer II, and large neurons in the putamen were weakly labeled. The level of ataxin-2 in Purkinje cells of normal individuals increased with age. Staining was more intense in individuals with SCA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9989626" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a yeast 2-hybrid system, <a href="#30" class="mim-tip-reference" title="Shibata, H., Huynh, D. P., Pulst, S.-M. <strong>A novel protein with RNA-binding motifs interacts with ataxin-2.</strong> Hum. Molec. Genet. 9: 1303-1313, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814712</a>] [<a href="https://doi.org/10.1093/hmg/9.9.1303" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10814712">Shibata et al. (2000)</a> identified a novel protein, A2BP1 (ataxin-2-binding protein-1; <a href="/entry/605104">605104</a>), which binds to the C terminus of ataxin-2. In sections from 3 SCA2 brains, neuronal labeling for A2BP1 as well as for ataxin-2 appeared to be enhanced and was more diffusely distributed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814712" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid screens, coaffinity purification analysis of transfected HEK293 cells, and bioinformatic analysis, <a href="#21" class="mim-tip-reference" title="Lim, J., Hao, T., Shaw, C., Patel, A. J., Szabo, G., Rual, J.-F., Fisk, C. J., Li, N., Smolyar, A., Hill, D. E., Barabasi, A.-L., Vidal, M., Zoghbi, H. Y. <strong>A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.</strong> Cell 125: 801-814, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16713569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16713569</a>] [<a href="https://doi.org/10.1016/j.cell.2006.03.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16713569">Lim et al. (2006)</a> developed an interaction network for 54 human proteins involved in 23 inherited ataxias. By database analysis, they expanded the core network to include more distantly related interacting proteins that could function as genetic modifiers. A majority (18 of 23) of ataxia-causing proteins interacted either directly or indirectly. A strong direct interaction was detected between ATXN1 and ATXN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16713569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Ralser, M., Nonhoff, U., Albrecht, M., Lengauer, T., Wanker, E. E., Lehrach, H., Krobitsch, S. <strong>Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways.</strong> Hum. Molec. Genet. 14: 2893-2909, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115810</a>] [<a href="https://doi.org/10.1093/hmg/ddi321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115810">Ralser et al. (2005)</a> demonstrated that ataxin-2 interacted with endophilin-A1 (SH3GL2; <a href="/entry/604465">604465</a>) and endophilin-A3 (SH3GL3; <a href="/entry/603362">603362</a>). In a yeast model system, expression of ataxin-2 as well as both endophilin proteins was toxic for yeast lacking Sac6, which encodes fimbrin (PLS3; <a href="/entry/300131">300131</a>) a protein involved in actin filament organization and endocytotic processes. Expression of huntingtin (<a href="/entry/613004">613004</a>), another polyglutamine protein interacting with endophilin-A3, was also toxic in Sac6-null yeast. These effects could be suppressed by simultaneous expression of 1 of the 2 human fimbrin orthologs, L-plastin (LCP1; <a href="/entry/153430">153430</a>) or T-plastin (PLS3). Ataxin-2 associated with L- and T-plastin, and overexpression of ataxin-2 led to accumulation of T-plastin in mammalian cells. <a href="#24" class="mim-tip-reference" title="Ralser, M., Nonhoff, U., Albrecht, M., Lengauer, T., Wanker, E. E., Lehrach, H., Krobitsch, S. <strong>Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways.</strong> Hum. Molec. Genet. 14: 2893-2909, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115810</a>] [<a href="https://doi.org/10.1093/hmg/ddi321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115810">Ralser et al. (2005)</a> suggested an interplay between ataxin-2, endophilin proteins, and huntingtin in plastin-associated cellular pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16115810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a> showed that the polyglutamine repeat protein ataxin-2 is a potent modifier of TDP43 (<a href="/entry/605078">605078</a>) toxicity in animal and cellular models of ALS (<a href="/entry/105400">105400</a>). ATXN2 and TDP43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP43 shows mislocalization in spinocerebellar ataxia-2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20740007" 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="#20" class="mim-tip-reference" title="Lim, C., Allada, R. <strong>ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila.</strong> Science 340: 875-879, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23687047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23687047</a>] [<a href="https://doi.org/10.1126/science.1234785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23687047">Lim and Allada (2013)</a> found that Atx2 is a translational activator of the rate-limiting clock component Period (PER; <a href="/entry/602260">602260</a>) in Drosophila. Atx2 specifically interacted with 'Twenty-four' (Tyf), an activator of Per translation. RNA interference-mediated depletion of Atx2 or the expression of a mutant Atx2 protein that does not associate with polyadenylate-binding protein (PABP; <a href="/entry/604679">604679</a>) suppressed behavioral rhythms and decreased abundance of Per. Although Atx2 can repress translation, depletion of Atx2 from Drosophila S2 cells inhibited translational activation by RNA-tethered Tyf and disrupted the association between Tyf and Pabp. Thus, <a href="#20" class="mim-tip-reference" title="Lim, C., Allada, R. <strong>ATAXIN-2 activates PERIOD translation to sustain circadian rhythms in Drosophila.</strong> Science 340: 875-879, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23687047/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23687047</a>] [<a href="https://doi.org/10.1126/science.1234785" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23687047">Lim and Allada (2013)</a> concluded that ATX2 coordinates an active translation complex important for PER expression and circadian rhythms in Drosophila. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23687047" 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="#33" class="mim-tip-reference" title="Zhang, Y., Ling, J., Yuan, C., Dubruille, R., Emery, P. <strong>A role for Drosophila ATX2 in activation of PER translation and circadian behavior.</strong> Science 340: 879-882, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23687048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23687048</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23687048[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1234746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23687048">Zhang et al. (2013)</a> independently found that the Drosophila homolog of ATXN2 was required for circadian locomotor behavior. Atx2 was necessary for Per accumulation in circadian pacemaker neurons and thus determined period length of circadian behavior. Atx2 was required for the function of Tyf, a crucial activator of Per translation. Atx2 formed a complex with Tyf and promoted its interaction with Pabp. <a href="#33" class="mim-tip-reference" title="Zhang, Y., Ling, J., Yuan, C., Dubruille, R., Emery, P. <strong>A role for Drosophila ATX2 in activation of PER translation and circadian behavior.</strong> Science 340: 879-882, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23687048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23687048</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23687048[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1234746" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23687048">Zhang et al. (2013)</a> concluded that their work uncovered a role for ATX2 in circadian timing and revealed that this protein functions as an activator of PER translation in circadian neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23687048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Ciura, S., Sellier, C., Campanari, M.-L., Charlet-Berguerand, N., Kabashi, E. <strong>The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway.</strong> Autophagy 12: 1406-1408, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27245636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27245636</a>] [<a href="https://doi.org/10.1080/15548627.2016.1189070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27245636">Ciura et al. (2016)</a> found that coexpression of intermediate polyglutamine repeats (30Q) within ATXN2 combined with C9ORF72 (<a href="/entry/614260">614260</a>) depletion increased aggregation of ATXN2 and neuronal toxicity. They concluded that C9ORF72 interacts genetically with ATXN2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27245636" 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 decrease in ataxin-2 suppresses TDP43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase the risk of ALS. <a href="#2" class="mim-tip-reference" title="Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., Pulst, S. M., Taylor, J. P., Rigo, F., Gitler, A. D. <strong>Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.</strong> Nature 544: 367-371, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28405022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28405022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28405022[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature22038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28405022">Becker et al. (2017)</a> used 2 independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP43 proteinopathy. First, they crossed ataxin-2 knockout mice with TDP43 transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP43, markedly increased survival, and improved motor function. Second, in a more therapeutically applicable approach, <a href="#2" class="mim-tip-reference" title="Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., Pulst, S. M., Taylor, J. P., Rigo, F., Gitler, A. D. <strong>Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.</strong> Nature 544: 367-371, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28405022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28405022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28405022[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature22038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28405022">Becker et al. (2017)</a> administered antisense oligonucleotides targeting ataxin-2 to the central nervous system of TDP43 transgenic mice. This single treatment markedly extended survival. <a href="#2" class="mim-tip-reference" title="Becker, L. A., Huang, B., Bieri, G., Ma, R., Knowles, D. A., Jafar-Nejad, P., Messing, J., Kim, H. J., Soriano, A., Auburger, G., Pulst, S. M., Taylor, J. P., Rigo, F., Gitler, A. D. <strong>Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice.</strong> Nature 544: 367-371, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28405022/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28405022</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28405022[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature22038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28405022">Becker et al. (2017)</a> suggested that, because TDP43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28405022" 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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In patients with spinocerebellar ataxia-2 (<a href="/entry/183090">183090</a>), <a href="#23" class="mim-tip-reference" title="Pulst, S.-M., Nechiporuk, A., Nechiporuk, T., Gispert, S., Chen, X.-N., Lopes-Cendes, I., Pearlman, S., Starkman, S., Orozco-Diaz, G., Lunkes, A., DeJong, P., Rouleau, G. A., Auburger, G., Korenberg, J. R., Figueroa, C., Sahba, S. <strong>Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2.</strong> Nature Genet. 14: 269-276, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896555</a>] [<a href="https://doi.org/10.1038/ng1196-269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896555">Pulst et al. (1996)</a> identified a (CAG)n repeat located in the 5-prime end of the coding region of the ATXN2 gene (<a href="#0001">601517.0001</a>). <a href="#3" class="mim-tip-reference" title="Cancel, G., Durr, A., Didierjean, O., Imbert, G., Burk, K., Lezin, A., Belal, S., Benomar, A., Abada-Bendib, M., Vial, C., Guimaraes, J., Chneiweiss, H., and 12 others. <strong>Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families.</strong> Hum. Molec. Genet. 6: 709-715, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9158145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9158145</a>] [<a href="https://doi.org/10.1093/hmg/6.5.709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9158145">Cancel et al. (1997)</a> screened 184 index patients with autosomal dominant cerebellar ataxia type I for the CAG repeat in the ataxin-2 gene. They found the mutation in 109 patients from 30 families of different geographic origins (15%) and in 2 isolated cases with no known family histories (2%). The SCA2 chromosomes contained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14 to 31 repeats), except 1 with 14 repeats, were interrupted by 1 to 3 repeats of CAA. As in other diseases caused by unstable mutations, a strong negative correlation was observed between the age at onset and the size of the CAG repeat. Frequency of several clinical signs such as myoclonus, dystonia, and myokymia increased with the number of CAG repeats, whereas the frequency of others was related to disease duration. The CAG repeat was highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant difference according to the parental sex. This instability was confirmed by the high degree of gonadal mosaicism observed in sperm DNA of 1 patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8896555+9158145" 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="#5" class="mim-tip-reference" title="Choudhry, S., Mukerji, M., Srivastava, A. K., Jain, S., Brahmachari, S. K. <strong>CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms.</strong> Hum. Molec. Genet. 10: 2437-2446, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11689490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11689490</a>] [<a href="https://doi.org/10.1093/hmg/10.21.2437" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11689490">Choudhry et al. (2001)</a> identified 2 novel single-nucleotide polymorphisms (SNPs) in exon 1 of the ATXN2 gene and genotyped 215 normal and 64 expanded chromosomes. The 2 biallelic SNPs distinguished 2 haplotypes, GT and CC, each of which formed a predominant haplotype associated with normal and expanded ATXN2 alleles. All the expanded alleles segregated with CC haplotype, which otherwise was associated with only 29.3% of the normal chromosomes. CAA interspersion analysis revealed that a majority of the normal alleles with CC haplotype were either pure or lacked the most proximal 5-prime CAA interruption. The repeat length variation at the ATXN2 locus also appeared to be polar, with changes occurring mostly at the 5-prime end of the repeat. The authors concluded that CAA interruptions may play an important role in conferring stability to ATXN2 repeats and that their absence may predispose alleles towards instability and pathologic expansion. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11689490" 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>Although repeat length and age at disease onset are inversely related, approximately 50% of the age at onset variance in SCA2 remains unexplained. Other familial factors have been proposed to account for at least part of the remaining variance in the polyglutamine disorders. The ability of polyglutamine tracts to interact with each other, as well as the presence of intranuclear inclusions in other polyglutamine disorders, led <a href="#14" class="mim-tip-reference" title="Hayes, S., Turecki, G., Brisebois, K., Lopes-Cendes, I., Gaspar, C., Riess, O., Ranum, L. P. W., Pulst, S.-M., Rouleau, G. A. <strong>CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2).</strong> Hum. Molec. Genet. 9: 1753-1758, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10915763/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10915763</a>] [<a href="https://doi.org/10.1093/hmg/9.12.1753" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10915763">Hayes et al. (2000)</a> to hypothesize that other CAG-containing proteins may interact with expanded ataxin-2 and affect the rate of protein accumulation, and thus influence age at onset. To test this hypothesis, they used step-wise multiple linear regression to examine 10 CAG-containing genes for possible influences on SCA2 age at onset. One locus, RAI1 (<a href="/entry/607642">607642</a>), contributed an additional 4.1% of the variance in SCA2 age at onset after accounting for the effect of the ATXN2 expanded repeat. SCA3 (<a href="/entry/109150">109150</a>) age at onset, on the other hand, showed no effect from the RAI1 locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10915763" 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="#16" class="mim-tip-reference" title="Huynh, D. P., Yang, H.-T., Vakharia, H., Nguyen, D., Pulst, S. M. <strong>Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death.</strong> Hum. Molec. Genet. 12: 1485-1496, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12812977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12812977</a>] [<a href="https://doi.org/10.1093/hmg/ddg175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12812977">Huynh et al. (2003)</a> confirmed that ataxin-2 is predominantly located in the Golgi apparatus. Deletion of endoplasmic reticulum (ER) exit and trans-Golgi signals in ataxin-2 resulted in an altered subcellular distribution. Expression of full-length ataxin-2 with an expanded repeat disrupted the normal morphology of the Golgi complex and colocalization with Golgi markers was lost. Intranuclear inclusions were only seen when the polyQ repeat was expanded to 104 glutamines, and even then were only observed in a small minority of cells. Expression of ataxin-2 with expanded repeats in PC12 and COS-1 cells increased cell death compared with normal ataxin-2 and elevated the levels of activated caspase-3 (<a href="/entry/600636">600636</a>) and TdT-mediated dUTP nick end labeling (TUNEL)-positive cells. These results suggested a link between cell death mediated by mutant ataxin-2 and the stability of the Golgi complex. <a href="#16" class="mim-tip-reference" title="Huynh, D. P., Yang, H.-T., Vakharia, H., Nguyen, D., Pulst, S. M. <strong>Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death.</strong> Hum. Molec. Genet. 12: 1485-1496, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12812977/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12812977</a>] [<a href="https://doi.org/10.1093/hmg/ddg175" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12812977">Huynh et al. (2003)</a> concluded that formation of intranuclear aggregates is not necessary for in vitro cell death caused by expression of full-length mutant ataxin-2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12812977" 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>Susceptibility to Late-Onset Parkinson Disease</em></strong></p><p>
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<a href="#12" class="mim-tip-reference" title="Gwinn-Hardy, K., Chen, J. Y., Liu, H.-C., Liu, T. Y., Boss, M., Seltzer, W., Adam, A., Singleton, A., Koroshetz, W., Waters, C., Hardy, J., Farrer, M. <strong>Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese.</strong> Neurology 55: 800-805, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10993999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10993999</a>] [<a href="https://doi.org/10.1212/wnl.55.6.800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10993999">Gwinn-Hardy et al. (2000)</a> described 4 patients from a Chinese kindred with parkinsonian features (<a href="/entry/168600">168600</a>) and CAG expansions at the SCA2 locus. The youngest patient had findings typical for the SCA2 ataxic phenotype, but also had parkinsonian features. His SCA2 CAG repeat length was 43. Three patients from earlier generations had mildly elevated CAG repeat lengths of 33 to 36 with varying phenotypes, but all predominantly parkinsonian features, including masked facies, diminished blink rate, and bradykinesia in addition to mild cerebellar findings such as broad-based gait. Two benefited from carbidopa-levodopa therapy. None of the patients had cognitive disturbance or resting tremor. The authors suggested that some cases of familial parkinsonism may be due to SCA2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10993999" 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>Among 23 Chinese patients with familial parkinsonism, <a href="#29" class="mim-tip-reference" title="Shan, D.-E., Soong, B.-W., Sun, C.-M., Lee, S.-J., Liao, K.-K., Liu, R.-S. <strong>Spinocerebellar ataxia type 2 presenting as familial levodopa-responsive parkinsonism.</strong> Ann. Neurol. 50: 812-815, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11761482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11761482</a>] [<a href="https://doi.org/10.1002/ana.10055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11761482">Shan et al. (2001)</a> identified 2 patients who had expanded trinucleotide repeats (mildly elevated at 36 and 37 repeats) in the ATXN2 gene. Both patients had onset of leg tremor at age 50 years, followed by gait difficulty, rigidity, and slow, hypometric saccades. L-DOPA produced marked improvement in symptoms in both patients. In addition, PET scan showed reduced dopamine distribution in the caudate and putamen in both patients. <a href="#29" class="mim-tip-reference" title="Shan, D.-E., Soong, B.-W., Sun, C.-M., Lee, S.-J., Liao, K.-K., Liu, R.-S. <strong>Spinocerebellar ataxia type 2 presenting as familial levodopa-responsive parkinsonism.</strong> Ann. Neurol. 50: 812-815, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11761482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11761482</a>] [<a href="https://doi.org/10.1002/ana.10055" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11761482">Shan et al. (2001)</a> noted that these 2 patients represented approximately one-tenth of their population with familial parkinsonism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11761482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Charles, P., Camuzat, A., Benammar, N., Sellal, F., Destee, A., Bonnet, A.-M., Lesage, S., Le Ber, I., Stevanin, G., Durr, A., Brice, A., French Parkinson's Disease Genetic Study Group. <strong>Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?</strong> Neurology 69: 1970-1975, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17568014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17568014</a>] [<a href="https://doi.org/10.1212/01.wnl.0000269323.21969.db" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17568014">Charles et al. (2007)</a> found that 3 (2%) of 164 French families with autosomal dominant parkinsonism (<a href="/entry/168600">168600</a>) had SCA2 expansions ranging in size from 37 to 39 repeats that were interrupted by CAA triplets. These interrupted expansions were stable in transmission. All 9 patients had levodopa-responsive parkinsonism without cerebellar signs and had less rigidity and more symmetric signs compared to patients with other causes of PD. Two sisters with both the SCA2 expansion and the LRRK2 mutation G2019S (<a href="/entry/609007#0006">609007.0006</a>) had earlier onset that their mother who had only the SCA2 expansion, suggesting an additive pathogenic effect in the sisters. As a phenotypic comparison, 53 SCA2 patients with similar-sized, uninterrupted SCA2 repeats showed predominant cerebellar ataxia with rare signs of parkinsonism. The findings suggested that the configuration of SCA2 repeat expansions plays an important role in phenotypic variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17568014" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Ross, O. A., Rutherford, N. J., Baker, M., Soto-Ortolaza, A. I., Carrasquillo, M. M., DeJesus-Hernandez, M., Adamson, J., Li, M., Volkening, K., Finger, E., Seeley, W. W., Hatanpaa, K. J., and 21 others. <strong>Ataxin-2 repeat-length variation and neurodegeneration.</strong> Hum. Molec. Genet. 20: 3207-3212, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21610160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21610160</a>] [<a href="https://doi.org/10.1093/hmg/ddr227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21610160">Ross et al. (2011)</a> found no association between intermediate ATXN2 CAG repeat expansions (greater than 30 units; <a href="#0002">601517.0002</a>) and PD in a study of 702 patients with Parkinson disease and 4,877 controls. Expansions were found in 2 (0.3%) patients and 9 (0.2%) controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21610160" 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>Susceptibility to Amyotrophic Lateral Sclerosis 13</em></strong></p><p>
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The genetic, biochemical, and neuropathologic interactions between TDP43 and ATXN2 raised the possibility to <a href="#9" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a> that mutations in ATXN2 could have a causative role in ALS (see ALS13, <a href="/entry/183090">183090</a>). The ATXN2 polyQ tract length, although variable, is most frequently 22-23, with expansions of greater than 34 causing SCA2. However, the variable nature of the polyQ repeat indicated a mechanism by which such mutations in ATXN2 could be linked to ALS: <a href="#9" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a> proposed that intermediate-length expansions greater than 23 but below the threshold for SCA2 may be associated with ALS. They studied the frequency of intermediate-length ATXN2 polyglutamine repeats in ALS, comparing 915 subjects with ALS with 980 neurologically normal subjects. Among those with ALS, 4.7% had repeat lengths of 27 to 33, whereas only 1.4% of neurologically normal subjects had glutamine expansions. The P value for this difference was 3.6 x 10(-5) with an odds ratio of 2.80. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20740007" 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 case-control study of 556 ALS patients and 471 controls of French or French Canadian origin, <a href="#8" class="mim-tip-reference" title="Daoud, H., Belzil, V., Martins, S., Sabbagh, M., Provencher, P., Lacomblez, L., Meininger, V., Camu, W., Dupre, N., Dion, P. A., Rouleau, G. A. <strong>Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis.</strong> Arch. Neurol. 68: 739-742, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21670397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21670397</a>] [<a href="https://doi.org/10.1001/archneurol.2011.111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21670397">Daoud et al. (2011)</a> found that 7.2% of patients and 5.1% of controls had 1 intermediate repeat allele (24-33 repeats), which was not significantly different. However, receiver operating characteristic curve analysis yielded a significant association between ALS and high-length ATXN2 repeat alleles (more than 29 CAG repeats). CAG repeats of 29 or higher were found in only 4 controls (0.8%), whereas they were found in 25 patients (4.5%) (OR, 5.5; p = 2.4 x 10(-4)). The association was even stronger for familial cases when stratified by familial versus sporadic cases (OR for familial cases, 9.29; p = 5.2 x 10(-5)). There was no correlation between size of repeat and age of onset. In addition, 2 familial and 9 sporadic ALS cases carried SCA2-sized pathogenic alleles (greater than 32 repeats), and none of them had features of SCA2 such as cerebellar or brainstem atrophy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21670397" 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>Among 1,845 sporadic and 103 familial ALS cases and 2,002 controls from Belgium and the Netherlands, <a href="#32" class="mim-tip-reference" title="Van Damme, P., Veldink, J. H., van Blitterswijk, M., Corveleyn, A., van Vught, P. W. J., Thijs, V., Dubois, B., Matthijs, G., van den Berg, L. H., Robberecht, W. <strong>Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2.