3539 lines
328 KiB
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328 KiB
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Entry
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- *603680 - ATAXIN 8 OPPOSITE STRAND; ATXN8OS
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*603680</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#populationGenetics">Population Genetics</a>
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/603680">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 role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000230223;t=ENST00000678624" 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=6315" 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=603680" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000230223;t=ENST00000678624" 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</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NR_002717,NR_185834,NR_185835,NR_185836,NR_185837,NR_185838,NR_185839,NR_185840,NR_185841,NR_185842" 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://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=603680" 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://www.proteinatlas.org/search/ATXN8OS" 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.uniprot.org/uniprotkb/P0DMR3" 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=6315" 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=ENSG00000230223;t=ENST00000678624" 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=ATXN8OS" 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=ATXN8OS" 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+6315" 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/ATXN8OS" 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:6315" 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/6315" 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=chr13&hgg_gene=ENST00000678624.1&hgg_start=70107421&hgg_end=70171738&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=603680[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=603680[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://gnomad.broadinstitute.org/gene/ENSG00000230223" 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=ATXN8OS" 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=ATXN8OS" 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=ATXN8OS" 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=ATXN8OS&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/PA34974" 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:10561" 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="http://v1.marrvel.org/search/gene/ATXN8OS#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="https://www.ncbi.nlm.nih.gov/gene/6315/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=6315" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:6315" 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=ATXN8OS&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> 715753001<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>
|
|
603680
|
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</span>
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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|
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ATAXIN 8 OPPOSITE STRAND; ATXN8OS
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
|
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SCA8 GENE; SCA8<br />
|
|
KLHL1AS
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ATXN8OS" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ATXN8OS</a></em></strong>
|
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</span>
|
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</p>
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/13/213?start=-3&limit=10&highlight=213">13q21.33</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr13:70107421-70171738&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'})">13:70,107,421-70,171,738</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
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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>
|
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</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
|
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<tr class="active">
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<th>
|
|
Location
|
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</th>
|
|
<th>
|
|
Phenotype
|
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|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=168600,608768" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/13/213?start=-3&limit=10&highlight=213">
|
|
13q21.33
|
|
</a>
|
|
</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
{Parkinson disease, 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">
|
|
|
|
<a href="/entry/168600"> 168600 </a>
|
|
|
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</span>
|
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</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>
|
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|
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</span>
|
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</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>
|
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia 8
|
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|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/608768"> 608768 </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>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
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</tbody>
|
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</table>
|
|
</div>
|
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</div>
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<div>
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<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/603680" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/603680" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<div>
|
|
<p />
|
|
</div>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
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|
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<div>
|
|
<a id="text" class="mim-anchor"></a>
|
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|
|
<h4>
|
|
|
|
<span class="mim-font">
|
|
<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
|
</h4>
|
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|
|
|
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|
|
<div>
|
|
<a id="description" class="mim-anchor"></a>
|
|
<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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|
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<div id="mimDescriptionFold" class="collapse in ">
|
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<span class="mim-text-font">
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<p>Spinocerebellar ataxia-8 (SCA8; <a href="/entry/608768">608768</a>) is a neurodegenerative disorder caused by a CTG/CAG trinucleotide repeat expansion on chromosome 13q21 (see <a href="#0001">603680.0001</a> and <a href="/entry/613289#0001">613289.0001</a>). Two genes span the CTG/CAG repeat and are expressed in opposite directions: ATXN8 (<a href="/entry/613289">613289</a>), which encodes a nearly pure polyglutamine expansion protein in the CAG direction, and ATXN8OS, which, when transcribed, produces a noncoding CUG expansion RNA (<a href="#15" class="mim-tip-reference" title="Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., Chen, G., Weatherspoon, M. R., Clark, H. B., Ebner, T. J., Day, J. W., Ranum. L. P. W. <strong>Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8.</strong> Nature Genet. 38: 758-769, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804541</a>] [<a href="https://doi.org/10.1038/ng1827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804541">Moseley et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16804541" 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>While searching for CAG repeat disorders in patients with undefined dominantly inherited ataxias, <a href="#11" class="mim-tip-reference" title="Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong> Nature Genet. 21: 379-384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>] [<a href="https://doi.org/10.1038/7710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192387">Koob et al. (1999)</a> identified 80 uninterrupted CAG repeats followed by 11 TAG repeats in genomic DNA from a mother and daughter with adult-onset spinocerebellar ataxia (SCA8; <a href="/entry/608768">608768</a>). The expansion was isolated directly from genomic DNA by RAPID (repeat analysis, pooled isolation, and detection) cloning. By strand-specific analysis, <a href="#11" class="mim-tip-reference" title="Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong> Nature Genet. 21: 379-384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>] [<a href="https://doi.org/10.1038/7710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192387">Koob et al. (1999)</a> determined that the SCA8 repeat was transcribed in the CTG orientation (reading 5-prime to 3-prime) on the complementary antisense strand from that of the CAG repeat. <a href="#11" class="mim-tip-reference" title="Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong> Nature Genet. 21: 379-384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>] [<a href="https://doi.org/10.1038/7710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192387">Koob et al. (1999)</a> found that the CTG repeat is present in the 3-prime terminal exon of the ATXN8OS gene, which they called SCA8, and is located in the 3-prime UTR of the ATXN8OS transcript, which has no ORFs. RT-PCR on cerebellum RNA from 2 unaffected individuals heterozygous for the SCA8 CTG marker detected both alleles in each RNA sample. Alternatively spliced ATXN8OS transcripts lacking an exon were also detected. The ATXN8OS transcript was detected at low levels in whole brain and lung by RT-PCR. Further analysis identified an mRNA transcribed in the opposite orientation to that of the ATXN8OS transcript, KLHL1 (<a href="/entry/605332">605332</a>), suggesting that ATXN8OS is an endogenous antisense RNA. The SCA8 CTG repeat is present in the antisense transcript, but not the KLHL1 sense transcript. Although the studies of <a href="#11" class="mim-tip-reference" title="Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong> Nature Genet. 21: 379-384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>] [<a href="https://doi.org/10.1038/7710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192387">Koob et al. (1999)</a> indicated that there is no translation of the SCA8 repeat in the CAG orientation into a polyglutamine tract, later studies by <a href="#15" class="mim-tip-reference" title="Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., Chen, G., Weatherspoon, M. R., Clark, H. B., Ebner, T. J., Day, J. W., Ranum. L. P. W. <strong>Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8.</strong> Nature Genet. 38: 758-769, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804541</a>] [<a href="https://doi.org/10.1038/ng1827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804541">Moseley et al. (2006)</a> showed that the CAG repeat on the sense strand is in the ATXN8 gene (<a href="/entry/613289">613289</a>) and is transcribed and translated. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10192387+16804541" 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="#11" class="mim-tip-reference" title="Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong> Nature Genet. 21: 379-384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>] [<a href="https://doi.org/10.1038/7710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192387">Koob et al. (1999)</a> determined that the ATXN8OS gene contains 4 exons, at least 1 of which is alternatively spliced. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10192387" 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="Nemes, J. P., Benzow, K. A., Moseley, M. L., Ranum, L. P. W., Koob, M. D. <strong>The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1).</strong> Hum. Molec. Genet. 9: 1543-1551, 2000. Note: Erratum: Hum. Molec. Genet. 9: 2777 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888605</a>] [<a href="https://doi.org/10.1093/hmg/9.10.1543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888605">Nemes et al. (2000)</a> assembled a 166-kb segment of genomic sequence containing the SCA8 repeat. ATXN8OS RNA transcripts containing the SCA8 CUG repeat tract are alternatively spliced, contain up to 5 exons, and span a genomic region of over 32 kb. The SCA8 CUG repeat is in the 3-prime terminal exon of these ATXN8OS transcripts, although <a href="#16" class="mim-tip-reference" title="Nemes, J. P., Benzow, K. A., Moseley, M. L., Ranum, L. P. W., Koob, M. D. <strong>The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1).</strong> Hum. Molec. Genet. 9: 1543-1551, 2000. Note: Erratum: Hum. Molec. Genet. 9: 2777 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888605</a>] [<a href="https://doi.org/10.1093/hmg/9.10.1543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888605">Nemes et al. (2000)</a> also identified transcripts with an alternative 3-prime terminal exon that lack the SCA8 repeat. They found that the most 5-prime exon of ATXN8OS is transcribed through the first exon of another gene, KLHL1 (<a href="/entry/605332">605332</a>), that is transcribed in the opposite orientation. This gene arrangement suggested that the ATXN8OS transcript may be an endogenous antisense RNA that overlaps the transcription and translation start sites as well as the first splice donor sequence of the sense gene, KLHL1. Since both of these genes are expressed in the cerebellum, <a href="#16" class="mim-tip-reference" title="Nemes, J. P., Benzow, K. A., Moseley, M. L., Ranum, L. P. W., Koob, M. D. <strong>The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1).</strong> Hum. Molec. Genet. 9: 1543-1551, 2000. Note: Erratum: Hum. Molec. Genet. 9: 2777 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888605</a>] [<a href="https://doi.org/10.1093/hmg/9.10.1543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888605">Nemes et al. (2000)</a> suggested that the pathogenic effect of the expansion may be mediated either directly or indirectly through one or both of these transcripts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10888605" 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="Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., Chen, G., Weatherspoon, M. R., Clark, H. B., Ebner, T. J., Day, J. W., Ranum. L. P. W. <strong>Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8.</strong> Nature Genet. 38: 758-769, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804541</a>] [<a href="https://doi.org/10.1038/ng1827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804541">Moseley et al. (2006)</a> determined that the ATXN8OS gene contains at least 6 exons that are subject to extensive alternative splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16804541" 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 PCR analysis of a chromosome hybrid panel and the CEPH library, <a href="#11" class="mim-tip-reference" title="Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong> Nature Genet. 