</strong> Neurology 76: 2066-2072, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21562247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21562247</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31821f445b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21562247">Van Damme et al. (2011)</a> found an association between ALS and an expanded CAG repeat of 29 or greater in the ATXN2 gene (OR, 1.92; p = 0.036). In controls, the repeat length ranged from 16 to 31, with 22 being the most abundant. Repeat sizes of 31 or less were not significantly different between patients and controls. However, receiver operating characteristic analysis showed that the greatest sensitivity and specificity of discriminating ALS from control was using a cutoff of 29 repeats: 1.5% of patients had 29 or more repeats compared to 0.8% of controls (OR, 1.92; p = 0.036). There was no correlation between repeat length and disease parameters. When combined in a metaanalysis with the data of <a href="#9" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a>, the association was highly significant (OR, 2.93; p less than 0.0001). Ten patients (0.05%) with sporadic ALS had repeat sizes of 32 or more, and none of these patients had signs of SCA2. Two of 91 families with ALS (2.2%) had expanded repeats: 1 with 31 repeats and the other with 33 repeats. In the 33-repeat family, which was consanguineous, 2 affected individuals had repeat expansions on both alleles, 33:33 and 33:31, respectively, although the phenotype was not significantly different from classic ALS, except for some sensory abnormalities. Two sibs from a third family with a heterozygous repeat length of 34 and 35, respectively, had classic SCA2 with no signs of upper motor neuron involvement. The findings indicated a genetic overlap between SCA2 and ALS13. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21562247+20740007" 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>Among 3,919 patients with various neurodegenerative diseases, including 532 with ALS, 641 with frontotemporal dementia (FTD; <a href="/entry/600274">600274</a>), 1,530 with Alzheimer disease (AD; <a href="/entry/104300">104300</a>), 702 with Parkinson disease (PD; <a href="/entry/168600">168600</a>), and 514 with progressive supranuclear palsy (PSP; <a href="/entry/601104">601104</a>), and 4,877 healthy controls, <a href="#25" class="mim-tip-reference" title="Ross, O. A., Rutherford, N. J., Baker, M., Soto-Ortolaza, A. I., Carrasquillo, M. M., DeJesus-Hernandez, M., Adamson, J., Li, M., Volkening, K., Finger, E., Seeley, W. W., Hatanpaa, K. J., and 21 others. <strong>Ataxin-2 repeat-length variation and neurodegeneration.</strong> Hum. Molec. Genet. 20: 3207-3212, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21610160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21610160</a>] [<a href="https://doi.org/10.1093/hmg/ddr227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21610160">Ross et al. (2011)</a> found that ATXN2 repeat lengths greater than 30 units were significantly associated with ALS (odds ratio of 5.57; p = 0.001) and with PSP (OR of 5.83; p = 0.004). Significant associations between repeats greater than 30 were not observed in patients with FTD, AD, or PD. Importantly, expanded repeat alleles (31 to 33) were also observed in 9 (0.2%) control individuals, indicating that caution should be taken when attributing specific disease phenotypes to these repeat lengths. However, 6 of the controls with expanded repeats were under the mean onset age of all patient groups except PD. The findings confirmed the role of ATXN2 as an important risk factor for ALS and suggested that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21610160" 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>Mutations in FUS (<a href="/entry/137070">137070</a>) cause amyotrophic lateral sclerosis-6 (ALS6; <a href="/entry/608030">608030</a>). <a href="#10" class="mim-tip-reference" title="Farg, M. A., Soo, K. Y., Warraich, S. T., Sundaramoorthy, V., Blair, I. P., Atkin, J. D. <strong>Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis.</strong> Hum. Molec. Genet. 22: 717-728, 2013. Note: Erratum: Hum. Molec. Genet. 29: 703-704, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23172909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23172909</a>] [<a href="https://doi.org/10.1093/hmg/dds479" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23172909">Farg et al. (2013)</a> found that ataxin-2 with an intermediate glutamine expansion (Q31) interacted with wildtype FUS and, more strongly, with FUS containing the arg521-to-cys (R521C; <a href="/entry/137070#0004">137070.0004</a>) or arg521-to-his (R521H; <a href="/entry/137070#0005">137070.0005</a>) mutations. The interactions were independent of RNA. Ataxin-2 colocalized with FUS in sporadic and FUS-linked familial ALS patient motor neurons, coprecipitated with FUS in ALS spinal cord lysates, and colocalized with FUS in the ER and Golgi compartments in a mouse neuronal cell line. Ataxin-2 Q31 exacerbated the cellular phenotype of mutant FUS, increasing translocation of FUS from the nucleus to the cytoplasm, markers of ER stress, and Golgi fragmentation. Neither FUS with the R521H mutation nor ataxin-2 Q31 alone induced apoptosis in transfected mouse neuronal cells, but coexpression of both induced markers of early apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23172909" 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="#18" class="mim-tip-reference" title="Kiehl, T.-R., Nechiporuk, A., Figueroa, K. P., Keating, M. T., Huynh, D. P., Pulst, S.-M. <strong>Generation and characterization of Sca2 (ataxin-2) knockout mice.</strong> Biochem. Biophys. Res. Commun. 339: 17-24, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16293225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16293225</a>] [<a href="https://doi.org/10.1016/j.bbrc.2005.10.186" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16293225">Kiehl et al. (2006)</a> found that Atxn2 -/- mice appeared normal and were fertile, but there was a significant reduction in the number of female Atxn2 +/- and Atxn2 -/- mice born. Histopathologic examination of the central nervous system and other organs demonstrated no morphologic abnormalities in Atxn2 -/- mice except in liver, which showed micro- and macrovesicular steatosis at 1 year of age. At this age, Atxn2 -/- mice were also susceptible to adult-onset obesity when placed on a moderately fat-enriched diet, but not when placed on a low-fat diet. Atxn2 -/- mice showed a slight deficit in motor performance in the rotarod test compared with wildtype controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16293225" 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="#19" class="mim-tip-reference" title="Lastres-Becker, I., Brodesser, S., Lutjohann, D., Azizov, M., Buchmann, J., Hintermann, E., Sandhoff, K., Schurmann, A., Nowock, J., Auburger, G. <strong>Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice.</strong> Hum. Molec. Genet. 17: 1465-1481, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250099</a>] [<a href="https://doi.org/10.1093/hmg/ddn035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250099">Lastres-Becker et al. (2008)</a> found that Atxn2 -/- mice showed reduced fertility, locomotor hyperactivity, and abdominal obesity and hepatosteatosis by age 6 months. Insulin levels were increased in pancreas and blood, consistent with insulin resistance, and the mice demonstrated increased serum cholesterol levels. These changes were associated with reduced insulin receptor (INSR; <a href="/entry/147670">147670</a>) expression in liver and cerebellum, although the mRNA levels were increased, suggesting a posttranscriptional effect on the insulin receptor status. Thus, loss of Atxn2 may affect cellular endocytosis machinery. Analysis of brain lipids in Atxn2 -/- mice showed increased gangliosides and decreased sphingomyelin in the cerebellum, and there was evidence for altered cholesterol homeostasis. <a href="#19" class="mim-tip-reference" title="Lastres-Becker, I., Brodesser, S., Lutjohann, D., Azizov, M., Buchmann, J., Hintermann, E., Sandhoff, K., Schurmann, A., Nowock, J., Auburger, G. <strong>Insulin receptor and lipid metabolism pathology in ataxin-2 knock-out mice.</strong> Hum. Molec. Genet. 17: 1465-1481, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18250099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18250099</a>] [<a href="https://doi.org/10.1093/hmg/ddn035" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18250099">Lastres-Becker et al. (2008)</a> postulated that these lipid changes may alter neuronal membrane signaling and excitability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18250099" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using the promoter region of Purkinje cell protein-2 (PCP2), <a href="#13" class="mim-tip-reference" title="Hansen, S. T., Meera, P., Otis, T. S., Pulst, S. M. <strong>Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2.</strong> Hum. Molec. Genet. 22: 271-283, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23087021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23087021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23087021[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/hmg/dds427" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23087021">Hansen et al. (2013)</a> created transgenic mice expressing human ATXN2 with a polyglutamine tract of 127 residues (ATXN2(Q127)) specifically in cerebellar Purkinje cells. Biochemical, behavioral, and electrophysiologic measures revealed no difference between ATXN2(Q127) animals and wildtype controls prior to 4 weeks of age. However, at 4 weeks of age, transgenic mice began to show reduced expression of select cerebellar genes, including Calb1 (<a href="/entry/114050">114050</a>) and Pcp2. At 8 weeks of age, ATXN2(Q127) animals showed reduced Purkinje cell firing frequency, followed by deficits in motor behavior. After 12 weeks of age, they showed reduced Purkinje cell numbers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23087021" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a zebrafish model, <a href="#6" class="mim-tip-reference" title="Ciura, S., Sellier, C., Campanari, M.-L., Charlet-Berguerand, N., Kabashi, E. <strong>The most prevalent genetic cause of ALS-FTD, C9orf72 synergizes the toxicity of ATXN2 intermediate polyglutamine repeats through the autophagy pathway.</strong> Autophagy 12: 1406-1408, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27245636/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27245636</a>] [<a href="https://doi.org/10.1080/15548627.2016.1189070" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27245636">Ciura et al. (2016)</a> showed that partial knockdown of C9orf72 combined with intermediate repeat expansion of Atxn2 caused locomotion deficits and abnormal axonal projections from spinal motor neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27245636" 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>Therapy</em></strong></p><p>
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<a href="#28" class="mim-tip-reference" title="Scoles, D. R., Meera, P., Schneider, M. D., Paul, S., Dansithong, W., Figueroa, K. P., Hung, G., Rigo, F., Bennett, C. F., Otis, T. S., Pulst, S. M. <strong>Antisense oligonucleotide therapy for spinocerebellar ataxia type 2.</strong> Nature 544: 362-366, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28405024/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28405024</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28405024[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature22044" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28405024">Scoles et al. (2017)</a> developed an antisense oligonucleotide, ASO7, that downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 (<a href="/entry/620791">620791</a>), and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28405024" 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">rs1885090126 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1885090126;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=rs1885090126" 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=rs1885090126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In patients with spinocerebellar ataxia-2 (<a href="/entry/183090">183090</a>), <a href="#23" class="mim-tip-reference" title="Pulst, S.-M., Nechiporuk, A., Nechiporuk, T., Gispert, S., Chen, X.-N., Lopes-Cendes, I., Pearlman, S., Starkman, S., Orozco-Diaz, G., Lunkes, A., DeJong, P., Rouleau, G. A., Auburger, G., Korenberg, J. R., Figueroa, C., Sahba, S. <strong>Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2.</strong> Nature Genet. 14: 269-276, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896555</a>] [<a href="https://doi.org/10.1038/ng1196-269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896555">Pulst et al. (1996)</a> identified a (CAG)n repeat located in the 5-prime end of the coding region of the ATXN2 gene. They detected expansions of 36 to 52 repeats in affected individuals the most common allele contained 37 repeats. They noted that the ATXN2 repeat is unusual in that only 2 alleles were demonstrated in the normal population. A common allele with 22 repeats was found in people of European descent. Using RT-PCR, <a href="#23" class="mim-tip-reference" title="Pulst, S.-M., Nechiporuk, A., Nechiporuk, T., Gispert, S., Chen, X.-N., Lopes-Cendes, I., Pearlman, S., Starkman, S., Orozco-Diaz, G., Lunkes, A., DeJong, P., Rouleau, G. A., Auburger, G., Korenberg, J. R., Figueroa, C., Sahba, S. <strong>Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2.</strong> Nature Genet. 14: 269-276, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896555</a>] [<a href="https://doi.org/10.1038/ng1196-269" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896555">Pulst et al. (1996)</a> determined that the ATXN2 (CAG)n repeat is transcribed in lymphoblastoid cell lines and that the cells could be used to express the expanded repeat genes from patients with SCA2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Sanpei, K., Takano, H., Igarashi, S., Sato, T., Oyake, M., Sasaki, H., Wakisaka, A., Tashiro, K., Ishida, Y., Ikeuchi, T., Koide, R., Saito, M., Sato, A., Tanaka, T., Hanyu, S., Takiyama, Y., Nishizawa, M., Shimizu, N., Nomura, Y., Segawa, M., Iwabuchi, K., Eguchi, I., Tanaka, H., Takahashi, H., Tsuji, S. <strong>Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT.</strong> Nature Genet. 14: 277-284, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896556</a>] [<a href="https://doi.org/10.1038/ng1196-277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896556">Sanpei et al. (1996)</a> analyzed 286 normal chromosomes and found that the (CAG)n repeats ranged in size from 15 to 24, with a unit of 22 repeats accounting for 94% of the alleles. In contrast, SCA2 patient chromosomes contained expanded repeats ranging in size from 35 to 59 units. <a href="#27" class="mim-tip-reference" title="Sanpei, K., Takano, H., Igarashi, S., Sato, T., Oyake, M., Sasaki, H., Wakisaka, A., Tashiro, K., Ishida, Y., Ikeuchi, T., Koide, R., Saito, M., Sato, A., Tanaka, T., Hanyu, S., Takiyama, Y., Nishizawa, M., Shimizu, N., Nomura, Y., Segawa, M., Iwabuchi, K., Eguchi, I., Tanaka, H., Takahashi, H., Tsuji, S. <strong>Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT.</strong> Nature Genet. 14: 277-284, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896556</a>] [<a href="https://doi.org/10.1038/ng1196-277" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896556">Sanpei et al. (1996)</a> reported that there was a strong inverse correlation between the size of the repeat and the onset of symptoms. <a href="#17" class="mim-tip-reference" title="Imbert, G., Saudou, F., Yvert, G., Devys, D., Trottier, Y., Garnier, J.-M., Weber, C., Mandel, J.-L., Cancel, G., Abbas, N., Durr, A., Didierjean, O., Stevanin, G., Agid, Y., Brice, A. <strong>Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats.</strong> Nature Genet. 14: 285-291, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896557</a>] [<a href="https://doi.org/10.1038/ng1196-285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896557">Imbert et al. (1996)</a> reported that normal ATXN2 alleles contained 17 to 29 (CAG)n repeats and 1 to 3 (CAA)n repeats (also glutamine-encoding). Mutated alleles contained 37 to 50 repeats and appeared to be particularly unstable in maternal and paternal transmissions. Sequence analysis of expanded repeats from 3 individuals revealed pure CAG stretches. <a href="#17" class="mim-tip-reference" title="Imbert, G., Saudou, F., Yvert, G., Devys, D., Trottier, Y., Garnier, J.-M., Weber, C., Mandel, J.-L., Cancel, G., Abbas, N., Durr, A., Didierjean, O., Stevanin, G., Agid, Y., Brice, A. <strong>Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats.</strong> Nature Genet. 14: 285-291, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896557</a>] [<a href="https://doi.org/10.1038/ng1196-285" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8896557">Imbert et al. (1996)</a> reported that there was a steep inverse correlation between the age of onset of disease and (CAG)n repeat number. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8896556+8896557" 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>Susceptibility to Late-Onset Parkinson Disease</p><p><a href="#12" class="mim-tip-reference" title="Gwinn-Hardy, K., Chen, J. Y., Liu, H.-C., Liu, T. Y., Boss, M., Seltzer, W., Adam, A., Singleton, A., Koroshetz, W., Waters, C., Hardy, J., Farrer, M. <strong>Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese.</strong> Neurology 55: 800-805, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10993999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10993999</a>] [<a href="https://doi.org/10.1212/wnl.55.6.800" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10993999">Gwinn-Hardy et al. (2000)</a> described 4 patients from a Chinese kindred with parkinsonian features (<a href="/entry/168600">168600</a>) and CAG expansions at the SCA2 locus. The youngest patient had findings typical for the SCA2 ataxic phenotype, but also had parkinsonian features. His SCA2 CAG repeat length was 43. Three patients from earlier generations had mildly elevated CAG repeat lengths of 33 to 36 with varying phenotypes, but all predominantly parkinsonian features, including masked facies, diminished blink rate, and bradykinesia in addition to mild cerebellar findings such as broad-based gait. Two benefited from carbidopa-levodopa therapy. None of the patients had cognitive disturbance or resting tremor. The authors suggested that some cases of familial parkinsonism may be due to SCA2 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10993999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Charles, P., Camuzat, A., Benammar, N., Sellal, F., Destee, A., Bonnet, A.-M., Lesage, S., Le Ber, I., Stevanin, G., Durr, A., Brice, A., French Parkinson's Disease Genetic Study Group. <strong>Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?</strong> Neurology 69: 1970-1975, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17568014/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17568014</a>] [<a href="https://doi.org/10.1212/01.wnl.0000269323.21969.db" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17568014">Charles et al. (2007)</a> found that 3 (2%) of 164 French families with autosomal dominant parkinsonism (<a href="/entry/168600">168600</a>) had SCA2 expansions ranging in size from 37 to 39 repeats that were interrupted by CAA triplets. These interrupted expansions were stable in transmission. All 9 patients had levodopa-responsive parkinsonism without cerebellar signs and had less rigidity and more symmetric signs compared to patients with other causes of PD. Two sisters with both the SCA2 expansion and the LRRK2 mutation G2019S (<a href="/entry/609007#0006">609007.0006</a>) had earlier onset that their mother who had only the SCA2 expansion, suggesting an additive pathogenic effect in the sisters. As a phenotypic comparison, 53 SCA2 patients with similar-sized, uninterrupted SCA2 repeats showed predominant cerebellar ataxia with rare signs of parkinsonism. The findings suggested that the configuration of SCA2 repeat expansions plays an important role in phenotypic variability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17568014" 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>.0002 AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO, 13</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">rs1885090126 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1885090126;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=rs1885090126" 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=rs1885090126" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Among 915 patients with amyotrophic lateral sclerosis, <a href="#9" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a> identified 43 (4.7%) with expansions of the ATXN2 polyQ repeat of intermediate length, 27 through 33 repeats (ALS13; <a href="/entry/183090">183090</a>). Among a neurologically normal control cohort of 980 individuals, similar expansions were detected in only 14 (1.4%) individuals (p = 3.6 x 10(-5), odds ratio, 2.80, 95% CI, 1.54-5.12). <a href="#9" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a> analyzed ATXN2 protein levels in patient-derived lymphoblastoid cells from ALS cases harboring intermediate-length polyQ expansions, ALS cases with normal-range repeat lengths, and controls. These studies showed that whereas the steady state levels of ATXN2 were comparable, cycloheximide treatment, which blocks new protein synthesis, revealed an increase in stability (or decreased degradation) of ATXN2 in cells with intermediate-length polyQ repeats. <a href="#9" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a> then found that polyQ expansions in ATXN2 enhance its interaction with TDP43 (<a href="/entry/605078">605078</a>). Both ATXN2 and TDP43 relocalize to stress granules, sites of RNA processing, under various stress situations such as heat shock and oxidative stress. Under normal conditions TDP43 localized to the nucleus and ATXN2 to the cytoplasm in both control cells and cells harboring polyQ repeat expansions. <a href="#9" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a> proposed that intermediate-length ATXN2 polyQ repeats might confer genetic risk for ALS by making TDP43 more prone to mislocalize from the nucleus to the cytoplasm under situations of stress. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20740007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The findings of <a href="#9" class="mim-tip-reference" title="Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others. <strong>Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS.</strong> Nature 466: 1069-1075, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09320" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20740007">Elden et al. (2010)</a> were replicated in 2 independent studies by <a href="#8" class="mim-tip-reference" title="Daoud, H., Belzil, V., Martins, S., Sabbagh, M., Provencher, P., Lacomblez, L., Meininger, V., Camu, W., Dupre, N., Dion, P. A., Rouleau, G. A. <strong>Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis.</strong> Arch. Neurol. 68: 739-742, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21670397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21670397</a>] [<a href="https://doi.org/10.1001/archneurol.2011.111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21670397">Daoud et al. (2011)</a> and <a href="#32" class="mim-tip-reference" title="Van Damme, P., Veldink, J. H., van Blitterswijk, M., Corveleyn, A., van Vught, P. W. J., Thijs, V., Dubois, B., Matthijs, G., van den Berg, L. H., Robberecht, W. <strong>Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2.</strong> Neurology 76: 2066-2072, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21562247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21562247</a>] [<a href="https://doi.org/10.1212/WNL.0b013e31821f445b" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21562247">Van Damme et al. (2011)</a>, who studied French, French Canadian, and Belgian populations. Each study identified an association between development of ALS and high-length ATXN2 repeat alleles (29 or more repeats), using receiver operating characteristic curve analysis of patients and controls. Neither study found a correlation between size of repeat and disease parameters. Moreover, each study found ALS patients with expansion sizes in the range of SCA2 (greater than 32 repeats), and none had features of SCA2 such as cerebellar or brainstem atrophy. The findings indicated a genetic overlap between SCA2 and ALS13. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21562247+21670397+20740007" 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="Corrado, L., Mazzini, L., Oggioni, G. D., Luciano, B., Godi, M., Brusco, A., D'Alfonso, S. <strong>ATXN-2 CAG repeat expansions are interrupted in ALS patients.</strong> Hum. Genet. 130: 575-580, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21537950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21537950</a>] [<a href="https://doi.org/10.1007/s00439-011-1000-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21537950">Corrado et al. (2011)</a> identified intermediate expansion of the CAG repeat (greater than 30 repeats) in exon 1 of the ATXN2 gene in 7 (3.0%) of 232 Italian patients with ALS. None of 395 controls had an allele larger than 30 repeats. Four of the 7 patients had an allele in the intermediate-fully pathologic range: 1 with 32 repeats, 2 with 33 repeats, and 1 with 37 repeats, accounting for 1.7% of the ALS cohort. Sequencing of these fully expanded alleles showed that they were all interrupted with at least one CAA triplet. The phenotype of the patients was typical of ALS with no signs or symptoms of ataxia or parkinsonism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21537950" 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>Among 3,919 patients with various neurodegenerative diseases, including 532 with ALS, 641 with frontotemporal dementia (FTD; <a href="/entry/600274">600274</a>), 1,530 with Alzheimer disease (AD; <a href="/entry/104300">104300</a>), 702 with Parkinson disease (PD; <a href="/entry/168600">168600</a>), and 514 with progressive supranuclear palsy (PSP; see <a href="/entry/601104">601104</a>), and 4,877 healthy controls, <a href="#25" class="mim-tip-reference" title="Ross, O. A., Rutherford, N. J., Baker, M., Soto-Ortolaza, A. I., Carrasquillo, M. M., DeJesus-Hernandez, M., Adamson, J., Li, M., Volkening, K., Finger, E., Seeley, W. W., Hatanpaa, K. J., and 21 others. <strong>Ataxin-2 repeat-length variation and neurodegeneration.</strong> Hum. Molec. Genet. 20: 3207-3212, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21610160/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21610160</a>] [<a href="https://doi.org/10.1093/hmg/ddr227" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21610160">Ross et al. (2011)</a> found that ATXN2 repeat lengths greater than 30 units were significantly associated with ALS (odds ratio of 5.57; p = 0.001) and with PSP (OR of 5.83; p = 0.004). Repeat expansions were found in 8 (1.5%) ALS patients, 4 (0.8%) PSP patients, and 9 (0.2%) controls. Significant associations between repeats greater than 30 were not observed in patients with FTD, AD, or PD. The findings of expanded repeat alleles (31 to 33) in control individuals indicated that caution should be taken when attributing specific disease phenotypes to these repeat lengths. However, 6 of the controls with expanded repeats were under the mean onset age of all patient groups except PD. The findings confirmed the role of ATXN2 as an important risk factor for ALS and suggested that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21610160" 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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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11689490/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11689490</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11689490" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Ciura, S., Sellier, C., Campanari, M.-L., Charlet-Berguerand, N., Kabashi, E.