21: 379-384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>] [<a href="https://doi.org/10.1038/7710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192387">Koob et al. (1999)</a> mapped the SCA8 CTG expansion, which is located within the 3-prime end of the ATXN8OS gene, to chromosome 13q21. <a href="#16" class="mim-tip-reference" title="Nemes, J. P., Benzow, K. A., Moseley, M. L., Ranum, L. P. W., Koob, M. D. <strong>The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1).</strong> Hum. Molec. Genet. 9: 1543-1551, 2000. Note: Erratum: Hum. Molec. Genet. 9: 2777 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888605</a>] [<a href="https://doi.org/10.1093/hmg/9.10.1543" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10888605">Nemes et al. (2000)</a> determined that the 5-prime end of the ATXN8OS gene overlaps the 5-prime end of the KLHL1 gene (<a href="/entry/605332">605332</a>) in the opposite orientation. <a href="#15" class="mim-tip-reference" title="Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., Chen, G., Weatherspoon, M. R., Clark, H. B., Ebner, T. J., Day, J. W., Ranum. L. P. W. <strong>Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8.</strong> Nature Genet. 38: 758-769, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804541</a>] [<a href="https://doi.org/10.1038/ng1827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804541">Moseley et al. (2006)</a> determined that the 3-prime end of the ATXN8OS gene, including the CTG expansion region, overlaps the 3-prime end of the ATXN8 gene (<a href="/entry/613289">613289</a>) in the opposite orientation. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10192387+10888605+16804541" 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 8 pedigrees with autosomal dominant spinocerebellar ataxia-8 (SCA8; <a href="/entry/608768">608768</a>), <a href="#11" class="mim-tip-reference" title="Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong> Nature Genet. 21: 379-384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>] [<a href="https://doi.org/10.1038/7710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192387">Koob et al. (1999)</a> identified CTG repeat expansions in the ATXN8OS gene (<a href="#0001">603680.0001</a>), on the opposite stand of the ATXN8 gene (<a href="/entry/613298">613298</a>). This 5-prime to 3-prime CTG repeat in ATXN8OS resulted in the production of an mRNA with an expanded CUG repeat in the 3-prime UTR. In the largest pedigree, which included affected members spanning at least 4 generations, repeat length ranged from 107 to 127 CTG repeats. However, 20 unaffected individuals also carried expanded repeats. A study of 1,200 alleles from the general population found that normal repeat length was 16 to 37 repeats in 99% of alleles; repeat lengths of up to 91 were seen in a small proportion of controls. Like the CTG expansion in DM, repeat length contracted with paternal transmission (-86 to +7) and expanded with maternal transmission (-11 to +600). <a href="#11" class="mim-tip-reference" title="Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong> Nature Genet. 21: 379-384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>] [<a href="https://doi.org/10.1038/7710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192387">Koob et al. (1999)</a> noted that maternal bias towards expansion had not been seen in the CAG repeat disorders causing other SCAs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10192387" 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="Stevanin, G., Herman, A., Durr, A., Jodice, C., Frontali, M., Agid, Y., Brice, A. <strong>Are (CTG)n expansions at the SCA8 locus rare polymorphisms? (Letter)</strong> Nature Genet. 24: 213 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700167</a>] [<a href="https://doi.org/10.1038/73408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700167">Stevanin et al. (2000)</a> and <a href="#25" class="mim-tip-reference" title="Worth, P. F., Houlden, H., Giunti, P., Davis, M. B., Wood, N. W. <strong>Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. (Letter)</strong> Nature Genet. 24: 214-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700168</a>] [<a href="https://doi.org/10.1038/73411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700168">Worth et al. (2000)</a> presented data challenging the significance of the expanded SCA8 repeat in SCA. Among 376 French control chromosomes, <a href="#20" class="mim-tip-reference" title="Stevanin, G., Herman, A., Durr, A., Jodice, C., Frontali, M., Agid, Y., Brice, A. <strong>Are (CTG)n expansions at the SCA8 locus rare polymorphisms? (Letter)</strong> Nature Genet. 24: 213 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700167</a>] [<a href="https://doi.org/10.1038/73408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700167">Stevanin et al. (2000)</a> found that 373 (99%) carried 3 to 28 repeats, whereas 3 alleles carried expanded repeats of 107, 111, and 123 repeats. Among 250 European index patients with different forms of ataxia, 487 chromosomes contained 2 to 25 repeats and 13 chromosomes (11 patients, including 2 homozygotes) contained 68 to 123 repeats. They found expansions of more than 91 repeats in 8 of 148 autosomal dominant cerebellar ataxia (ADCA) families, in an apparently sporadic ataxia patient, in a patient with neuropathologically confirmed Lafora disease, and in a patient with familial essential tremor. <a href="#20" class="mim-tip-reference" title="Stevanin, G., Herman, A., Durr, A., Jodice, C., Frontali, M., Agid, Y., Brice, A. <strong>Are (CTG)n expansions at the SCA8 locus rare polymorphisms? (Letter)</strong> Nature Genet. 24: 213 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700167</a>] [<a href="https://doi.org/10.1038/73408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700167">Stevanin et al. (2000)</a> suggested that the expanded repeat is a rare polymorphism. Among 1,306 control chromosomes, <a href="#25" class="mim-tip-reference" title="Worth, P. F., Houlden, H., Giunti, P., Davis, M. B., Wood, N. W. <strong>Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. (Letter)</strong> Nature Genet. 24: 214-215, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700168</a>] [<a href="https://doi.org/10.1038/73411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700168">Worth et al. (2000)</a> found that 97% contained 15 to 31 repeats, whereas 5 had large, expanded alleles of 174, 133, 103, 101, and 100 repeats. Among 98 unrelated cases of ADCA, 1 patient had alleles with 23 and 152 CTA/CTG repeats. However, the 92-year-old asymptomatic mother of another affected patient carried 127 repeats, and the authors concluded that the expanded alleles may be polymorphisms in linkage disequilibrium with mutations in a different gene on 13q21. <a href="#13" class="mim-tip-reference" title="Moseley, M. L., Schut, L. J., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>Reply to Stevanin et al. and Worth et al. (Letter)</strong> Nature Genet. 24: 215 only, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700169</a>] [<a href="https://doi.org/10.1038/73415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10700169">Moseley et al. (2000)</a> referred to 5 lines of evidence they thought supported the hypothesis that the SCA8 CTG expansion causes ataxia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10700168+10700169+10700167" 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="#18" class="mim-tip-reference" title="Silveira, I., Alonso, I., Guimaraes, L., Mendonca, P., Santos, C., Maciel, P., Fidalgo de Matos, J. M., Costa, M., Barbot, C., Tuna, A., Barros, J., Jardim, L., Coutinho, P., Sequeiros, J. <strong>High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles.</strong> Am. J. Hum. Genet. 66: 830-840, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712199</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712199[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712199">Silveira et al. (2000)</a> found that normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15 to 21 CTGs), intermediate (22 to 37 CTGs), and large (40 to 91 CTGs) alleles; large alleles accounted for only 0.7% of all normal-size alleles. No expanded alleles (more than 100 CTGs) were found in controls. Expansion of the CTG tract was found in 5 families with ataxia; expanded alleles, all paternally transmitted, were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in 1 patient, an expanded allele of 152 CTGs had mostly contraction in size, often into the normal range; in the sperm of 2 normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, their results showed no overlapping between control (15-91) and pathogenic (100-152) alleles, and a high instability in spermatogenesis for both expanded and normal alleles, suggesting a high mutation rate at the SCA8 locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10712199" 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 contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with 1 or more CCG, CTA, CTC, CCA, or CTT interruptions. By analyzing sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members from the large 7-generation SCA8 family reported by <a href="#11" class="mim-tip-reference" title="Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong> Nature Genet. 21: 379-384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>] [<a href="https://doi.org/10.1038/7710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192387">Koob et al. (1999)</a>, <a href="#14" class="mim-tip-reference" title="Moseley, M. L., Schut, L. J., Bird, T. D., Koob, M. D., Day, J. W., Ranum, L. P. W. <strong>SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance.</strong> Hum. Molec. Genet. 9: 2125-2130, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10958651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10958651</a>] [<a href="https://doi.org/10.1093/hmg/9.14.2125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10958651">Moseley et al. (2000)</a> found 6 different sequence configurations of the CTG repeat. In 2 instances, duplication of CCG interruptions occurred over a single generation, and in other instances duplications that had occurred in different branches of the family could be inferred. When the SCA8 repeat tract was evaluated in sperm samples from individuals with expansions of 80 to 800 repeats in leukocytes, contractions to repeat lengths of less than 100 CTGs were observed, a size not often associated with disease. The authors hypothesized that the en masse repeat contractions in sperm may underlie the reduced penetrance associated with paternal transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10192387+10958651" 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="Day, J. W., Schut, L. J., Moseley, M. L., Durand, A. C., Ranum, L. P. W. <strong>Spinocerebellar ataxia type I: clinical features in a large family.</strong> Neurology 55: 649-657, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10980728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10980728</a>] [<a href="https://doi.org/10.1212/wnl.55.5.649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10980728">Day et al. (2000)</a> reported findings from a further study of the large SCA8 family. CTG tracts were longer in affected (mean = 116 CTG repeats) than in unaffected expansion carriers (mean = 90). Quantitative dexterity testing did not detect even subtle signs of ataxia in unaffected expansion carriers. All 21 affected family members inherited an expansion from their mothers. The maternal penetrance bias was consistent with maternal repeat expansions yielding alleles above the pathogenic threshold in the family (more than 107 CTG) and paternal contractions resulting in shorter alleles. Consistent with the reduced penetrance of paternal transmissions, CTG tracts in all or nearly all sperm (84 to 99) were significantly shorter than in the blood (116) of an affected man. The authors concluded that the biologic relationship between repeat length and ataxia indicates that the CTG repeat is directly involved in SCA8 pathogenesis. They noted that diagnostic testing and genetic counseling are complicated by the reduced penetrance, which often makes the inheritance appear recessive or sporadic, and by interfamilial differences in the length of a stable (CTA)n tract preceding the CTG repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10980728" 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="#17" class="mim-tip-reference" title="Schols, L., Bauer, I., Zuhlke, C., Schulte, T., Kolmel, C., Burk, K., Topka, H., Bauer, P., Przuntek, H., Riess, O. <strong>Do CTG expansions at the SCA8 locus cause ataxia?</strong> Ann. Neurol. 54: 110-115, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12838526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12838526</a>] [<a href="https://doi.org/10.1002/ana.10608" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12838526">Schols et al. (2003)</a> questioned whether the CTG repeat in SCA8 causes ataxia. Analyzing the alleles of 1,262 German patients with ataxia, they concluded that the CTG repeat is a rare polymorphism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12838526" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Corral, J., Genis, D., Banchs, I., San Nicolas, H., Armstrong, J., Volpini, V. <strong>Giant SCA8 alleles in nine children whose mother has two moderately large ones.</strong> Ann. Neurol. 57: 549-553, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15786481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15786481</a>] [<a href="https://doi.org/10.1002/ana.20421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15786481">Corral et al. (2005)</a> reported a woman with cerebellar ataxia who had 2 expansions of the SCA8 CTG repeat (111 and 197 repeats). All 9 of her children were unaffected but had inherited greatly expanded alleles from their mother, ranging from 401 to 1,126 repeats. In all 9 cases, the allele inherited from the father was 18 or 19 repeats. By contrast, in 2 additional families in which 3 affected fathers had homozygous expanded CTG repeats, the unaffected children did not inherit additionally expanded repeats. <a href="#3" class="mim-tip-reference" title="Corral, J., Genis, D., Banchs, I., San Nicolas, H., Armstrong, J., Volpini, V. <strong>Giant SCA8 alleles in nine children whose mother has two moderately large ones.</strong> Ann. Neurol. 57: 549-553, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15786481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15786481</a>] [<a href="https://doi.org/10.1002/ana.20421" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15786481">Corral et al. (2005)</a> suggested that the maternal transmission and expansion of the SCA8 CTG allele observed in their family resulted from gene conversion related to female meiosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15786481" 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="Daughters, R. S., Tuttle, D. L., Gao, W., Ikeda, Y., Moseley, M. L., Ebner, T. J., Swanson, M. S., Ranum, L. P. <strong>RNA gain-of-function in spinocerebellar ataxia type 8.</strong> PLoS Genet. 5: e1000600, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19680539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19680539</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19680539[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19680539">Daughters et al. (2009)</a> presented evidence that the expanded CTG repeat in the ATXN8OS gene is transcribed into an mRNA with an expanded CUG repeat, conferring a toxic gain of function that plays a role in the SCA8 phenotype. In brain tissue from humans and mice with SCA8, ATXN8OS mRNA containing the expanded repeat was found to accumulate as ribonuclear inclusions, or RNA foci, that colocalized with the RNA-binding protein MBNL1 (<a href="/entry/606516">606516</a>) in selected cerebellar cortical neurons in the brain. In Sca8 mice, genetic loss of Mbnl1 enhanced motor deficits, suggesting that loss of MBNL1 plays a role in SCA8 pathogenesis. In Sca8 mice and SCA8 human brains, sequestration of MBNL1 in RNA foci resulted in dysregulation of downstream splicing patterns normally regulated by the CUGBP1 (<a href="/entry/601074">601074</a>)/MBNL1 pathway, including that of mouse GABA transporter-4 (GAT4, or SLC6A11; <a href="/entry/607952">607952</a>). These changes in Gat4 were associated with loss of GABAergic inhibition in the granular cell layer. These data indicated that expanded CUG ATXN8OS mRNA transcripts can dysregulate gene pathways in the brain, similar to the mechanism involved in myotonic dystrophy (DM1; <a href="/entry/160900">160900</a>), which is caused by a CTG repeat expansion in the 3-prime UTR region of the DMPK gene (<a href="/entry/605377">605377</a>) on chromosome 19q13. <a href="#4" class="mim-tip-reference" title="Daughters, R. S., Tuttle, D. L., Gao, W., Ikeda, Y., Moseley, M. L., Ebner, T. J., Swanson, M. S., Ranum, L. P. <strong>RNA gain-of-function in spinocerebellar ataxia type 8.</strong> PLoS Genet. 5: e1000600, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19680539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19680539</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19680539[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19680539">Daughters et al. (2009)</a> also suggested that the findings may have relevance for other mainly CAG repeat expansion disorders, in which an expanded CTG repeat on the opposite stand may also have toxic effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19680539" 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="#26" class="mim-tip-reference" title="Wu, Y. R., Lin, H. Y., Chen, C. M., Gwinn-Hardy, K., Ro, L. S., Wang, Y. C., Li, S. H., Hwang, J. C., Fang, K., Hsieh-Li, H. M., Li, M. L., Tung, L. C., Su, M. T., Lu, K. T., Lee-Chen, G. J. <strong>Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease.</strong> Clin. Genet. 65: 209-214, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756671</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00213.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14756671">Wu et al. (2004)</a> identified repeat expansions at the SCA8 locus in 4 (1.5%) of 264 patients with typical late-onset levodopa-responsive Parkinson disease (<a href="/entry/168600">168600</a>). The expansions ranged in size from 75 to 92. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14756671" 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>Possible Roles in Other Neurologic Disorders</em></strong></p><p>
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<a href="#24" class="mim-tip-reference" title="Vincent, J. B., Neves-Pereira, M. L., Paterson, A. D., Yamamoto, E., Parikh, S. V., Macciardi, F., Gurling, H. M., Potkin, S. G., Pato, C. N., Macedo, A., Kovacs, M., Davies, M., Lieberman, J. A., Meltzer, H. Y., Petronis, A, Kennedy, J. L. <strong>An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: a common expansion locus.</strong> Am. J. Hum. Genet. 66: 819-829, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712198[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/302803" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712198">Vincent et al. (2000)</a> observed large trinucleotide (CTA/CTG) repeat alleles (more than 100 repeats) at 13q21 in 1.25% of patients with various psychiatric disorders compared to 0.7% of healthy controls and none of individuals affected by or with a family history of SCA. The authors concluded that the high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10712198" 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 observation of large SCA8 alleles in healthy control subjects and nonataxic patients, together with a lack of segregation of the expanded repeat with ataxia in several families, has raised questions about the pathogenic role of the SCA8 expansion. <a href="#19" class="mim-tip-reference" title="Sobrido, M.-J., Cholfin, J. A., Perlman, S., Pulst, S. M., Geschwind, D. H. <strong>SCA8 repeat expansions in ataxia: a controversial association.</strong> Neurology 57: 1310-1312, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11591855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11591855</a>] [<a href="https://doi.org/10.1212/wnl.57.7.1310" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11591855">Sobrido et al. (2001)</a> found allele sizes within the proposed pathogenic range in 3 patients with ataxia of unknown etiology, in 2 individuals from pedigrees with either SCA2 or Friedreich ataxia (<a href="/entry/229300">229300</a>), and in 2 patients with Alzheimer disease. They suggested that sizing of SCA8 alleles should not be a routine diagnostic test until its etiologic role is clarified and the pathogenic threshold determined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11591855" 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 study in Italy, <a href="#1" class="mim-tip-reference" title="Cellini, E., Nacmias, B., Forleo, P., Piacentini, S., Guarnieri, B. M., Serio, A., Calabro, A., Renzi, D., Sorbi, S. <strong>Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Italy.</strong> Arch. Neurol. 58: 1856-1859, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11708995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11708995</a>] [<a href="https://doi.org/10.1001/archneur.58.11.1856" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11708995">Cellini et al. (2001)</a> analyzed material from 167 patients affected by sporadic, autosomal dominant, and autosomal recessive hereditary ataxia for expanded CTA/CTG repeats. They found abnormally expanded repeats in 5 ataxic patients: 3 with pure cerebellar ataxia, 1 with vitamin E deficiency, and 1 sporadic case with gluten ataxia. They concluded that CTG expansions may be linked to SCA8. The patients presented peculiar phenotypic features, suggesting that additional factors may predispose to the disorder. In the patient with expanded SCA8 CTA/CTG triplet repeats and vitamin E deficiency reported by <a href="#1" class="mim-tip-reference" title="Cellini, E., Nacmias, B., Forleo, P., Piacentini, S., Guarnieri, B. M., Serio, A., Calabro, A., Renzi, D., Sorbi, S. <strong>Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Italy.</strong> Arch. Neurol. 58: 1856-1859, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11708995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11708995</a>] [<a href="https://doi.org/10.1001/archneur.58.11.1856" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11708995">Cellini et al. (2001)</a>, <a href="#2" class="mim-tip-reference" title="Cellini, E., Piacentini, S., Nacmias, B., Forleo, P., Tedde, A., Bagnoli, S., Ciantelli, M., Sorbi, S. <strong>A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia.</strong> Arch. Neurol. 59: 1952-1953, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12470185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12470185</a>] [<a href="https://doi.org/10.1001/archneur.59.12.1952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12470185">Cellini et al. (2002)</a> identified compound heterozygosity for mutations in the TTPA gene (<a href="/entry/600415#0004">600415.0004</a> and <a href="/entry/600415#0006">600415.0006</a>), yielding a nonfunctional protein. Mutations in the TTPA gene have been associated with Friedreich-like ataxia (AVED; <a href="/entry/277460">277460</a>). Clinically, she had progressive ataxia from the age of 7 years, becoming wheelchair bound at age 17, and cerebellar atrophy. Supplementation with vitamin E did not improve symptoms. The authors suggested that the SCA mutations acted in the neurodegenerative process, worsening the neurologic signs caused by the vitamin E deficit. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12470185+11708995" 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="Topisirovic, I., Dragasevic, N., Savic, D., Ristic, A., Keckarevic, M., Keckarevic, D., Culjkovic, B., Petrovic, I., Romac, S., Kostic, V. S. <strong>Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Yugoslavia.</strong> Clin. Genet. 62: 321-324, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12372061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12372061</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.620412.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12372061">Topisirovic et al. (2002)</a> studied the length of the SCA8 CTA/CTG expansions (which they called combined repeats, or CRs) in 115 patients with ataxia, 64 unrelated individuals with nontriplet neuromuscular diseases, 70 unrelated patients with schizophrenia, and 125 healthy controls. Only 1 patient with apparently sporadic ataxia was identified with an expansion of 100 CRs, which he had inherited from his asymptomatic father (140 CRs) and transmitted the mutation to his son (92 CRs). Paternal transmission in this family produced contractions of 40 and 8 CRs, respectively. None of the subjects from the other studied groups had an expansion at the SCA8 locus. In the control group, the number of CRs at the SCA8 locus ranged from 14 to 34. The findings supported the hypothesis that allelic variants of the expansion mutation at the SCA8 locus can predispose to ataxia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12372061" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Sulek, A., Hoffman-Zacharska, D., Zdzienicka, E., Zaremba, J. <strong>SCA8 repeat expansion coexists with SCA1--not only with SCA6. (Letter)</strong> Am. J. Hum. Genet. 73: 972-974, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14508711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14508711</a>] [<a href="https://doi.org/10.1086/378524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14508711">Sulek et al. (2003)</a> demonstrated that SCA8 repeat expansion coexists not only with SCA6, but also with SCA1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14508711" 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="Factor, S. A., Qian, J., Lava, N. S., Hubbard, J. D., Payami, H. <strong>False-positive SCA8 gene test in a patient with pathologically proven multiple system atrophy. (Letter)</strong> Ann. Neurol. 57: 462-463, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732096</a>] [<a href="https://doi.org/10.1002/ana.20389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732096">Factor et al. (2005)</a> reported a patient with onset of dysarthria and impairment of balance and coordination at age 53 years that rapidly progressed to include gait and postural instability, urinary incontinence, impotence, and depression. MRI showed cerebellar and pontine atrophy. Molecular analysis identified an expansion of 145 CTA/CTG repeats in one allele and 28 repeats in the other allele, which is consistent with SCA8. However, postmortem examination showed findings consistent with multiple system atrophy. <a href="#7" class="mim-tip-reference" title="Factor, S. A., Qian, J., Lava, N. S., Hubbard, J. D., Payami, H. <strong>False-positive SCA8 gene test in a patient with pathologically proven multiple system atrophy. (Letter)</strong> Ann. Neurol. 57: 462-463, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15732096/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15732096</a>] [<a href="https://doi.org/10.1002/ana.20389" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15732096">Factor et al. (2005)</a> noted that the association between the SCA8 repeat expansion and ataxia is controversial, and suggested that testing sporadic cases with late-onset ataxia may lead to misdiagnosis, as in their case. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15732096" 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>Among 75 dominant ataxic independent nuclear families in Spain, <a href="#22" class="mim-tip-reference" title="Tazon, B., Badenas, C., Jimenez, L., Munoz, E., Mila, M. <strong>SCA8 in the Spanish population including one homozygous patient.</strong> Clin. Genet. 62: 404-409, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12431257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12431257</a>] [<a href="https://doi.org/10.1034/j.1399-0004.2002.620509.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12431257">Tazon et al. (2002)</a> found 3 with SCA8, representing 4%. A 25-year-old man with a clinical picture of progressive ataxia and dysarthria beginning at age 12 years was homozygous for the expansion of the CTA/CTG 3-prime untranslated region of SCA8. On neurologic examination, he showed ataxia, slight dysarthria, and nystagmus to extreme lateral gaze. Cranial MRI showed global atrophy of cerebellum, but the brainstem was spared. Ataxia had been present in his grandfather and father. His mother, who had no ataxia antecedents in her family, was healthy at age 52; a molecular study of SCA8 revealed 1 allele that could be considered as premutated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12431257" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Juvonen, V., Kairisto, V., Hietala, M., Savontaus, M.-L. <strong>Calculating predictive values for the large repeat alleles at the SCA8 locus in patients with ataxia. (Letter)</strong> J. Med. Genet. 39: 935-936, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12471210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12471210</a>] [<a href="https://doi.org/10.1136/jmg.39.12.935" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12471210">Juvonen et al. (2002)</a> identified SCA8 repeat expansions in 22 of 251 unrelated Finnish SCA patients. They defined alleles with 15 to 40 combined repeats as normal, and those with 80 to 800 as expanded. None of the 22 SCA8-positive patients had expansions at SCA1, 2, 3, 6, 7, 10 (<a href="/entry/603516">603516</a>), 12 (<a href="/entry/604326">604326</a>), 17 (<a href="/entry/607136">607136</a>), DRPLA (<a href="/entry/607462">607462</a>), or FXN (<a href="/entry/606829">606829</a>) loci. Thirteen of the patients had a family history of SCA, which was compatible with a dominant inheritance pattern in 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12471210" 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="Izumi, Y., Maruyama, H., Oda, M., Morino, H., Okada, T., Ito, H., Sasaki, I., Tanaka, H., Komure, O., Udaka, F., Nakamura, S., Kawakami, H. <strong>SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6.</strong> Am. J. Hum. Genet. 72: 704-709, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12545428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12545428</a>] [<a href="https://doi.org/10.1086/367775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12545428">Izumi et al. (2003)</a> analyzed the SCA8 CTA/CTG repeat in a large group of Japanese subjects. The frequency of large alleles (85 to 399 CTA/CTG repeats) was 1.9% in spinocerebellar ataxia, 0.4% in Parkinson disease (PD; <a href="/entry/168600">168600</a>), 0.3% in Alzheimer disease, and 0% in a healthy control group; the frequency was significantly higher in the group with SCA than in the control group. Homozygotes for large alleles were observed only in the group with SCA. In 5 patients with SCA from 2 families, a large SCA8 CTA/CTG repeat and a large SCA6 (<a href="/entry/183086">183086</a>; <a href="/entry/601011">601011</a>) CAG repeat coexisted. Age at onset was correlated with SCA8 repeats rather than SCA6 repeats in these 5 patients. In 1 of these families, at least 1 patient showed only a large SCA8 CTA/CTG repeat allele, with no large SCA6 CAG repeat allele. <a href="#9" class="mim-tip-reference" title="Izumi, Y., Maruyama, H., Oda, M., Morino, H., Okada, T., Ito, H., Sasaki, I., Tanaka, H., Komure, O., Udaka, F., Nakamura, S., Kawakami, H. <strong>SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6.