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Corrado, L., Mazzini, L., Oggioni, G. D., Luciano, B., Godi, M., Brusco, A., D'Alfonso, S.
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<strong>ATXN-2 CAG repeat expansions are interrupted in ALS patients.</strong>
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Hum. Genet. 130: 575-580, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21537950/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21537950</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21537950" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Daoud, H., Belzil, V., Martins, S., Sabbagh, M., Provencher, P., Lacomblez, L., Meininger, V., Camu, W., Dupre, N., Dion, P. A., Rouleau, G. A.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21670397/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21670397</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21670397" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1001/archneurol.2011.111" target="_blank">Full Text</a>]
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Elden, A. C., Kim, H.-J., Hart, M. P., Chen-Plotkin, A. S., Johnson, B. S., Fang, X., Armakola, M., Geser, F., Greene, R., Lu, M. M., Padmanabhan, A., Clay-Falcone, D., and 11 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20740007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20740007</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20740007[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=20740007" 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/nature09320" target="_blank">Full Text</a>]
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<a id="Farg2013" class="mim-anchor"></a>
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Farg, M. A., Soo, K. Y., Warraich, S. T., Sundaramoorthy, V., Blair, I. P., Atkin, J. D.
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<strong>Ataxin-2 interacts with FUS and intermediate-length polyglutamine expansions enhance FUS-related pathology in amyotrophic lateral sclerosis.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23172909/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23172909</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23172909" 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/dds479" target="_blank">Full Text</a>]
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Goldberg, Y. P., Nicholson, D. W., Rasper, D. M., Kalchman, M. A., Koide, H. B., Graham, R. K., Bromm, M., Kazemi-Esfarjani, P., Thornberry, N. A., Vaillancourt, J. P., Hayden, M. R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8696339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8696339</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8696339" 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/ng0896-442" target="_blank">Full Text</a>]
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Gwinn-Hardy, K., Chen, J. Y., Liu, H.-C., Liu, T. Y., Boss, M., Seltzer, W., Adam, A., Singleton, A., Koroshetz, W., Waters, C., Hardy, J., Farrer, M.
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<strong>Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10993999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10993999</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10993999" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/wnl.55.6.800" target="_blank">Full Text</a>]
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Hansen, S. T., Meera, P., Otis, T. S., Pulst, S. M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23087021/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23087021</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23087021[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=23087021" 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/dds427" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.12.1753" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11761482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11761482</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11761482" 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.10055" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Shibata2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Shibata, H., Huynh, D. P., Pulst, S.-M.
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<strong>A novel protein with RNA-binding motifs interacts with ataxin-2.</strong>
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Hum. Molec. Genet. 9: 1303-1313, 2000. Note: Erratum: Hum. Molec. Genet. 9: 1903 only, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10814712/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10814712</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10814712" 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/9.9.1303" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Trottier1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Trottier, Y., Lutz, Y., Stevanin, G., Imbert, G., Devys, D., Cancel, G., Saudou, F., Weber, C., David, G., Tora, L., Agid, Y., Brice, A., Mandel, J.-L.
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<strong>Polyglutamine expansion as a pathological epitope in Huntington's disease and four dominant cerebellar ataxias.</strong>
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Nature 378: 403-406, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7477379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7477379</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7477379" 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/10.1038/378403a0" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Van Damme2011" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Van Damme, P., Veldink, J. H., van Blitterswijk, M., Corveleyn, A., van Vught, P. W. J., Thijs, V., Dubois, B., Matthijs, G., van den Berg, L. H., Robberecht, W.
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|
<strong>Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2.</strong>
|
|
Neurology 76: 2066-2072, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21562247/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21562247</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21562247" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e31821f445b" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="33" class="mim-anchor"></a>
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<a id="Zhang2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, Y., Ling, J., Yuan, C., Dubruille, R., Emery, P.
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<strong>A role for Drosophila ATX2 in activation of PER translation and circadian behavior.</strong>
|
|
Science 340: 879-882, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23687048/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23687048</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23687048[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=23687048" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1234746" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/12/2018
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 03/12/2018<br>Paul J. Converse - updated : 10/10/2017<br>Patricia A. Hartz - updated : 5/23/2014<br>Patricia A. Hartz - updated : 7/17/2013<br>Ada Hamosh - updated : 6/24/2013<br>Cassandra L. Kniffin - updated : 5/30/2012<br>Cassandra L. Kniffin - updated : 11/7/2011<br>Cassandra L. Kniffin - updated : 10/6/2011<br>Ada Hamosh - updated : 9/14/2010<br>Cassandra L. Kniffin - updated : 7/29/2010<br>George E. Tiller - updated : 4/22/2009<br>Patricia A. Hartz - updated : 1/15/2009<br>George E. Tiller - updated : 4/22/2005<br>Victor A. McKusick - updated : 3/21/2003<br>Cassandra L. Kniffin - reorganized : 9/13/2002<br>George E. Tiller - updated : 5/3/2002<br>Victor A. McKusick - updated : 8/28/2000<br>George E. Tiller - updated : 6/30/2000<br>Paul J. Converse - updated : 6/7/2000<br>Orest Hurko - updated : 3/22/1999<br>Stylianos E. Antonarakis - updated : 10/8/1998<br>Victor A. McKusick - updated : 6/23/1997
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</span>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Moyra Smith : 11/19/1996
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</span>
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</div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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mgross : 04/18/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 01/27/2021<br>carol : 01/26/2021<br>alopez : 10/31/2019<br>alopez : 10/31/2019<br>alopez : 03/12/2018<br>alopez : 03/12/2018<br>mgross : 10/10/2017<br>carol : 06/24/2016<br>mgross : 5/23/2014<br>mcolton : 5/22/2014<br>mcolton : 2/24/2014<br>carol : 10/25/2013<br>mgross : 7/17/2013<br>alopez : 6/24/2013<br>terry : 11/28/2012<br>terry : 6/1/2012<br>carol : 5/31/2012<br>ckniffin : 5/30/2012<br>carol : 12/5/2011<br>carol : 11/9/2011<br>ckniffin : 11/7/2011<br>carol : 10/13/2011<br>terry : 10/12/2011<br>ckniffin : 10/6/2011<br>ckniffin : 11/16/2010<br>alopez : 9/21/2010<br>alopez : 9/21/2010<br>alopez : 9/21/2010<br>terry : 9/14/2010<br>terry : 9/14/2010<br>wwang : 8/6/2010<br>ckniffin : 7/29/2010<br>carol : 9/15/2009<br>wwang : 5/7/2009<br>terry : 4/22/2009<br>mgross : 1/15/2009<br>tkritzer : 4/22/2005<br>tkritzer : 11/8/2004<br>alopez : 3/21/2003<br>terry : 3/21/2003<br>carol : 9/13/2002<br>ckniffin : 9/13/2002<br>ckniffin : 9/11/2002<br>ckniffin : 8/28/2002<br>cwells : 5/14/2002<br>cwells : 5/3/2002<br>alopez : 8/28/2000<br>terry : 8/28/2000<br>alopez : 6/30/2000<br>carol : 6/8/2000<br>carol : 6/7/2000<br>mgross : 9/22/1999<br>terry : 9/15/1999<br>carol : 3/22/1999<br>carol : 10/8/1998<br>carol : 7/22/1998<br>carol : 5/19/1998<br>carol : 5/12/1998<br>terry : 7/28/1997<br>terry : 7/8/1997<br>joanna : 7/7/1997<br>terry : 6/23/1997<br>terry : 6/18/1997<br>terry : 12/4/1996<br>mark : 11/20/1996<br>terry : 11/20/1996<br>mark : 11/19/1996<br>mark : 11/19/1996
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</span>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601517
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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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ATAXIN 2; ATXN2
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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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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ATXN2</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 715751004;
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</span>
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</p>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 12q24.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:111,452,214-111,599,673 </span>
|
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</em>
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</strong>
|
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="3">
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<span class="mim-font">
|
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12q24.12
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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, susceptibility to, 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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183090
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</span>
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</td>
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<td>
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<span class="mim-font">
|
|
Autosomal dominant
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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{Parkinson disease, late-onset, susceptibility to}
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
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168600
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Multifactorial
|
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
|
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Spinocerebellar ataxia 2
|
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</span>
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
183090
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
Autosomal dominant
|
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</span>
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</td>
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<td>
|
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<span class="mim-font">
|
|
3
|
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
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</h4>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<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">
|
|
<p>Ataxin-2, the protein encoded by the ATXN2 gene, contains a polyglutamine tract, long expansions (greater than 33 repeats) of which result in spinocerebellar ataxia-2 (SCA2; 183090), an autosomal dominant form of olivopontocerebellar atrophy. Intermediate-length expansions (27-33 glutamines) contribute to susceptibility to amyotrophic lateral sclerosis (ALS13; see 183090).</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>Using a monoclonal antibody that recognizes expanded polyglutamine stretches in TATA box-binding protein (600075), mutant huntingtin (613004), mutant ataxin-1 (164400), and glutamine expanded proteins in patients with SCA3 (109150), Trottier et al. (1995) used Western blotting to detect a 150-kD protein in a patient with SCA2, but not his normal relative. By analogy to other disorders associated with anticipation in expanded triplet repeats, they suggested that this may be the protein encoded by the mutant gene responsible for this disorder. </p><p>Pulst et al. (1996) isolated the ATXN2 gene through a positional cloning approach. They assembled a 1.1-Mb contig in the 12q24.1 region where the disease SCA2 had been mapped, and then identified a genomic clone that contained CAG repeats. By screening human adult and human fetal brain libraries, Pulst et al. (1996) identified a cDNA clone with a 3,936-kb open reading frame (ORF) that encodes a 1,312-amino acid polypeptide with a molecular mass of 140 kD. The (CAG)n repeat (601517.0001) is located in the 5-prime end of the coding region of the ATXN2 gene, which they also referred to as the ataxin-2 gene. The ataxin-2 gene showed no homology with genes of known function. ATXN2 did, however, show homology with cDNAs in an EST database, and Pulst et al. (1996) cloned a related human cDNA they called ataxin-2-related protein (A2RP; GenBank U70671) and a cDNA for a mouse gene homologous to ATXN2. These 2 genes, however, lacked the polyglutamine repeat region. </p><p>Sanpei et al. (1996) devised a novel strategy for identification of triplet-repeat expansion genes referred to by them as DIRECT (direct identification of repeat expansion and cloning technique). This technique involved preparation of a probe with high specific radioactivity by PCR internal labeling, preparation of single-stranded probe, and detection of disease-specific expanded repeats by Southern blot hybridization under stringent conditions, followed by cloning of the genomic segment containing the pathologically expanded repeat. Sanpei et al. (1996) applied this technique to the identification of expanded repeats in patients with SCA2. Southern blots of genomic DNA digested with TspEI revealed a 2.5-kb fragment which was absent from normal individuals. A genomic clone containing the expanded (CAG)n repeat was isolated and sequenced, and was predicted to encode a 1,313-amino acid polypeptide with a molecular mass of 140 kD, referred to as ataxin-2. Northern blot analysis with ataxin-2 gene sequences revealed a 4.7-kb transcript which was expressed in brain, heart, liver, muscle, pancreas, and placenta. Sanpei et al. (1996) noted that there was another ATG codon 120 codons downstream of the first ATG codon and that if this was a functional initiation site, the smaller transcript would result in a predicted 124-kD polypeptide. </p><p>The gene encoding the protein that is mutant in SCA2 was also cloned by Imbert et al. (1996), who screened cDNA expression libraries with an antibody specific for polyglutamine repeats. They identified 6 unreported (CAG)n repeat expansion-containing genes and designed primers from the DNA region flanking the gene associated with SCA2 patients. One genomic clone they isolated (DAN1), which corresponded to ATXN2, was fully sequenced and was found to contain a 2,745-bp ORF, a 243-bp untranslated region, and a GC-rich upstream sequence. They found a putative internal poly(A) site and presented amino acid sequences from 2 reading frames of the 2,745-bp ORF that may be related by ribosomal frameshifting. A 2.5-kb fragment of the DAN1 clone was used to probe Northern blots, from which they detected ubiquitous expression in brain, heart, skeletal muscle, and placenta. They also summarized their findings on the (CAG)n and (CAA)n repeats identified in both normal and affected individuals (see 601517.0001). From zoo blot analysis they found that the gene was highly conserved in 5 different mammalian species and in chicken. Imbert et al. (1996) reported that ATXN2 mutant protein is cytoplasmic in location and has an apparent molecular weight of 150 kD. </p><p>Nechiporuk et al. (1998) isolated and characterized the mouse homolog of the ATXN2 gene. Sequence and amino acid analyses revealed 89% and 91% identity at the nucleotide and amino acid level, respectively. However, there was no extended polyglutamine tract in the mouse Sca2 cDNA, suggesting that the normal function of ATXN2 is not dependent on this domain. Northern blot analysis of mouse tissues indicated that the mouse gene is expressed in most tissues, but at varying levels. Alternative splicing seen in human ATXN2 was conserved in the mouse. By Northern blot analysis, ATXN2 was found to be expressed during embryogenesis as early as day 8 of gestation. Immunohistochemical staining using affinity-purified antibodies demonstrated that ataxin-2 is expressed in the cytoplasm of Purkinje cells as well as in other neurons of the CNS. </p><p>By RT-PCR of human peripheral blood lymphocyte total RNA, Affaitati et al. (2001) cloned an ATXN21 splice variant lacking exon 21. In this variant, which the authors called ATXN2 type IV, exon 20 is spliced in-frame to exon 22, resulting in a deduced protein of 1,294 amino acids. RT-PCR detected both full-length ATXN2 and ATXN2 type IV in human brain, spinal cord, cerebellum, heart, and placenta. Both variants were also detected in mouse brain, heart, and liver, as well as in all stages of mouse development examined. </p>
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<strong>Gene Structure</strong>
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<p>By genomic sequence analysis, Sahba et al. (1998) determined that the ATXN2 gene contains 25 exons and spans approximately 130 kb. Exon sizes range from 37 to 890 bp. The CAG repeat is in exon 1. Sahba et al. (1998) also identified an isoform resulting from alternative splicing in exon 10, predicted to encode a protein truncated by 70 amino acids. </p>
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<strong>Gene Function</strong>
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<p>Sanpei et al. (1996) reported that ataxin-2 contained a consensus cleavage site (amino acids DXXD) for apopain (600636) at amino acid residues 397-400. They noted that apopain is the human counterpart of the nematode cysteine protease death-gene product CED3 and that apopain may be involved in the processing of huntingtin (613004). Furthermore, Goldberg et al. (1996) reported that the rate of cleavage increases with the length of the polyglutamine repeat and suggested that the truncated protein products may be toxic to neuronal cells. </p><p>Huynh et al. (1999) used antibodies to study the distribution of ataxin-2 in normal individuals and patients with SCA2. The staining was cytoplasmic. Highest levels were observed in the ependyma and choroid plexus. High levels were present in cerebellar Purkinje cells, large neurons of the substantia nigra, and the trochlear nuclei. Moderate staining was observed in apical cytoplasm of hippocampal and cortical pyramidal neurons, olivary nuclei, inferior colliculus, globus pallidus, and amygdala. Glial cells in the superficial molecular area of the cerebral cortex, granule cells in cortical layer II, and large neurons in the putamen were weakly labeled. The level of ataxin-2 in Purkinje cells of normal individuals increased with age. Staining was more intense in individuals with SCA2. </p><p>Using a yeast 2-hybrid system, Shibata et al. (2000) identified a novel protein, A2BP1 (ataxin-2-binding protein-1; 605104), which binds to the C terminus of ataxin-2. In sections from 3 SCA2 brains, neuronal labeling for A2BP1 as well as for ataxin-2 appeared to be enhanced and was more diffusely distributed. </p><p>Using yeast 2-hybrid screens, coaffinity purification analysis of transfected HEK293 cells, and bioinformatic analysis, Lim et al. (2006) developed an interaction network for 54 human proteins involved in 23 inherited ataxias. By database analysis, they expanded the core network to include more distantly related interacting proteins that could function as genetic modifiers. A majority (18 of 23) of ataxia-causing proteins interacted either directly or indirectly. A strong direct interaction was detected between ATXN1 and ATXN2. </p><p>Ralser et al. (2005) demonstrated that ataxin-2 interacted with endophilin-A1 (SH3GL2; 604465) and endophilin-A3 (SH3GL3; 603362). In a yeast model system, expression of ataxin-2 as well as both endophilin proteins was toxic for yeast lacking Sac6, which encodes fimbrin (PLS3; 300131) a protein involved in actin filament organization and endocytotic processes. Expression of huntingtin (613004), another polyglutamine protein interacting with endophilin-A3, was also toxic in Sac6-null yeast. These effects could be suppressed by simultaneous expression of 1 of the 2 human fimbrin orthologs, L-plastin (LCP1; 153430) or T-plastin (PLS3). Ataxin-2 associated with L- and T-plastin, and overexpression of ataxin-2 led to accumulation of T-plastin in mammalian cells. Ralser et al. (2005) suggested an interplay between ataxin-2, endophilin proteins, and huntingtin in plastin-associated cellular pathways. </p><p>Elden et al. (2010) showed that the polyglutamine repeat protein ataxin-2 is a potent modifier of TDP43 (605078) toxicity in animal and cellular models of ALS (105400). ATXN2 and TDP43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP43 shows mislocalization in spinocerebellar ataxia-2. </p><p>Lim and Allada (2013) found that Atx2 is a translational activator of the rate-limiting clock component Period (PER; 602260) in Drosophila. Atx2 specifically interacted with 'Twenty-four' (Tyf), an activator of Per translation. RNA interference-mediated depletion of Atx2 or the expression of a mutant Atx2 protein that does not associate with polyadenylate-binding protein (PABP; 604679) suppressed behavioral rhythms and decreased abundance of Per. Although Atx2 can repress translation, depletion of Atx2 from Drosophila S2 cells inhibited translational activation by RNA-tethered Tyf and disrupted the association between Tyf and Pabp. Thus, Lim and Allada (2013) concluded that ATX2 coordinates an active translation complex important for PER expression and circadian rhythms in Drosophila. </p><p>Zhang et al. (2013) independently found that the Drosophila homolog of ATXN2 was required for circadian locomotor behavior. Atx2 was necessary for Per accumulation in circadian pacemaker neurons and thus determined period length of circadian behavior. Atx2 was required for the function of Tyf, a crucial activator of Per translation. Atx2 formed a complex with Tyf and promoted its interaction with Pabp. Zhang et al. (2013) concluded that their work uncovered a role for ATX2 in circadian timing and revealed that this protein functions as an activator of PER translation in circadian neurons. </p><p>Ciura et al. (2016) found that coexpression of intermediate polyglutamine repeats (30Q) within ATXN2 combined with C9ORF72 (614260) depletion increased aggregation of ATXN2 and neuronal toxicity. They concluded that C9ORF72 interacts genetically with ATXN2. </p><p>A decrease in ataxin-2 suppresses TDP43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase the risk of ALS. Becker et al. (2017) used 2 independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP43 proteinopathy. First, they crossed ataxin-2 knockout mice with TDP43 transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP43, markedly increased survival, and improved motor function. Second, in a more therapeutically applicable approach, Becker et al. (2017) administered antisense oligonucleotides targeting ataxin-2 to the central nervous system of TDP43 transgenic mice. This single treatment markedly extended survival. Becker et al. (2017) suggested that, because TDP43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Spinocerebellar Ataxia 2</em></strong></p><p>