</strong> Am. J. Hum. Genet. 72: 704-709, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12545428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12545428</a>] [<a href="https://doi.org/10.1086/367775" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12545428">Izumi et al. (2003)</a> speculated that the presence of a large SCA8 CTA/CTG repeat allele influences the function of channels such as the alpha-1A-voltage-dependent calcium channel (CACNA1A; <a href="/entry/601011">601011</a>), resulting in the development of cerebellar ataxia, especially in homozygous patients. They discussed the possibility that SCA8 works through SCA6 gene products. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12545428" 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 study in Taiwan, <a href="#26" class="mim-tip-reference" title="Wu, Y. R., Lin, H. Y., Chen, C. M., Gwinn-Hardy, K., Ro, L. S., Wang, Y. C., Li, S. H., Hwang, J. C., Fang, K., Hsieh-Li, H. M., Li, M. L., Tung, L. C., Su, M. T., Lu, K. T., Lee-Chen, G. J. <strong>Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease.</strong> Clin. Genet. 65: 209-214, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756671</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00213.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14756671">Wu et al. (2004)</a> detected abnormal expansions of trinucleotide repeats in both the SCA8 and SCA17 (<a href="/entry/607136">607136</a>) genes in patients with Parkinson disease. The clinical presentation of these patients was typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14756671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Ikeda, Y., Dalton, J. C., Moseley, M. L., Gardner, K. L., Bird, T. D., Ashizawa, T., Seltzer, W. K., Pandolfo, M., Milunsky, A., Potter, N. T., Shoji, M., Vincent, J. B., Day, J. W., Ranum, L. P. W. <strong>Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia.</strong> Am. J. Hum. Genet. 75: 3-16, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15152344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15152344</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15152344[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/422014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15152344">Ikeda et al. (2004)</a> described the molecular genetic features and disease penetrance of 37 families with SCA8 ataxia from the United States, Canada, Japan, and Mexico. SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only 1 or 2 affected individuals are found in a given family. By haplotype analysis using 17 short tandem repeat (STR) markers spanning a region of approximately 1 Mb in families with ataxia, as well as a group of expansion carriers in the general population and a group of psychiatric patients, <a href="#8" class="mim-tip-reference" title="Ikeda, Y., Dalton, J. C., Moseley, M. L., Gardner, K. L., Bird, T. D., Ashizawa, T., Seltzer, W. K., Pandolfo, M., Milunsky, A., Potter, N. T., Shoji, M., Vincent, J. B., Day, J. W., Ranum, L. P. W. <strong>Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia.</strong> Am. J. Hum. Genet. 75: 3-16, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15152344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15152344</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15152344[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/422014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15152344">Ikeda et al. (2004)</a> sought to clarify the genetic basis of the reduced penetrance and to investigate whether CTG expansions among different populations share a common ancestral background. Two major ancestrally related haplotypes (A and A-prime) were found among white families with ataxia, normal controls, and patients with major psychosis, indicating a common ancestral origin of both pathogenic and nonpathogenic SCA8 expansions among whites. Two additional and distinct haplotypes were found among a group of Japanese families with ataxia (haplotype B) and a Mexican family with ataxia (haplotype C). The findings that SCA8 expansions on 3 independently arising haplotypes are found among patients with ataxia and cosegregate with ataxia when multiple family members are affected further supported the direct role of the CTG expansion in disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15152344" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Martins, S., Seixas, A. I., Magalhaes, P., Coutinho, P., Sequeiros, J., Silveira, I. <strong>Haplotype diversity and somatic instability in normal and expanded SCA8 alleles.</strong> Am. J. Med. Genet. 139B: 109-114, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16184604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16184604</a>] [<a href="https://doi.org/10.1002/ajmg.b.30235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16184604">Martins et al. (2005)</a> performed haplotype and sequencing analysis in a large region encompassing the SCA8 gene (CTA)n (CTG)n repeat and 6 SNP markers in 4 SCA8 families of Portuguese descent. Two different haplotypes, AG-Expanded-GTTG and AG-Expanded-CTTG, were identified. The same haplotypes were also the most frequently identified (AG-Normal-GTTG and AG-Normal-CTTG) in the normal population of 20 control Portuguese families, suggesting that the mutated state arose from common backgrounds. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16184604" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#15" class="mim-tip-reference" title="Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., Chen, G., Weatherspoon, M. R., Clark, H. B., Ebner, T. J., Day, J. W., Ranum. L. P. W. <strong>Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8.</strong> Nature Genet. 38: 758-769, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804541</a>] [<a href="https://doi.org/10.1038/ng1827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804541">Moseley et al. (2006)</a> reported a transgenic mouse model in which the full-length human SCA8 mutation is transcribed using its endogenous promoter. They found that (CTG)116 expansion, but not (CTG)11 control lines, develop a progressive neurologic phenotype, with in vivo imaging showing reduced cerebellar-cortical inhibition. Both polyleucine- and polyglutamine-containing expansion proteins have been reported to form intranuclear inclusions that are recognized by the 1C2 monoclonal antibody (<a href="#27" class="mim-tip-reference" title="Zoghbi, H. Y., Orr, H. T. <strong>Glutamine repeats and neurodegeneration.</strong> Ann. Rev. Neurosci. 23: 217-247, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10845064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10845064</a>] [<a href="https://doi.org/10.1146/annurev.neuro.23.1.217" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10845064">Zoghbi and Orr, 2000</a>; <a href="#6" class="mim-tip-reference" title="Dorsman, J. C., Pepers, B., Langenberg, D., Kerkdijk, H., Ijszenga, M., den Dunnen, J. T., Roos, R. A. C., van Ommen, G.-J., B. <strong>Strong aggregation and increased toxicity of polyleucine over polyglutamine stretches in mammalian cells.</strong> Hum. Molec. Genet. 11: 1487-1496, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12045202/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12045202</a>] [<a href="https://doi.org/10.1093/hmg/11.13.1487" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12045202">Dorsman et al., 2002</a>). <a href="#15" class="mim-tip-reference" title="Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., Chen, G., Weatherspoon, M. R., Clark, H. B., Ebner, T. J., Day, J. W., Ranum. L. P. W. <strong>Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8.</strong> Nature Genet. 38: 758-769, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804541</a>] [<a href="https://doi.org/10.1038/ng1827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804541">Moseley et al. (2006)</a> found that 1C2-positive intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein, encoded on a previously unidentified antiparallel transcript, ATXN8 (<a href="/entry/613289">613289</a>), spanning the repeat in the CAG direction. The neurologic phenotype in SCA8 BAC expansion but not BAC control lines demonstrated the pathogenicity of the (CTG-CAG)n expansion. Moreover, the expression of noncoding (CUG)n expansion ATXN8OS transcripts and the discovery of intranuclear polyglutamine inclusions suggested that SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and the RNA levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12045202+10845064+16804541" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In patients with spinocerebellar ataxia-8 (SCA8; <a href="/entry/608768">608768</a>), <a href="#11" class="mim-tip-reference" title="Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W. <strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong> Nature Genet. 21: 379-384, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>] [<a href="https://doi.org/10.1038/7710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10192387">Koob et al. (1999)</a> identified a CAG repeat expansion in the 5-prime to 3-prime orientation of the ATXN8 template strand (ATXN8; <a href="/entry/613289#0001">613289.0001</a>) that did not appear to be translated into a polyglutamine-containing protein. However, the corresponding 5-prime-to-3-prime CTG repeat expansion in the ATXN8OS gene on the opposite strand was found to be transcribed into an mRNA with an expanded CUG repeat in its 3-prime UTR. The mRNA with the expanded CUG repeat was not translated. <a href="#15" class="mim-tip-reference" title="Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., Chen, G., Weatherspoon, M. R., Clark, H. B., Ebner, T. J., Day, J. W., Ranum. L. P. W. <strong>Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8.</strong> Nature Genet. 38: 758-769, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804541</a>] [<a href="https://doi.org/10.1038/ng1827" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16804541">Moseley et al. (2006)</a> found that the CAG repeat in the ATXN8 gene was transcribed into a protein with an expanded polyglutamine tract in patients with SCA8. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10192387+16804541" 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 37 families with SCA8 ataxia from the United States, Canada, Japan, and Mexico, <a href="#8" class="mim-tip-reference" title="Ikeda, Y., Dalton, J. C., Moseley, M. L., Gardner, K. L., Bird, T. D., Ashizawa, T., Seltzer, W. K., Pandolfo, M., Milunsky, A., Potter, N. T., Shoji, M., Vincent, J. B., Day, J. W., Ranum, L. P. W. <strong>Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia.</strong> Am. J. Hum. Genet. 75: 3-16, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15152344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15152344</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15152344[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1086/422014" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15152344">Ikeda et al. (2004)</a> identified 3 different ancestral haplotypes containing the ATXN8OS gene that segregated with the families according to population: Caucasian, Japanese, and Mexican. <a href="#12" class="mim-tip-reference" title="Martins, S., Seixas, A. I., Magalhaes, P., Coutinho, P., Sequeiros, J., Silveira, I. <strong>Haplotype diversity and somatic instability in normal and expanded SCA8 alleles.</strong> Am. J. Med. Genet. 139B: 109-114, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16184604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16184604</a>] [<a href="https://doi.org/10.1002/ajmg.b.30235" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16184604">Martins et al. (2005)</a> performed haplotype and sequencing analysis in a large region encompassing the ATXN8OS gene (CTA)n (CTG)n repeat and 6 SNP markers in 4 SCA8 families of Portuguese descent. Two different haplotypes, AG-Expanded-GTTG and AG-Expanded-CTTG, were identified. The same haplotypes were also the most frequently identified (AG-Normal-GTTG and AG-Normal-CTTG) in the normal population of 20 control Portuguese families, suggesting that the mutated state arose from common backgrounds. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15152344+16184604" 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="Daughters, R. S., Tuttle, D. L., Gao, W., Ikeda, Y., Moseley, M. L., Ebner, T. J., Swanson, M. S., Ranum, L. P. <strong>RNA gain-of-function in spinocerebellar ataxia type 8.</strong> PLoS Genet. 5: e1000600, 2009. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19680539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19680539</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19680539[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1371/journal.pgen.1000600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19680539">Daughters et al. (2009)</a> presented evidence that the expanded CTG repeat in the ATXN8OS gene is transcribed into an mRNA with an expanded CUG repeat, conferring a toxic gain of function that plays a role in the SCA8 phenotype. In brain tissue from humans and mice with SCA8, ATXN8OS mRNA containing the expanded repeat was found to accumulate as ribonuclear inclusions, or RNA foci, that colocalized with the RNA-binding protein MBNL1 (<a href="/entry/606516">606516</a>) in selected cerebellar cortical neurons in the brain. Sequestration of MBNL1 in RNA foci resulted in dysregulation of downstream splicing patterns normally regulated by the CUGBP1 (<a href="/entry/601074">601074</a>)/MBNL1 pathway, including that of mouse GABA transporter-4 (GAT4, or SLC6A11; <a href="/entry/607952">607952</a>). These changes in Gat4 were associated with loss of GABAergic inhibition in the granular cell layer. These data indicated that expanded CUG ATXN8OS mRNA transcripts can have a toxic gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19680539" 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="#26" class="mim-tip-reference" title="Wu, Y. R., Lin, H. Y., Chen, C. M., Gwinn-Hardy, K., Ro, L. S., Wang, Y. C., Li, S. H., Hwang, J. C., Fang, K., Hsieh-Li, H. M., Li, M. L., Tung, L. C., Su, M. T., Lu, K. T., Lee-Chen, G. J. <strong>Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease.</strong> Clin. Genet. 65: 209-214, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756671</a>] [<a href="https://doi.org/10.1111/j.0009-9163.2004.00213.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14756671">Wu et al. (2004)</a> identified repeat expansions at the SCA8 locus in 4 (1.5%) of 264 patients with typical late-onset levodopa-responsive Parkinson disease (<a href="/entry/168600">168600</a>). The expansions ranged in size from 75 to 92. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14756671" 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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Cellini, E., Nacmias, B., Forleo, P., Piacentini, S., Guarnieri, B. M., Serio, A., Calabro, A., Renzi, D., Sorbi, S.