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In patients with spinocerebellar ataxia-2 (183090), Pulst et al. (1996) identified a (CAG)n repeat located in the 5-prime end of the coding region of the ATXN2 gene (601517.0001). Cancel et al. (1997) screened 184 index patients with autosomal dominant cerebellar ataxia type I for the CAG repeat in the ataxin-2 gene. They found the mutation in 109 patients from 30 families of different geographic origins (15%) and in 2 isolated cases with no known family histories (2%). The SCA2 chromosomes contained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14 to 31 repeats), except 1 with 14 repeats, were interrupted by 1 to 3 repeats of CAA. As in other diseases caused by unstable mutations, a strong negative correlation was observed between the age at onset and the size of the CAG repeat. Frequency of several clinical signs such as myoclonus, dystonia, and myokymia increased with the number of CAG repeats, whereas the frequency of others was related to disease duration. The CAG repeat was highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant difference according to the parental sex. This instability was confirmed by the high degree of gonadal mosaicism observed in sperm DNA of 1 patient. </p><p>Choudhry et al. (2001) identified 2 novel single-nucleotide polymorphisms (SNPs) in exon 1 of the ATXN2 gene and genotyped 215 normal and 64 expanded chromosomes. The 2 biallelic SNPs distinguished 2 haplotypes, GT and CC, each of which formed a predominant haplotype associated with normal and expanded ATXN2 alleles. All the expanded alleles segregated with CC haplotype, which otherwise was associated with only 29.3% of the normal chromosomes. CAA interspersion analysis revealed that a majority of the normal alleles with CC haplotype were either pure or lacked the most proximal 5-prime CAA interruption. The repeat length variation at the ATXN2 locus also appeared to be polar, with changes occurring mostly at the 5-prime end of the repeat. The authors concluded that CAA interruptions may play an important role in conferring stability to ATXN2 repeats and that their absence may predispose alleles towards instability and pathologic expansion. </p><p>Although repeat length and age at disease onset are inversely related, approximately 50% of the age at onset variance in SCA2 remains unexplained. Other familial factors have been proposed to account for at least part of the remaining variance in the polyglutamine disorders. The ability of polyglutamine tracts to interact with each other, as well as the presence of intranuclear inclusions in other polyglutamine disorders, led Hayes et al. (2000) to hypothesize that other CAG-containing proteins may interact with expanded ataxin-2 and affect the rate of protein accumulation, and thus influence age at onset. To test this hypothesis, they used step-wise multiple linear regression to examine 10 CAG-containing genes for possible influences on SCA2 age at onset. One locus, RAI1 (607642), contributed an additional 4.1% of the variance in SCA2 age at onset after accounting for the effect of the ATXN2 expanded repeat. SCA3 (109150) age at onset, on the other hand, showed no effect from the RAI1 locus. </p><p>Huynh et al. (2003) confirmed that ataxin-2 is predominantly located in the Golgi apparatus. Deletion of endoplasmic reticulum (ER) exit and trans-Golgi signals in ataxin-2 resulted in an altered subcellular distribution. Expression of full-length ataxin-2 with an expanded repeat disrupted the normal morphology of the Golgi complex and colocalization with Golgi markers was lost. Intranuclear inclusions were only seen when the polyQ repeat was expanded to 104 glutamines, and even then were only observed in a small minority of cells. Expression of ataxin-2 with expanded repeats in PC12 and COS-1 cells increased cell death compared with normal ataxin-2 and elevated the levels of activated caspase-3 (600636) and TdT-mediated dUTP nick end labeling (TUNEL)-positive cells. These results suggested a link between cell death mediated by mutant ataxin-2 and the stability of the Golgi complex. Huynh et al. (2003) concluded that formation of intranuclear aggregates is not necessary for in vitro cell death caused by expression of full-length mutant ataxin-2. </p><p><strong><em>Susceptibility to Late-Onset Parkinson Disease</em></strong></p><p>
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Gwinn-Hardy et al. (2000) described 4 patients from a Chinese kindred with parkinsonian features (168600) and CAG expansions at the SCA2 locus. The youngest patient had findings typical for the SCA2 ataxic phenotype, but also had parkinsonian features. His SCA2 CAG repeat length was 43. Three patients from earlier generations had mildly elevated CAG repeat lengths of 33 to 36 with varying phenotypes, but all predominantly parkinsonian features, including masked facies, diminished blink rate, and bradykinesia in addition to mild cerebellar findings such as broad-based gait. Two benefited from carbidopa-levodopa therapy. None of the patients had cognitive disturbance or resting tremor. The authors suggested that some cases of familial parkinsonism may be due to SCA2 mutations. </p><p>Among 23 Chinese patients with familial parkinsonism, Shan et al. (2001) identified 2 patients who had expanded trinucleotide repeats (mildly elevated at 36 and 37 repeats) in the ATXN2 gene. Both patients had onset of leg tremor at age 50 years, followed by gait difficulty, rigidity, and slow, hypometric saccades. L-DOPA produced marked improvement in symptoms in both patients. In addition, PET scan showed reduced dopamine distribution in the caudate and putamen in both patients. Shan et al. (2001) noted that these 2 patients represented approximately one-tenth of their population with familial parkinsonism. </p><p>Charles et al. (2007) found that 3 (2%) of 164 French families with autosomal dominant parkinsonism (168600) had SCA2 expansions ranging in size from 37 to 39 repeats that were interrupted by CAA triplets. These interrupted expansions were stable in transmission. All 9 patients had levodopa-responsive parkinsonism without cerebellar signs and had less rigidity and more symmetric signs compared to patients with other causes of PD. Two sisters with both the SCA2 expansion and the LRRK2 mutation G2019S (609007.0006) had earlier onset that their mother who had only the SCA2 expansion, suggesting an additive pathogenic effect in the sisters. As a phenotypic comparison, 53 SCA2 patients with similar-sized, uninterrupted SCA2 repeats showed predominant cerebellar ataxia with rare signs of parkinsonism. The findings suggested that the configuration of SCA2 repeat expansions plays an important role in phenotypic variability. </p><p>Ross et al. (2011) found no association between intermediate ATXN2 CAG repeat expansions (greater than 30 units; 601517.0002) and PD in a study of 702 patients with Parkinson disease and 4,877 controls. Expansions were found in 2 (0.3%) patients and 9 (0.2%) controls. </p><p><strong><em>Susceptibility to Amyotrophic Lateral Sclerosis 13</em></strong></p><p>
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The genetic, biochemical, and neuropathologic interactions between TDP43 and ATXN2 raised the possibility to Elden et al. (2010) that mutations in ATXN2 could have a causative role in ALS (see ALS13, 183090). The ATXN2 polyQ tract length, although variable, is most frequently 22-23, with expansions of greater than 34 causing SCA2. However, the variable nature of the polyQ repeat indicated a mechanism by which such mutations in ATXN2 could be linked to ALS: Elden et al. (2010) proposed that intermediate-length expansions greater than 23 but below the threshold for SCA2 may be associated with ALS. They studied the frequency of intermediate-length ATXN2 polyglutamine repeats in ALS, comparing 915 subjects with ALS with 980 neurologically normal subjects. Among those with ALS, 4.7% had repeat lengths of 27 to 33, whereas only 1.4% of neurologically normal subjects had glutamine expansions. The P value for this difference was 3.6 x 10(-5) with an odds ratio of 2.80. </p><p>In a case-control study of 556 ALS patients and 471 controls of French or French Canadian origin, Daoud et al. (2011) found that 7.2% of patients and 5.1% of controls had 1 intermediate repeat allele (24-33 repeats), which was not significantly different. However, receiver operating characteristic curve analysis yielded a significant association between ALS and high-length ATXN2 repeat alleles (more than 29 CAG repeats). CAG repeats of 29 or higher were found in only 4 controls (0.8%), whereas they were found in 25 patients (4.5%) (OR, 5.5; p = 2.4 x 10(-4)). The association was even stronger for familial cases when stratified by familial versus sporadic cases (OR for familial cases, 9.29; p = 5.2 x 10(-5)). There was no correlation between size of repeat and age of onset. In addition, 2 familial and 9 sporadic ALS cases carried SCA2-sized pathogenic alleles (greater than 32 repeats), and none of them had features of SCA2 such as cerebellar or brainstem atrophy. </p><p>Among 1,845 sporadic and 103 familial ALS cases and 2,002 controls from Belgium and the Netherlands, Van Damme et al. (2011) found an association between ALS and an expanded CAG repeat of 29 or greater in the ATXN2 gene (OR, 1.92; p = 0.036). In controls, the repeat length ranged from 16 to 31, with 22 being the most abundant. Repeat sizes of 31 or less were not significantly different between patients and controls. However, receiver operating characteristic analysis showed that the greatest sensitivity and specificity of discriminating ALS from control was using a cutoff of 29 repeats: 1.5% of patients had 29 or more repeats compared to 0.8% of controls (OR, 1.92; p = 0.036). There was no correlation between repeat length and disease parameters. When combined in a metaanalysis with the data of Elden et al. (2010), the association was highly significant (OR, 2.93; p less than 0.0001). Ten patients (0.05%) with sporadic ALS had repeat sizes of 32 or more, and none of these patients had signs of SCA2. Two of 91 families with ALS (2.2%) had expanded repeats: 1 with 31 repeats and the other with 33 repeats. In the 33-repeat family, which was consanguineous, 2 affected individuals had repeat expansions on both alleles, 33:33 and 33:31, respectively, although the phenotype was not significantly different from classic ALS, except for some sensory abnormalities. Two sibs from a third family with a heterozygous repeat length of 34 and 35, respectively, had classic SCA2 with no signs of upper motor neuron involvement. The findings indicated a genetic overlap between SCA2 and ALS13. </p><p>Among 3,919 patients with various neurodegenerative diseases, including 532 with ALS, 641 with frontotemporal dementia (FTD; 600274), 1,530 with Alzheimer disease (AD; 104300), 702 with Parkinson disease (PD; 168600), and 514 with progressive supranuclear palsy (PSP; 601104), and 4,877 healthy controls, Ross et al. (2011) found that ATXN2 repeat lengths greater than 30 units were significantly associated with ALS (odds ratio of 5.57; p = 0.001) and with PSP (OR of 5.83; p = 0.004). Significant associations between repeats greater than 30 were not observed in patients with FTD, AD, or PD. Importantly, expanded repeat alleles (31 to 33) were also observed in 9 (0.2%) control individuals, indicating that caution should be taken when attributing specific disease phenotypes to these repeat lengths. However, 6 of the controls with expanded repeats were under the mean onset age of all patient groups except PD. The findings confirmed the role of ATXN2 as an important risk factor for ALS and suggested that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy. </p><p>Mutations in FUS (137070) cause amyotrophic lateral sclerosis-6 (ALS6; 608030). Farg et al. (2013) found that ataxin-2 with an intermediate glutamine expansion (Q31) interacted with wildtype FUS and, more strongly, with FUS containing the arg521-to-cys (R521C; 137070.0004) or arg521-to-his (R521H; 137070.0005) mutations. The interactions were independent of RNA. Ataxin-2 colocalized with FUS in sporadic and FUS-linked familial ALS patient motor neurons, coprecipitated with FUS in ALS spinal cord lysates, and colocalized with FUS in the ER and Golgi compartments in a mouse neuronal cell line. Ataxin-2 Q31 exacerbated the cellular phenotype of mutant FUS, increasing translocation of FUS from the nucleus to the cytoplasm, markers of ER stress, and Golgi fragmentation. Neither FUS with the R521H mutation nor ataxin-2 Q31 alone induced apoptosis in transfected mouse neuronal cells, but coexpression of both induced markers of early apoptosis. </p>
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<strong>Animal Model</strong>