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<strong>Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Italy.</strong>
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Arch. Neurol. 58: 1856-1859, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11708995/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11708995</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11708995" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Cellini, E., Piacentini, S., Nacmias, B., Forleo, P., Tedde, A., Bagnoli, S., Ciantelli, M., Sorbi, S.
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<strong>A family with spinocerebellar ataxia type 8 expansion and vitamin E deficiency ataxia.</strong>
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Arch. Neurol. 59: 1952-1953, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12470185/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12470185</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12470185" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Corral, J., Genis, D., Banchs, I., San Nicolas, H., Armstrong, J., Volpini, V.
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<strong>Giant SCA8 alleles in nine children whose mother has two moderately large ones.</strong>
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Ann. Neurol. 57: 549-553, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15786481/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15786481</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15786481" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>RNA gain-of-function in spinocerebellar ataxia type 8.</strong>
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PLoS Genet. 5: e1000600, 2009. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19680539/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19680539</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19680539[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=19680539" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="5" class="mim-anchor"></a>
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<a id="Day2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Day, J. W., Schut, L. J., Moseley, M. L., Durand, A. C., Ranum, L. P. W.
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<strong>Spinocerebellar ataxia type I: clinical features in a large family.</strong>
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[<a href="https://doi.org/10.1212/wnl.55.5.649" target="_blank">Full Text</a>]
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<div class="">
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<p class="mim-text-font">
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Dorsman, J. C., Pepers, B., Langenberg, D., Kerkdijk, H., Ijszenga, M., den Dunnen, J. T., Roos, R. A. C., van Ommen, G.-J., B.
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<strong>Strong aggregation and increased toxicity of polyleucine over polyglutamine stretches in mammalian cells.</strong>
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Hum. Molec. Genet. 11: 1487-1496, 2002.
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[<a href="https://doi.org/10.1093/hmg/11.13.1487" target="_blank">Full Text</a>]
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<p class="mim-text-font">
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Factor, S. A., Qian, J., Lava, N. S., Hubbard, J. D., Payami, H.
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<strong>False-positive SCA8 gene test in a patient with pathologically proven multiple system atrophy. (Letter)</strong>
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Ann. Neurol. 57: 462-463, 2005.
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[<a href="https://doi.org/10.1002/ana.20389" target="_blank">Full Text</a>]
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</p>
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<a id="Ikeda2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ikeda, Y., Dalton, J. C., Moseley, M. L., Gardner, K. L., Bird, T. D., Ashizawa, T., Seltzer, W. K., Pandolfo, M., Milunsky, A., Potter, N. T., Shoji, M., Vincent, J. B., Day, J. W., Ranum, L. P. W.
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<strong>Spinocerebellar ataxia type 8: molecular genetic comparisons and haplotype analysis of 37 families with ataxia.</strong>
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Am. J. Hum. Genet. 75: 3-16, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15152344/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15152344</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15152344[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=15152344" 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/10.1086/422014" target="_blank">Full Text</a>]
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</p>
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</div>
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<a id="9" class="mim-anchor"></a>
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<a id="Izumi2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Izumi, Y., Maruyama, H., Oda, M., Morino, H., Okada, T., Ito, H., Sasaki, I., Tanaka, H., Komure, O., Udaka, F., Nakamura, S., Kawakami, H.
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<strong>SCA8 repeat expansion: large CTA/CTG repeat alleles are more common in ataxic patients, including those with SCA6.</strong>
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Am. J. Hum. Genet. 72: 704-709, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12545428/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12545428</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12545428" 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/10.1086/367775" target="_blank">Full Text</a>]
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</p>
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</div>
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<a id="10" class="mim-anchor"></a>
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<a id="Juvonen2002" class="mim-anchor"></a>
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<div class="">
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Juvonen, V., Kairisto, V., Hietala, M., Savontaus, M.-L.
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<strong>Calculating predictive values for the large repeat alleles at the SCA8 locus in patients with ataxia. (Letter)</strong>
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J. Med. Genet. 39: 935-936, 2002.
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[<a href="https://doi.org/10.1136/jmg.39.12.935" target="_blank">Full Text</a>]
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<a id="Koob1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Koob, M. D., Moseley, M. L., Schut, L. J., Benzow, K. A., Bird, T. D., Day, J. W., Ranum, L. P. W.
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<strong>An untranslated CTG expansion causes a novel form of spinocerebellar ataxia (SCA8).</strong>
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Nature Genet. 21: 379-384, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10192387/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10192387</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10192387" 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/10.1038/7710" target="_blank">Full Text</a>]
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<a id="Martins2005" class="mim-anchor"></a>
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<div class="">
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<strong>Haplotype diversity and somatic instability in normal and expanded SCA8 alleles.</strong>
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Am. J. Med. Genet. 139B: 109-114, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16184604/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16184604</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16184604" 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/ajmg.b.30235" target="_blank">Full Text</a>]
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<a id="Moseley2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Moseley, M. L., Schut, L. J., Bird, T. D., Day, J. W., Ranum, L. P. W.
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<strong>Reply to Stevanin et al. and Worth et al. (Letter)</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700169/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700169</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10700169" 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/10.1038/73415" target="_blank">Full Text</a>]
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<a id="14" class="mim-anchor"></a>
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<a id="Moseley2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Moseley, M. L., Schut, L. J., Bird, T. D., Koob, M. D., Day, J. W., Ranum, L. P. W.
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<strong>SCA8 CTG repeat: en masse contractions in sperm and intergenerational sequence changes may play a role in reduced penetrance.</strong>
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Hum. Molec. Genet. 9: 2125-2130, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10958651/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10958651</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10958651" 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/9.14.2125" target="_blank">Full Text</a>]
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</p>
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<a id="15" class="mim-anchor"></a>
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<a id="Moseley2006" class="mim-anchor"></a>
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<div class="">
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Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., Chen, G., Weatherspoon, M. R., Clark, H. B., Ebner, T. J., Day, J. W., Ranum. L. P. W.
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<strong>Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8.</strong>
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Nature Genet. 38: 758-769, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16804541/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16804541</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16804541" 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/ng1827" target="_blank">Full Text</a>]
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<a id="16" class="mim-anchor"></a>
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<a id="Nemes2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Nemes, J. P., Benzow, K. A., Moseley, M. L., Ranum, L. P. W., Koob, M. D.
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<strong>The SCA8 transcript is an antisense RNA to a brain-specific transcript encoding a novel actin-binding protein (KLHL1).</strong>
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Hum. Molec. Genet. 9: 1543-1551, 2000. Note: Erratum: Hum. Molec. Genet. 9: 2777 only, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10888605/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10888605</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10888605" 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/9.10.1543" target="_blank">Full Text</a>]
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<a id="17" class="mim-anchor"></a>
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<a id="Schols2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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<strong>Do CTG expansions at the SCA8 locus cause ataxia?</strong>
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Ann. Neurol. 54: 110-115, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12838526/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12838526</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12838526" 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.10608" target="_blank">Full Text</a>]
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<a id="18" class="mim-anchor"></a>
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<a id="Silveira2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Silveira, I., Alonso, I., Guimaraes, L., Mendonca, P., Santos, C., Maciel, P., Fidalgo de Matos, J. M., Costa, M., Barbot, C., Tuna, A., Barros, J., Jardim, L., Coutinho, P., Sequeiros, J.
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<strong>High germinal instability of the (CTG)n at the SCA8 locus of both expanded and normal alleles.</strong>
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Am. J. Hum. Genet. 66: 830-840, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712199/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712199</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712199[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=10712199" 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/10.1086/302827" target="_blank">Full Text</a>]
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<a id="19" class="mim-anchor"></a>
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<a id="Sobrido2001" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sobrido, M.-J., Cholfin, J. A., Perlman, S., Pulst, S. M., Geschwind, D. H.
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<strong>SCA8 repeat expansions in ataxia: a controversial association.</strong>
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Neurology 57: 1310-1312, 2001.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11591855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11591855</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11591855" 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.57.7.1310" target="_blank">Full Text</a>]
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<a id="20" class="mim-anchor"></a>
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<a id="Stevanin2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Stevanin, G., Herman, A., Durr, A., Jodice, C., Frontali, M., Agid, Y., Brice, A.
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<strong>Are (CTG)n expansions at the SCA8 locus rare polymorphisms? (Letter)</strong>
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Nature Genet. 24: 213 only, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700167/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700167</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10700167" 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/10.1038/73408" target="_blank">Full Text</a>]
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<a id="21" class="mim-anchor"></a>
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<a id="Sulek2003" class="mim-anchor"></a>
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<div class="">
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Sulek, A., Hoffman-Zacharska, D., Zdzienicka, E., Zaremba, J.
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<strong>SCA8 repeat expansion coexists with SCA1--not only with SCA6. (Letter)</strong>
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Am. J. Hum. Genet. 73: 972-974, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14508711/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14508711</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14508711" 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/10.1086/378524" 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="22" class="mim-anchor"></a>
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<a id="Tazon2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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|
Tazon, B., Badenas, C., Jimenez, L., Munoz, E., Mila, M.
|
|
<strong>SCA8 in the Spanish population including one homozygous patient.</strong>
|
|
Clin. Genet. 62: 404-409, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12431257/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12431257</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12431257" 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/10.1034/j.1399-0004.2002.620509.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="23" class="mim-anchor"></a>
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<a id="Topisirovic2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Topisirovic, I., Dragasevic, N., Savic, D., Ristic, A., Keckarevic, M., Keckarevic, D., Culjkovic, B., Petrovic, I., Romac, S., Kostic, V. S.
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|
<strong>Genetic and clinical analysis of spinocerebellar ataxia type 8 repeat expansion in Yugoslavia.</strong>
|
|
Clin. Genet. 62: 321-324, 2002.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12372061/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12372061</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12372061" 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/10.1034/j.1399-0004.2002.620412.x" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="24" class="mim-anchor"></a>
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<a id="Vincent2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Vincent, J. B., Neves-Pereira, M. L., Paterson, A. D., Yamamoto, E., Parikh, S. V., Macciardi, F., Gurling, H. M., Potkin, S. G., Pato, C. N., Macedo, A., Kovacs, M., Davies, M., Lieberman, J. A., Meltzer, H. Y., Petronis, A, Kennedy, J. L.
|
|
<strong>An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: a common expansion locus.</strong>
|
|
Am. J. Hum. Genet. 66: 819-829, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712198/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712198</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10712198[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=10712198" 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/10.1086/302803" 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="25" class="mim-anchor"></a>
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<a id="Worth2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Worth, P. F., Houlden, H., Giunti, P., Davis, M. B., Wood, N. W.
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<strong>Large, expanded repeats in SCA8 are not confined to patients with cerebellar ataxia. (Letter)</strong>
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Nature Genet. 24: 214-215, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10700168/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10700168</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10700168" 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/10.1038/73411" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="26" class="mim-anchor"></a>
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<a id="Wu2004" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wu, Y. R., Lin, H. Y., Chen, C. M., Gwinn-Hardy, K., Ro, L. S., Wang, Y. C., Li, S. H., Hwang, J. C., Fang, K., Hsieh-Li, H. M., Li, M. L., Tung, L. C., Su, M. T., Lu, K. T., Lee-Chen, G. J.
|
|
<strong>Genetic testing in spinocerebellar ataxia in Taiwan: expansions of trinucleotide repeats in SCA8 and SCA17 are associated with typical Parkinson's disease.</strong>
|
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Clin. Genet. 65: 209-214, 2004.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14756671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14756671</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14756671" 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/10.1111/j.0009-9163.2004.00213.x" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="27" class="mim-anchor"></a>
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<a id="Zoghbi2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zoghbi, H. Y., Orr, H. T.
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<strong>Glutamine repeats and neurodegeneration.</strong>
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Ann. Rev. Neurosci. 23: 217-247, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10845064/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10845064</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10845064" 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/10.1146/annurev.neuro.23.1.217" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 3/3/2010
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Matthew B. Gross - updated : 3/1/2010<br>Patricia A. Hartz - updated : 3/1/2010<br>Victor A. McKusick - updated : 6/30/2006<br>Cassandra L. Kniffin - updated : 6/30/2005<br>Cassandra L. Kniffin - reorganized : 7/2/2004<br>Victor A. McKusick - updated : 6/10/2004<br>Victor A. McKusick - updated : 2/25/2004<br>Victor A. McKusick - updated : 10/7/2003<br>Cassandra L. Kniffin - updated : 8/14/2003<br>Victor A. McKusick - updated : 6/30/2003<br>Victor A. McKusick - updated : 2/26/2003<br>Cassandra L. Kniffin - updated : 2/13/2003<br>Victor A. McKusick - updated : 12/18/2002<br>Victor A. McKusick - updated : 11/6/2002<br>Victor A. McKusick - updated : 12/21/2001<br>Victor A. McKusick - updated : 12/5/2001<br>Victor A. McKusick - updated : 10/12/2001<br>Majed J. Dasouki - updated : 1/30/2001<br>George E. Tiller - updated : 11/17/2000<br>George E. Tiller - updated : 10/13/2000<br>Victor A. McKusick - updated : 4/10/2000<br>Paul J. Converse - updated : 4/4/2000<br>Victor A. McKusick - updated : 3/1/2000
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh : 3/29/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
|
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/31/2019
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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 : 01/31/2017<br>terry : 06/07/2012<br>terry : 11/30/2010<br>ckniffin : 11/16/2010<br>terry : 9/9/2010<br>carol : 5/25/2010<br>mgross : 3/3/2010<br>ckniffin : 3/3/2010<br>ckniffin : 3/3/2010<br>mgross : 3/1/2010<br>mgross : 3/1/2010<br>mgross : 3/1/2010<br>mgross : 3/1/2010<br>mgross : 2/17/2010<br>joanna : 2/5/2010<br>carol : 1/4/2010<br>carol : 3/12/2007<br>wwang : 11/28/2006<br>terry : 8/25/2006<br>carol : 8/24/2006<br>alopez : 7/5/2006<br>terry : 6/30/2006<br>wwang : 7/14/2005<br>wwang : 7/13/2005<br>ckniffin : 6/30/2005<br>terry : 3/3/2005<br>carol : 7/2/2004<br>ckniffin : 6/30/2004<br>alopez : 6/10/2004<br>terry : 6/10/2004<br>joanna : 3/17/2004<br>tkritzer : 3/1/2004<br>terry : 2/25/2004<br>cwells : 11/5/2003<br>tkritzer : 10/10/2003<br>terry : 10/7/2003<br>cwells : 8/20/2003<br>ckniffin : 8/14/2003<br>tkritzer : 7/8/2003<br>terry : 6/30/2003<br>ckniffin : 4/3/2003<br>alopez : 2/27/2003<br>terry : 2/26/2003<br>carol : 2/24/2003<br>ckniffin : 2/13/2003<br>carol : 12/23/2002<br>tkritzer : 12/20/2002<br>terry : 12/18/2002<br>tkritzer : 11/13/2002<br>tkritzer : 11/12/2002<br>terry : 11/6/2002<br>ckniffin : 8/7/2002<br>cwells : 1/10/2002<br>cwells : 1/2/2002<br>terry : 12/21/2001<br>alopez : 12/11/2001<br>terry : 12/5/2001<br>mcapotos : 10/26/2001<br>mcapotos : 10/12/2001<br>carol : 1/30/2001<br>mcapotos : 12/4/2000<br>mcapotos : 11/28/2000<br>terry : 11/17/2000<br>alopez : 10/13/2000<br>mcapotos : 5/3/2000<br>mcapotos : 4/28/2000<br>terry : 4/10/2000<br>carol : 4/4/2000<br>alopez : 3/1/2000<br>terry : 3/1/2000<br>terry : 3/1/2000<br>alopez : 3/29/1999<br>alopez : 3/29/1999
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
|
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<span class="mim-font">
|
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<strong>*</strong> 603680
|
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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>
|
|
<span class="mim-font">
|
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|
|
ATAXIN 8 OPPOSITE STRAND; ATXN8OS
|
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
SCA8 GENE; SCA8<br />
|
|
KLHL1AS
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: ATXN8OS</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> 715753001;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
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Cytogenetic location: 13q21.33
|
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 13:70,107,421-70,171,738 </span>
|
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</em>
|
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</strong>
|
|
<span class="small">(from NCBI)</span>
|
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</span>
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</p>
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</div>
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<div>
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<br />
|
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
|
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</h4>
|
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<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
|
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</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
13q21.33
|
|
</span>
|
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</td>
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
{Parkinson disease, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
168600
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Multifactorial
|
|
</span>
|
|
</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
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</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia 8
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
608768
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Spinocerebellar ataxia-8 (SCA8; 608768) is a neurodegenerative disorder caused by a CTG/CAG trinucleotide repeat expansion on chromosome 13q21 (see 603680.0001 and 613289.0001). Two genes span the CTG/CAG repeat and are expressed in opposite directions: ATXN8 (613289), which encodes a nearly pure polyglutamine expansion protein in the CAG direction, and ATXN8OS, which, when transcribed, produces a noncoding CUG expansion RNA (Moseley et al., 2006). </p>
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<strong>Cloning and Expression</strong>
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<p>While searching for CAG repeat disorders in patients with undefined dominantly inherited ataxias, Koob et al. (1999) identified 80 uninterrupted CAG repeats followed by 11 TAG repeats in genomic DNA from a mother and daughter with adult-onset spinocerebellar ataxia (SCA8; 608768). The expansion was isolated directly from genomic DNA by RAPID (repeat analysis, pooled isolation, and detection) cloning. By strand-specific analysis, Koob et al. (1999) determined that the SCA8 repeat was transcribed in the CTG orientation (reading 5-prime to 3-prime) on the complementary antisense strand from that of the CAG repeat. Koob et al. (1999) found that the CTG repeat is present in the 3-prime terminal exon of the ATXN8OS gene, which they called SCA8, and is located in the 3-prime UTR of the ATXN8OS transcript, which has no ORFs. RT-PCR on cerebellum RNA from 2 unaffected individuals heterozygous for the SCA8 CTG marker detected both alleles in each RNA sample. Alternatively spliced ATXN8OS transcripts lacking an exon were also detected. The ATXN8OS transcript was detected at low levels in whole brain and lung by RT-PCR. Further analysis identified an mRNA transcribed in the opposite orientation to that of the ATXN8OS transcript, KLHL1 (605332), suggesting that ATXN8OS is an endogenous antisense RNA. The SCA8 CTG repeat is present in the antisense transcript, but not the KLHL1 sense transcript. Although the studies of Koob et al. (1999) indicated that there is no translation of the SCA8 repeat in the CAG orientation into a polyglutamine tract, later studies by Moseley et al. (2006) showed that the CAG repeat on the sense strand is in the ATXN8 gene (613289) and is transcribed and translated. </p>
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<strong>Gene Structure</strong>
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<p>Koob et al. (1999) determined that the ATXN8OS gene contains 4 exons, at least 1 of which is alternatively spliced. </p><p>Nemes et al. (2000) assembled a 166-kb segment of genomic sequence containing the SCA8 repeat. ATXN8OS RNA transcripts containing the SCA8 CUG repeat tract are alternatively spliced, contain up to 5 exons, and span a genomic region of over 32 kb. The SCA8 CUG repeat is in the 3-prime terminal exon of these ATXN8OS transcripts, although Nemes et al. (2000) also identified transcripts with an alternative 3-prime terminal exon that lack the SCA8 repeat. They found that the most 5-prime exon of ATXN8OS is transcribed through the first exon of another gene, KLHL1 (605332), that is transcribed in the opposite orientation. This gene arrangement suggested that the ATXN8OS transcript may be an endogenous antisense RNA that overlaps the transcription and translation start sites as well as the first splice donor sequence of the sense gene, KLHL1. Since both of these genes are expressed in the cerebellum, Nemes et al. (2000) suggested that the pathogenic effect of the expansion may be mediated either directly or indirectly through one or both of these transcripts. </p><p>Moseley et al. (2006) determined that the ATXN8OS gene contains at least 6 exons that are subject to extensive alternative splicing. </p>
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<strong>Mapping</strong>
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<p>By PCR analysis of a chromosome hybrid panel and the CEPH library, Koob et al. (1999) mapped the SCA8 CTG expansion, which is located within the 3-prime end of the ATXN8OS gene, to chromosome 13q21. Nemes et al. (2000) determined that the 5-prime end of the ATXN8OS gene overlaps the 5-prime end of the KLHL1 gene (605332) in the opposite orientation. Moseley et al. (2006) determined that the 3-prime end of the ATXN8OS gene, including the CTG expansion region, overlaps the 3-prime end of the ATXN8 gene (613289) in the opposite orientation. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Spinocerebellar Ataxia 8</em></strong></p><p>