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<p>Kiehl et al. (2006) found that Atxn2 -/- mice appeared normal and were fertile, but there was a significant reduction in the number of female Atxn2 +/- and Atxn2 -/- mice born. Histopathologic examination of the central nervous system and other organs demonstrated no morphologic abnormalities in Atxn2 -/- mice except in liver, which showed micro- and macrovesicular steatosis at 1 year of age. At this age, Atxn2 -/- mice were also susceptible to adult-onset obesity when placed on a moderately fat-enriched diet, but not when placed on a low-fat diet. Atxn2 -/- mice showed a slight deficit in motor performance in the rotarod test compared with wildtype controls. </p><p>Lastres-Becker et al. (2008) found that Atxn2 -/- mice showed reduced fertility, locomotor hyperactivity, and abdominal obesity and hepatosteatosis by age 6 months. Insulin levels were increased in pancreas and blood, consistent with insulin resistance, and the mice demonstrated increased serum cholesterol levels. These changes were associated with reduced insulin receptor (INSR; 147670) expression in liver and cerebellum, although the mRNA levels were increased, suggesting a posttranscriptional effect on the insulin receptor status. Thus, loss of Atxn2 may affect cellular endocytosis machinery. Analysis of brain lipids in Atxn2 -/- mice showed increased gangliosides and decreased sphingomyelin in the cerebellum, and there was evidence for altered cholesterol homeostasis. Lastres-Becker et al. (2008) postulated that these lipid changes may alter neuronal membrane signaling and excitability. </p><p>Using the promoter region of Purkinje cell protein-2 (PCP2), Hansen et al. (2013) created transgenic mice expressing human ATXN2 with a polyglutamine tract of 127 residues (ATXN2(Q127)) specifically in cerebellar Purkinje cells. Biochemical, behavioral, and electrophysiologic measures revealed no difference between ATXN2(Q127) animals and wildtype controls prior to 4 weeks of age. However, at 4 weeks of age, transgenic mice began to show reduced expression of select cerebellar genes, including Calb1 (114050) and Pcp2. At 8 weeks of age, ATXN2(Q127) animals showed reduced Purkinje cell firing frequency, followed by deficits in motor behavior. After 12 weeks of age, they showed reduced Purkinje cell numbers. </p><p>Using a zebrafish model, Ciura et al. (2016) showed that partial knockdown of C9orf72 combined with intermediate repeat expansion of Atxn2 caused locomotion deficits and abnormal axonal projections from spinal motor neurons. </p><p><strong><em>Therapy</em></strong></p><p>
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Scoles et al. (2017) developed an antisense oligonucleotide, ASO7, that downregulated ATXN2 mRNA and protein, which resulted in delayed onset of the SCA2 phenotype. After delivery by intracerebroventricular injection to ATXN2-Q127 mice, ASO7 localized to Purkinje cells, reduced cerebellar ATXN2 expression below 75% for more than 10 weeks without microglial activation, and reduced the levels of cerebellar ATXN2. Treatment of symptomatic mice with ASO7 improved motor function compared to saline-treated mice. ASO7 had a similar effect in the BAC-Q72 SCA2 mouse model, and in both mouse models it normalized protein levels of several SCA2-related proteins expressed in Purkinje cells, including Rgs8, Pcp2, Pcp4, Homer3, Cep76 (620791), and Fam107b. Notably, the firing frequency of Purkinje cells returned to normal even when treatment was initiated more than 12 weeks after the onset of the motor phenotype in BAC-Q72 mice. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>2 Selected Examples):</strong>
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<strong>.0001 SPINOCEREBELLAR ATAXIA 2</strong>
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PARKINSON DISEASE, LATE-ONSET, SUSCEPTIBILITY TO, INCLUDED
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ATXN2, (CAG)n REPEAT EXPANSION, LONG
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SNP: rs1885090126,
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ClinVar: RCV001195091, RCV003485686
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<p>In patients with spinocerebellar ataxia-2 (183090), Pulst et al. (1996) identified a (CAG)n repeat located in the 5-prime end of the coding region of the ATXN2 gene. They detected expansions of 36 to 52 repeats in affected individuals the most common allele contained 37 repeats. They noted that the ATXN2 repeat is unusual in that only 2 alleles were demonstrated in the normal population. A common allele with 22 repeats was found in people of European descent. Using RT-PCR, Pulst et al. (1996) determined that the ATXN2 (CAG)n repeat is transcribed in lymphoblastoid cell lines and that the cells could be used to express the expanded repeat genes from patients with SCA2. </p><p>Sanpei et al. (1996) analyzed 286 normal chromosomes and found that the (CAG)n repeats ranged in size from 15 to 24, with a unit of 22 repeats accounting for 94% of the alleles. In contrast, SCA2 patient chromosomes contained expanded repeats ranging in size from 35 to 59 units. Sanpei et al. (1996) reported that there was a strong inverse correlation between the size of the repeat and the onset of symptoms. Imbert et al. (1996) reported that normal ATXN2 alleles contained 17 to 29 (CAG)n repeats and 1 to 3 (CAA)n repeats (also glutamine-encoding). Mutated alleles contained 37 to 50 repeats and appeared to be particularly unstable in maternal and paternal transmissions. Sequence analysis of expanded repeats from 3 individuals revealed pure CAG stretches. Imbert et al. (1996) reported that there was a steep inverse correlation between the age of onset of disease and (CAG)n repeat number. </p><p>Susceptibility to Late-Onset Parkinson Disease</p><p>Gwinn-Hardy et al. (2000) described 4 patients from a Chinese kindred with parkinsonian features (168600) and CAG expansions at the SCA2 locus. The youngest patient had findings typical for the SCA2 ataxic phenotype, but also had parkinsonian features. His SCA2 CAG repeat length was 43. Three patients from earlier generations had mildly elevated CAG repeat lengths of 33 to 36 with varying phenotypes, but all predominantly parkinsonian features, including masked facies, diminished blink rate, and bradykinesia in addition to mild cerebellar findings such as broad-based gait. Two benefited from carbidopa-levodopa therapy. None of the patients had cognitive disturbance or resting tremor. The authors suggested that some cases of familial parkinsonism may be due to SCA2 mutations. </p><p>Charles et al. (2007) found that 3 (2%) of 164 French families with autosomal dominant parkinsonism (168600) had SCA2 expansions ranging in size from 37 to 39 repeats that were interrupted by CAA triplets. These interrupted expansions were stable in transmission. All 9 patients had levodopa-responsive parkinsonism without cerebellar signs and had less rigidity and more symmetric signs compared to patients with other causes of PD. Two sisters with both the SCA2 expansion and the LRRK2 mutation G2019S (609007.0006) had earlier onset that their mother who had only the SCA2 expansion, suggesting an additive pathogenic effect in the sisters. As a phenotypic comparison, 53 SCA2 patients with similar-sized, uninterrupted SCA2 repeats showed predominant cerebellar ataxia with rare signs of parkinsonism. The findings suggested that the configuration of SCA2 repeat expansions plays an important role in phenotypic variability. </p>
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<span class="mim-font">
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<strong>.0002 AMYOTROPHIC LATERAL SCLEROSIS, SUSCEPTIBILITY TO, 13</strong>
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</span>
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</h4>
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ATXN2, (CAG)n REPEAT EXPANSION, INTERMEDIATE
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<br />
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SNP: rs1885090126,
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ClinVar: RCV000008583
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<p>Among 915 patients with amyotrophic lateral sclerosis, Elden et al. (2010) identified 43 (4.7%) with expansions of the ATXN2 polyQ repeat of intermediate length, 27 through 33 repeats (ALS13; 183090). Among a neurologically normal control cohort of 980 individuals, similar expansions were detected in only 14 (1.4%) individuals (p = 3.6 x 10(-5), odds ratio, 2.80, 95% CI, 1.54-5.12). Elden et al. (2010) analyzed ATXN2 protein levels in patient-derived lymphoblastoid cells from ALS cases harboring intermediate-length polyQ expansions, ALS cases with normal-range repeat lengths, and controls. These studies showed that whereas the steady state levels of ATXN2 were comparable, cycloheximide treatment, which blocks new protein synthesis, revealed an increase in stability (or decreased degradation) of ATXN2 in cells with intermediate-length polyQ repeats. Elden et al. (2010) then found that polyQ expansions in ATXN2 enhance its interaction with TDP43 (605078). Both ATXN2 and TDP43 relocalize to stress granules, sites of RNA processing, under various stress situations such as heat shock and oxidative stress. Under normal conditions TDP43 localized to the nucleus and ATXN2 to the cytoplasm in both control cells and cells harboring polyQ repeat expansions. Elden et al. (2010) proposed that intermediate-length ATXN2 polyQ repeats might confer genetic risk for ALS by making TDP43 more prone to mislocalize from the nucleus to the cytoplasm under situations of stress. </p><p>The findings of Elden et al. (2010) were replicated in 2 independent studies by Daoud et al. (2011) and Van Damme et al. (2011), who studied French, French Canadian, and Belgian populations. Each study identified an association between development of ALS and high-length ATXN2 repeat alleles (29 or more repeats), using receiver operating characteristic curve analysis of patients and controls. Neither study found a correlation between size of repeat and disease parameters. Moreover, each study found ALS patients with expansion sizes in the range of SCA2 (greater than 32 repeats), and none had features of SCA2 such as cerebellar or brainstem atrophy. The findings indicated a genetic overlap between SCA2 and ALS13. </p><p>Corrado et al. (2011) identified intermediate expansion of the CAG repeat (greater than 30 repeats) in exon 1 of the ATXN2 gene in 7 (3.0%) of 232 Italian patients with ALS. None of 395 controls had an allele larger than 30 repeats. Four of the 7 patients had an allele in the intermediate-fully pathologic range: 1 with 32 repeats, 2 with 33 repeats, and 1 with 37 repeats, accounting for 1.7% of the ALS cohort. Sequencing of these fully expanded alleles showed that they were all interrupted with at least one CAA triplet. The phenotype of the patients was typical of ALS with no signs or symptoms of ataxia or parkinsonism. </p><p>Among 3,919 patients with various neurodegenerative diseases, including 532 with ALS, 641 with frontotemporal dementia (FTD; 600274), 1,530 with Alzheimer disease (AD; 104300), 702 with Parkinson disease (PD; 168600), and 514 with progressive supranuclear palsy (PSP; see 601104), and 4,877 healthy controls, Ross et al. (2011) found that ATXN2 repeat lengths greater than 30 units were significantly associated with ALS (odds ratio of 5.57; p = 0.001) and with PSP (OR of 5.83; p = 0.004). Repeat expansions were found in 8 (1.5%) ALS patients, 4 (0.8%) PSP patients, and 9 (0.2%) controls. Significant associations between repeats greater than 30 were not observed in patients with FTD, AD, or PD. The findings of expanded repeat alleles (31 to 33) in control individuals indicated that caution should be taken when attributing specific disease phenotypes to these repeat lengths. However, 6 of the controls with expanded repeats were under the mean onset age of all patient groups except PD. The findings confirmed the role of ATXN2 as an important risk factor for ALS and suggested that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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Ada Hamosh - updated : 03/12/2018<br>Ada Hamosh - updated : 03/12/2018<br>Paul J. Converse - updated : 10/10/2017<br>Patricia A. Hartz - updated : 5/23/2014<br>Patricia A. Hartz - updated : 7/17/2013<br>Ada Hamosh - updated : 6/24/2013<br>Cassandra L. Kniffin - updated : 5/30/2012<br>Cassandra L. Kniffin - updated : 11/7/2011<br>Cassandra L. Kniffin - updated : 10/6/2011<br>Ada Hamosh - updated : 9/14/2010<br>Cassandra L. Kniffin - updated : 7/29/2010<br>George E. Tiller - updated : 4/22/2009<br>Patricia A. Hartz - updated : 1/15/2009<br>George E. Tiller - updated : 4/22/2005<br>Victor A. McKusick - updated : 3/21/2003<br>Cassandra L. Kniffin - reorganized : 9/13/2002<br>George E. Tiller - updated : 5/3/2002<br>Victor A. McKusick - updated : 8/28/2000<br>George E. Tiller - updated : 6/30/2000<br>Paul J. Converse - updated : 6/7/2000<br>Orest Hurko - updated : 3/22/1999<br>Stylianos E. Antonarakis - updated : 10/8/1998<br>Victor A. McKusick - updated : 6/23/1997
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