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In 8 pedigrees with autosomal dominant spinocerebellar ataxia-8 (SCA8; 608768), Koob et al. (1999) identified CTG repeat expansions in the ATXN8OS gene (603680.0001), on the opposite stand of the ATXN8 gene (613298). This 5-prime to 3-prime CTG repeat in ATXN8OS resulted in the production of an mRNA with an expanded CUG repeat in the 3-prime UTR. In the largest pedigree, which included affected members spanning at least 4 generations, repeat length ranged from 107 to 127 CTG repeats. However, 20 unaffected individuals also carried expanded repeats. A study of 1,200 alleles from the general population found that normal repeat length was 16 to 37 repeats in 99% of alleles; repeat lengths of up to 91 were seen in a small proportion of controls. Like the CTG expansion in DM, repeat length contracted with paternal transmission (-86 to +7) and expanded with maternal transmission (-11 to +600). Koob et al. (1999) noted that maternal bias towards expansion had not been seen in the CAG repeat disorders causing other SCAs. </p><p>Stevanin et al. (2000) and Worth et al. (2000) presented data challenging the significance of the expanded SCA8 repeat in SCA. Among 376 French control chromosomes, Stevanin et al. (2000) found that 373 (99%) carried 3 to 28 repeats, whereas 3 alleles carried expanded repeats of 107, 111, and 123 repeats. Among 250 European index patients with different forms of ataxia, 487 chromosomes contained 2 to 25 repeats and 13 chromosomes (11 patients, including 2 homozygotes) contained 68 to 123 repeats. They found expansions of more than 91 repeats in 8 of 148 autosomal dominant cerebellar ataxia (ADCA) families, in an apparently sporadic ataxia patient, in a patient with neuropathologically confirmed Lafora disease, and in a patient with familial essential tremor. Stevanin et al. (2000) suggested that the expanded repeat is a rare polymorphism. Among 1,306 control chromosomes, Worth et al. (2000) found that 97% contained 15 to 31 repeats, whereas 5 had large, expanded alleles of 174, 133, 103, 101, and 100 repeats. Among 98 unrelated cases of ADCA, 1 patient had alleles with 23 and 152 CTA/CTG repeats. However, the 92-year-old asymptomatic mother of another affected patient carried 127 repeats, and the authors concluded that the expanded alleles may be polymorphisms in linkage disequilibrium with mutations in a different gene on 13q21. Moseley et al. (2000) referred to 5 lines of evidence they thought supported the hypothesis that the SCA8 CTG expansion causes ataxia. </p><p>Silveira et al. (2000) found that normal SCA8 chromosomes showed an apparently trimodal distribution, with classes of small (15 to 21 CTGs), intermediate (22 to 37 CTGs), and large (40 to 91 CTGs) alleles; large alleles accounted for only 0.7% of all normal-size alleles. No expanded alleles (more than 100 CTGs) were found in controls. Expansion of the CTG tract was found in 5 families with ataxia; expanded alleles, all paternally transmitted, were characterized mostly by repeat-size contraction. There was a high germinal instability of both expanded and normal alleles: in 1 patient, an expanded allele of 152 CTGs had mostly contraction in size, often into the normal range; in the sperm of 2 normal controls, contractions were also more frequent, but occasional expansions into the upper limit of the normal size range were also seen. In conclusion, their results showed no overlapping between control (15-91) and pathogenic (100-152) alleles, and a high instability in spermatogenesis for both expanded and normal alleles, suggesting a high mutation rate at the SCA8 locus. </p><p>In contrast to other triplet repeat diseases, expanded alleles found in affected SCA8 individuals can have either a pure uninterrupted CTG repeat tract or an allele with 1 or more CCG, CTA, CTC, CCA, or CTT interruptions. By analyzing sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members from the large 7-generation SCA8 family reported by Koob et al. (1999), Moseley et al. (2000) found 6 different sequence configurations of the CTG repeat. In 2 instances, duplication of CCG interruptions occurred over a single generation, and in other instances duplications that had occurred in different branches of the family could be inferred. When the SCA8 repeat tract was evaluated in sperm samples from individuals with expansions of 80 to 800 repeats in leukocytes, contractions to repeat lengths of less than 100 CTGs were observed, a size not often associated with disease. The authors hypothesized that the en masse repeat contractions in sperm may underlie the reduced penetrance associated with paternal transmission. </p><p>Day et al. (2000) reported findings from a further study of the large SCA8 family. CTG tracts were longer in affected (mean = 116 CTG repeats) than in unaffected expansion carriers (mean = 90). Quantitative dexterity testing did not detect even subtle signs of ataxia in unaffected expansion carriers. All 21 affected family members inherited an expansion from their mothers. The maternal penetrance bias was consistent with maternal repeat expansions yielding alleles above the pathogenic threshold in the family (more than 107 CTG) and paternal contractions resulting in shorter alleles. Consistent with the reduced penetrance of paternal transmissions, CTG tracts in all or nearly all sperm (84 to 99) were significantly shorter than in the blood (116) of an affected man. The authors concluded that the biologic relationship between repeat length and ataxia indicates that the CTG repeat is directly involved in SCA8 pathogenesis. They noted that diagnostic testing and genetic counseling are complicated by the reduced penetrance, which often makes the inheritance appear recessive or sporadic, and by interfamilial differences in the length of a stable (CTA)n tract preceding the CTG repeat. </p><p>Schols et al. (2003) questioned whether the CTG repeat in SCA8 causes ataxia. Analyzing the alleles of 1,262 German patients with ataxia, they concluded that the CTG repeat is a rare polymorphism. </p><p>Corral et al. (2005) reported a woman with cerebellar ataxia who had 2 expansions of the SCA8 CTG repeat (111 and 197 repeats). All 9 of her children were unaffected but had inherited greatly expanded alleles from their mother, ranging from 401 to 1,126 repeats. In all 9 cases, the allele inherited from the father was 18 or 19 repeats. By contrast, in 2 additional families in which 3 affected fathers had homozygous expanded CTG repeats, the unaffected children did not inherit additionally expanded repeats. Corral et al. (2005) suggested that the maternal transmission and expansion of the SCA8 CTG allele observed in their family resulted from gene conversion related to female meiosis. </p><p>Daughters et al. (2009) presented evidence that the expanded CTG repeat in the ATXN8OS gene is transcribed into an mRNA with an expanded CUG repeat, conferring a toxic gain of function that plays a role in the SCA8 phenotype. In brain tissue from humans and mice with SCA8, ATXN8OS mRNA containing the expanded repeat was found to accumulate as ribonuclear inclusions, or RNA foci, that colocalized with the RNA-binding protein MBNL1 (606516) in selected cerebellar cortical neurons in the brain. In Sca8 mice, genetic loss of Mbnl1 enhanced motor deficits, suggesting that loss of MBNL1 plays a role in SCA8 pathogenesis. In Sca8 mice and SCA8 human brains, sequestration of MBNL1 in RNA foci resulted in dysregulation of downstream splicing patterns normally regulated by the CUGBP1 (601074)/MBNL1 pathway, including that of mouse GABA transporter-4 (GAT4, or SLC6A11; 607952). These changes in Gat4 were associated with loss of GABAergic inhibition in the granular cell layer. These data indicated that expanded CUG ATXN8OS mRNA transcripts can dysregulate gene pathways in the brain, similar to the mechanism involved in myotonic dystrophy (DM1; 160900), which is caused by a CTG repeat expansion in the 3-prime UTR region of the DMPK gene (605377) on chromosome 19q13. Daughters et al. (2009) also suggested that the findings may have relevance for other mainly CAG repeat expansion disorders, in which an expanded CTG repeat on the opposite stand may also have toxic effects. </p><p><strong><em>Susceptibility to Late-Onset Parkinson Disease</em></strong></p><p>
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Wu et al. (2004) identified repeat expansions at the SCA8 locus in 4 (1.5%) of 264 patients with typical late-onset levodopa-responsive Parkinson disease (168600). The expansions ranged in size from 75 to 92. </p><p><strong><em>Possible Roles in Other Neurologic Disorders</em></strong></p><p>
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Vincent et al. (2000) observed large trinucleotide (CTA/CTG) repeat alleles (more than 100 repeats) at 13q21 in 1.25% of patients with various psychiatric disorders compared to 0.7% of healthy controls and none of individuals affected by or with a family history of SCA. The authors concluded that the high frequency of large alleles at this locus is inconsistent with the much rarer occurrence of SCA8. </p><p>The observation of large SCA8 alleles in healthy control subjects and nonataxic patients, together with a lack of segregation of the expanded repeat with ataxia in several families, has raised questions about the pathogenic role of the SCA8 expansion. Sobrido et al. (2001) found allele sizes within the proposed pathogenic range in 3 patients with ataxia of unknown etiology, in 2 individuals from pedigrees with either SCA2 or Friedreich ataxia (229300), and in 2 patients with Alzheimer disease. They suggested that sizing of SCA8 alleles should not be a routine diagnostic test until its etiologic role is clarified and the pathogenic threshold determined. </p><p>In a study in Italy, Cellini et al. (2001) analyzed material from 167 patients affected by sporadic, autosomal dominant, and autosomal recessive hereditary ataxia for expanded CTA/CTG repeats. They found abnormally expanded repeats in 5 ataxic patients: 3 with pure cerebellar ataxia, 1 with vitamin E deficiency, and 1 sporadic case with gluten ataxia. They concluded that CTG expansions may be linked to SCA8. The patients presented peculiar phenotypic features, suggesting that additional factors may predispose to the disorder. In the patient with expanded SCA8 CTA/CTG triplet repeats and vitamin E deficiency reported by Cellini et al. (2001), Cellini et al. (2002) identified compound heterozygosity for mutations in the TTPA gene (600415.0004 and 600415.0006), yielding a nonfunctional protein. Mutations in the TTPA gene have been associated with Friedreich-like ataxia (AVED; 277460). Clinically, she had progressive ataxia from the age of 7 years, becoming wheelchair bound at age 17, and cerebellar atrophy. Supplementation with vitamin E did not improve symptoms. The authors suggested that the SCA mutations acted in the neurodegenerative process, worsening the neurologic signs caused by the vitamin E deficit. </p><p>Topisirovic et al. (2002) studied the length of the SCA8 CTA/CTG expansions (which they called combined repeats, or CRs) in 115 patients with ataxia, 64 unrelated individuals with nontriplet neuromuscular diseases, 70 unrelated patients with schizophrenia, and 125 healthy controls. Only 1 patient with apparently sporadic ataxia was identified with an expansion of 100 CRs, which he had inherited from his asymptomatic father (140 CRs) and transmitted the mutation to his son (92 CRs). Paternal transmission in this family produced contractions of 40 and 8 CRs, respectively. None of the subjects from the other studied groups had an expansion at the SCA8 locus. In the control group, the number of CRs at the SCA8 locus ranged from 14 to 34. The findings supported the hypothesis that allelic variants of the expansion mutation at the SCA8 locus can predispose to ataxia. </p><p>Sulek et al. (2003) demonstrated that SCA8 repeat expansion coexists not only with SCA6, but also with SCA1. </p><p>Factor et al. (2005) reported a patient with onset of dysarthria and impairment of balance and coordination at age 53 years that rapidly progressed to include gait and postural instability, urinary incontinence, impotence, and depression. MRI showed cerebellar and pontine atrophy. Molecular analysis identified an expansion of 145 CTA/CTG repeats in one allele and 28 repeats in the other allele, which is consistent with SCA8. However, postmortem examination showed findings consistent with multiple system atrophy. Factor et al. (2005) noted that the association between the SCA8 repeat expansion and ataxia is controversial, and suggested that testing sporadic cases with late-onset ataxia may lead to misdiagnosis, as in their case. </p>
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<h4>
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<span class="mim-font">
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<strong>Population Genetics</strong>
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</h4>
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<span class="mim-text-font">
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<p>Among 75 dominant ataxic independent nuclear families in Spain, Tazon et al. (2002) found 3 with SCA8, representing 4%. A 25-year-old man with a clinical picture of progressive ataxia and dysarthria beginning at age 12 years was homozygous for the expansion of the CTA/CTG 3-prime untranslated region of SCA8. On neurologic examination, he showed ataxia, slight dysarthria, and nystagmus to extreme lateral gaze. Cranial MRI showed global atrophy of cerebellum, but the brainstem was spared. Ataxia had been present in his grandfather and father. His mother, who had no ataxia antecedents in her family, was healthy at age 52; a molecular study of SCA8 revealed 1 allele that could be considered as premutated. </p><p>Juvonen et al. (2002) identified SCA8 repeat expansions in 22 of 251 unrelated Finnish SCA patients. They defined alleles with 15 to 40 combined repeats as normal, and those with 80 to 800 as expanded. None of the 22 SCA8-positive patients had expansions at SCA1, 2, 3, 6, 7, 10 (603516), 12 (604326), 17 (607136), DRPLA (607462), or FXN (606829) loci. Thirteen of the patients had a family history of SCA, which was compatible with a dominant inheritance pattern in 9. </p><p>Izumi et al. (2003) analyzed the SCA8 CTA/CTG repeat in a large group of Japanese subjects. The frequency of large alleles (85 to 399 CTA/CTG repeats) was 1.9% in spinocerebellar ataxia, 0.4% in Parkinson disease (PD; 168600), 0.3% in Alzheimer disease, and 0% in a healthy control group; the frequency was significantly higher in the group with SCA than in the control group. Homozygotes for large alleles were observed only in the group with SCA. In 5 patients with SCA from 2 families, a large SCA8 CTA/CTG repeat and a large SCA6 (183086; 601011) CAG repeat coexisted. Age at onset was correlated with SCA8 repeats rather than SCA6 repeats in these 5 patients. In 1 of these families, at least 1 patient showed only a large SCA8 CTA/CTG repeat allele, with no large SCA6 CAG repeat allele. Izumi et al. (2003) speculated that the presence of a large SCA8 CTA/CTG repeat allele influences the function of channels such as the alpha-1A-voltage-dependent calcium channel (CACNA1A; 601011), resulting in the development of cerebellar ataxia, especially in homozygous patients. They discussed the possibility that SCA8 works through SCA6 gene products. </p><p>In a study in Taiwan, Wu et al. (2004) detected abnormal expansions of trinucleotide repeats in both the SCA8 and SCA17 (607136) genes in patients with Parkinson disease. The clinical presentation of these patients was typical of idiopathic PD with the following characteristics: late onset of disease, resting tremor in the limbs, rigidity, bradykinesia, and a good response to levodopa. </p><p>Ikeda et al. (2004) described the molecular genetic features and disease penetrance of 37 families with SCA8 ataxia from the United States, Canada, Japan, and Mexico. SCA8 shows a complex inheritance pattern with extremes of incomplete penetrance, in which often only 1 or 2 affected individuals are found in a given family. By haplotype analysis using 17 short tandem repeat (STR) markers spanning a region of approximately 1 Mb in families with ataxia, as well as a group of expansion carriers in the general population and a group of psychiatric patients, Ikeda et al. (2004) sought to clarify the genetic basis of the reduced penetrance and to investigate whether CTG expansions among different populations share a common ancestral background. Two major ancestrally related haplotypes (A and A-prime) were found among white families with ataxia, normal controls, and patients with major psychosis, indicating a common ancestral origin of both pathogenic and nonpathogenic SCA8 expansions among whites. Two additional and distinct haplotypes were found among a group of Japanese families with ataxia (haplotype B) and a Mexican family with ataxia (haplotype C). The findings that SCA8 expansions on 3 independently arising haplotypes are found among patients with ataxia and cosegregate with ataxia when multiple family members are affected further supported the direct role of the CTG expansion in disease pathogenesis. </p><p>Martins et al. (2005) performed haplotype and sequencing analysis in a large region encompassing the SCA8 gene (CTA)n (CTG)n repeat and 6 SNP markers in 4 SCA8 families of Portuguese descent. Two different haplotypes, AG-Expanded-GTTG and AG-Expanded-CTTG, were identified. The same haplotypes were also the most frequently identified (AG-Normal-GTTG and AG-Normal-CTTG) in the normal population of 20 control Portuguese families, suggesting that the mutated state arose from common backgrounds. </p>
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<strong>Animal Model</strong>
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<p>Moseley et al. (2006) reported a transgenic mouse model in which the full-length human SCA8 mutation is transcribed using its endogenous promoter. They found that (CTG)116 expansion, but not (CTG)11 control lines, develop a progressive neurologic phenotype, with in vivo imaging showing reduced cerebellar-cortical inhibition. Both polyleucine- and polyglutamine-containing expansion proteins have been reported to form intranuclear inclusions that are recognized by the 1C2 monoclonal antibody (Zoghbi and Orr, 2000; Dorsman et al., 2002). Moseley et al. (2006) found that 1C2-positive intranuclear inclusions in cerebellar Purkinje and brainstem neurons in SCA8 expansion mice and human SCA8 autopsy tissue result from translation of a polyglutamine protein, encoded on a previously unidentified antiparallel transcript, ATXN8 (613289), spanning the repeat in the CAG direction. The neurologic phenotype in SCA8 BAC expansion but not BAC control lines demonstrated the pathogenicity of the (CTG-CAG)n expansion. Moreover, the expression of noncoding (CUG)n expansion ATXN8OS transcripts and the discovery of intranuclear polyglutamine inclusions suggested that SCA8 pathogenesis involves toxic gain-of-function mechanisms at both the protein and the RNA levels. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>1 Selected Example):</strong>
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<span class="mim-font">
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<strong>.0001 SPINOCEREBELLAR ATAXIA 8</strong>
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<span class="mim-text-font">
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PARKINSON DISEASE, LATE-ONSET, SUSCEPTIBILITY TO, INCLUDED
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ATXN8OS, (CTG)n REPEAT EXPANSION
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ClinVar: RCV000000215, RCV000006519, RCV001260914
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<p>In patients with spinocerebellar ataxia-8 (SCA8; 608768), Koob et al. (1999) identified a CAG repeat expansion in the 5-prime to 3-prime orientation of the ATXN8 template strand (ATXN8; 613289.0001) that did not appear to be translated into a polyglutamine-containing protein. However, the corresponding 5-prime-to-3-prime CTG repeat expansion in the ATXN8OS gene on the opposite strand was found to be transcribed into an mRNA with an expanded CUG repeat in its 3-prime UTR. The mRNA with the expanded CUG repeat was not translated. Moseley et al. (2006) found that the CAG repeat in the ATXN8 gene was transcribed into a protein with an expanded polyglutamine tract in patients with SCA8. </p><p>In 37 families with SCA8 ataxia from the United States, Canada, Japan, and Mexico, Ikeda et al. (2004) identified 3 different ancestral haplotypes containing the ATXN8OS gene that segregated with the families according to population: Caucasian, Japanese, and Mexican. Martins et al. (2005) performed haplotype and sequencing analysis in a large region encompassing the ATXN8OS gene (CTA)n (CTG)n repeat and 6 SNP markers in 4 SCA8 families of Portuguese descent. Two different haplotypes, AG-Expanded-GTTG and AG-Expanded-CTTG, were identified. The same haplotypes were also the most frequently identified (AG-Normal-GTTG and AG-Normal-CTTG) in the normal population of 20 control Portuguese families, suggesting that the mutated state arose from common backgrounds. </p><p>Daughters et al. (2009) presented evidence that the expanded CTG repeat in the ATXN8OS gene is transcribed into an mRNA with an expanded CUG repeat, conferring a toxic gain of function that plays a role in the SCA8 phenotype. In brain tissue from humans and mice with SCA8, ATXN8OS mRNA containing the expanded repeat was found to accumulate as ribonuclear inclusions, or RNA foci, that colocalized with the RNA-binding protein MBNL1 (606516) in selected cerebellar cortical neurons in the brain. Sequestration of MBNL1 in RNA foci resulted in dysregulation of downstream splicing patterns normally regulated by the CUGBP1 (601074)/MBNL1 pathway, including that of mouse GABA transporter-4 (GAT4, or SLC6A11; 607952). These changes in Gat4 were associated with loss of GABAergic inhibition in the granular cell layer. These data indicated that expanded CUG ATXN8OS mRNA transcripts can have a toxic gain of function. </p><p>Susceptibility to Late-Onset Parkinson Disease</p><p>Wu et al. (2004) identified repeat expansions at the SCA8 locus in 4 (1.5%) of 264 patients with typical late-onset levodopa-responsive Parkinson disease (168600). The expansions ranged in size from 75 to 92. </p>
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<div>
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<h4>
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<span class="mim-font">
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Moseley, M. L., Zu, T., Ikeda, Y., Gao, W., Mosemiller, A. K., Daughters, R. S., Chen, G., Weatherspoon, M. R., Clark, H. B., Ebner, T. J., Day, J. W., Ranum. L. P. W.
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Stevanin, G., Herman, A., Durr, A., Jodice, C., Frontali, M., Agid, Y., Brice, A.
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Vincent, J. B., Neves-Pereira, M. L., Paterson, A. D., Yamamoto, E., Parikh, S. V., Macciardi, F., Gurling, H. M., Potkin, S. G., Pato, C. N., Macedo, A., Kovacs, M., Davies, M., Lieberman, J. A., Meltzer, H. Y., Petronis, A, Kennedy, J. L.
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<strong>An unstable trinucleotide-repeat region on chromosome 13 implicated in spinocerebellar ataxia: a common expansion locus.</strong>
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<div>
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</div>
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<span class="text-nowrap mim-text-font">
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Contributors:
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Cassandra L. Kniffin - updated : 3/3/2010<br>Matthew B. Gross - updated : 3/1/2010<br>Patricia A. Hartz - updated : 3/1/2010<br>Victor A. McKusick - updated : 6/30/2006<br>Cassandra L. Kniffin - updated : 6/30/2005<br>Cassandra L. Kniffin - reorganized : 7/2/2004<br>Victor A. McKusick - updated : 6/10/2004<br>Victor A. McKusick - updated : 2/25/2004<br>Victor A. McKusick - updated : 10/7/2003<br>Cassandra L. Kniffin - updated : 8/14/2003<br>Victor A. McKusick - updated : 6/30/2003<br>Victor A. McKusick - updated : 2/26/2003<br>Cassandra L. Kniffin - updated : 2/13/2003<br>Victor A. McKusick - updated : 12/18/2002<br>Victor A. McKusick - updated : 11/6/2002<br>Victor A. McKusick - updated : 12/21/2001<br>Victor A. McKusick - updated : 12/5/2001<br>Victor A. McKusick - updated : 10/12/2001<br>Majed J. Dasouki - updated : 1/30/2001<br>George E. Tiller - updated : 11/17/2000<br>George E. Tiller - updated : 10/13/2000<br>Victor A. McKusick - updated : 4/10/2000<br>Paul J. Converse - updated : 4/4/2000<br>Victor A. McKusick - updated : 3/1/2000
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Ada Hamosh : 3/29/1999
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alopez : 10/31/2019<br>carol : 01/31/2017<br>terry : 06/07/2012<br>terry : 11/30/2010<br>ckniffin : 11/16/2010<br>terry : 9/9/2010<br>carol : 5/25/2010<br>mgross : 3/3/2010<br>ckniffin : 3/3/2010<br>ckniffin : 3/3/2010<br>mgross : 3/1/2010<br>mgross : 3/1/2010<br>mgross : 3/1/2010<br>mgross : 3/1/2010<br>mgross : 2/17/2010<br>joanna : 2/5/2010<br>carol : 1/4/2010<br>carol : 3/12/2007<br>wwang : 11/28/2006<br>terry : 8/25/2006<br>carol : 8/24/2006<br>alopez : 7/5/2006<br>terry : 6/30/2006<br>wwang : 7/14/2005<br>wwang : 7/13/2005<br>ckniffin : 6/30/2005<br>terry : 3/3/2005<br>carol : 7/2/2004<br>ckniffin : 6/30/2004<br>alopez : 6/10/2004<br>terry : 6/10/2004<br>joanna : 3/17/2004<br>tkritzer : 3/1/2004<br>terry : 2/25/2004<br>cwells : 11/5/2003<br>tkritzer : 10/10/2003<br>terry : 10/7/2003<br>cwells : 8/20/2003<br>ckniffin : 8/14/2003<br>tkritzer : 7/8/2003<br>terry : 6/30/2003<br>ckniffin : 4/3/2003<br>alopez : 2/27/2003<br>terry : 2/26/2003<br>carol : 2/24/2003<br>ckniffin : 2/13/2003<br>carol : 12/23/2002<br>tkritzer : 12/20/2002<br>terry : 12/18/2002<br>tkritzer : 11/13/2002<br>tkritzer : 11/12/2002<br>terry : 11/6/2002<br>ckniffin : 8/7/2002<br>cwells : 1/10/2002<br>cwells : 1/2/2002<br>terry : 12/21/2001<br>alopez : 12/11/2001<br>terry : 12/5/2001<br>mcapotos : 10/26/2001<br>mcapotos : 10/12/2001<br>carol : 1/30/2001<br>mcapotos : 12/4/2000<br>mcapotos : 11/28/2000<br>terry : 11/17/2000<br>alopez : 10/13/2000<br>mcapotos : 5/3/2000<br>mcapotos : 4/28/2000<br>terry : 4/10/2000<br>carol : 4/4/2000<br>alopez : 3/1/2000<br>terry : 3/1/2000<br>terry : 3/1/2000<br>alopez : 3/29/1999<br>alopez : 3/29/1999
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