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Entry
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- *607462 - ATROPHIN 1; ATN1
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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">*607462</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</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>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/607462">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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</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-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="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=ENSG00000111676;t=ENST00000396684" 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=1822" 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=607462" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<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=ENSG00000111676;t=ENST00000396684" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001007026,NM_001424176,NM_001424177,NM_001424178,NM_001424179,NM_001424180,NM_001424182,NM_001940" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001940" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=607462" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=06311&isoform_id=06311_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/ATN1" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/862330,915326,1732417,1732444,2647945,30353865,55750041,55750053,119609112,119609113,119609114,317373480,2574688517,2574688519,2574688521,2574688523,2574688525,2574688529" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P54259" 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=1822" 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=ENSG00000111676;t=ENST00000396684" 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=ATN1" 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=ATN1" 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+1822" 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/ATN1" 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:1822" 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/1822" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr12&hgg_gene=ENST00000396684.3&hgg_start=6924459&hgg_end=6942321&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://medlineplus.gov/genetics/gene/atn1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607462[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=607462[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/ATN1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000111676" 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.gwascentral.org/search?q=ATN1" 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=ATN1" 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=ATN1&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/PA27487" 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:3033" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0010825.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:104725" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/ATN1#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:104725" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/1822/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=1822" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00001194;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-426" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellLines">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellLinesLinksFold" id="mimCellLinesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellLinesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cell Lines</div>
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</div>
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</a>
|
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</span>
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</span>
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</div>
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<div id="mimCellLinesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://catalog.coriell.org/Search?q=OmimNum:607462" class="definition" title="Coriell Cell Repositories; cell cultures and DNA derived from cell cultures." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'CCR', 'domain': 'ccr.coriell.org'})">Coriell</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
|
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</div>
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</a>
|
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</span>
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</span>
|
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</div>
|
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=ATN1&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> 68116008<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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607462
|
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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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ATROPHIN 1; ATN1
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
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<div>
|
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
DRPLA GENE; DRPLA
|
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</span>
|
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</h4>
|
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</div>
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</div>
|
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<div>
|
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<br />
|
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=ATN1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ATN1</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>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/12/79?start=-3&limit=10&highlight=79">12p13.31</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr12:6924459-6942321&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">12:6,924,459-6,942,321</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=618494,125370" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/79?start=-3&limit=10&highlight=79">
|
|
12p13.31
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Congenital hypotonia, epilepsy, developmental delay, and digital anomalies
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/618494"> 618494 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
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<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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|
|
|
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|
|
|
</tr>
|
|
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|
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Dentatorubral-pallidoluysian atrophy
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/125370"> 125370 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
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<td>
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<p>The ATN1 gene encodes atrophin-1, a member of a class of evolutionarily conserved transcriptional corepressors involved in nuclear signaling. ATN1 is believed to play a role as a nuclear transcriptional regulator important for brain and other organ system development (summary by <a href="#20" class="mim-tip-reference" title="Palmer, E. E., Hong, S., Al Zahrani, F., Hashem, M. O., Aleisa, F. A., Ahmed, H. M. J., Kandula, T., Macintosh, R., Minoche, A. E., Puttick, C., Gayevskiy, V., Drew, A. P., and 31 others. <strong>De novo variants disrupting the HX repeat motif of ATN1 cause a recognizable non-progressive neurocognitive syndrome.</strong> Am. J. Hum. Genet. 104: 542-552, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 778 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30827498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30827498</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30827498">Palmer et al., 2019</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30827498" 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 the search for a candidate gene for dentatorubral-pallidoluysian atrophy (DRPLA; <a href="/entry/125370">125370</a>), an inherited neurodegenerative disorder that demonstrates genetic anticipation characteristic of unstable expansion of trinucleotide repeats, <a href="#8" class="mim-tip-reference" title="Koide, R., Ikeuchi, T., Onodera, O., Tanaka, H., Igarashi, S., Endo, K., Takahashi, H., Kondo, R., Ishikawa, A., Hayashi, T., Saito, M., Tomoda, A., Miike, T., Naito, H., Ikuta, F., Tsuji, S. <strong>Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA).</strong> Nature Genet. 6: 9-13, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136840</a>] [<a href="https://doi.org/10.1038/ng0194-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8136840">Koide et al. (1994)</a> searched a catalog of genes expressed in human brain identified by <a href="#10" class="mim-tip-reference" title="Li, S.-H., McInnis, M. G., Margolis, R. L., Antonarakis, S. E., Ross, C. A. <strong>Novel triplet repeat containing genes in human brain: cloning, expression, and length polymorphisms.</strong> Genomics 16: 572-579, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8325628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8325628</a>] [<a href="https://doi.org/10.1006/geno.1993.1232" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8325628">Li et al. (1993)</a> that contained trinucleotide repeats. One of these, B37, which was known to map to chromosome 12, was examined and found to show CAG repeat expansion (<a href="#0001">607462.0001</a>) in 22 individuals with DRPLA. By screening adult human occipital cortex and fetal human brain cDNA libraries, <a href="#18" class="mim-tip-reference" title="Onodera, O., Oyake, M., Takano, H., Ikeuchi, T., Igarashi, S., Tsuji, S. <strong>Molecular cloning of a full-length cDNA for dentatorubral-pallidoluysian atrophy and regional expressions of the expanded alleles in the CNS.</strong> Am. J. Hum. Genet. 57: 1050-1060, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7485154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7485154</a>]" pmid="7485154">Onodera et al. (1995)</a> isolated a full-length DRPLA cDNA encoding a deduced 1,185-amino acid protein with a predicted molecular mass of 125 kD. The (CAG)n repeat that is expanded in patients with DRPLA is located at position 1462 and is predicted to code for a polyglutamine tract. There was high heterozygosity of the length of the polyglutamine tract, ranging from 8 to 35 repeat units in 140 normal chromosomes. Northern blot analysis revealed a 4.7-kb transcript that is widely expressed in various tissues, including heart, lung, kidney, placenta, skeletal muscle, and brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8136840+8325628+7485154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using antibodies against a synthetic peptide corresponding to the sequence of the C-terminus of the DRPLA gene product, <a href="#31" class="mim-tip-reference" title="Yazawa, I., Nukina, N., Hashida, H., Goto, J., Yamada, M., Kanazawa, I. <strong>Abnormal gene product identified in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) brain.</strong> Nature Genet. 10: 99-103, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7647802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7647802</a>] [<a href="https://doi.org/10.1038/ng0595-99" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7647802">Yazawa et al. (1995)</a> identified the DRPLA gene product in normal human brains as a protein of approximately 190 kD. They also found a larger protein of approximately 205 kD specifically in DRPLA brains. Immunohistochemically, the DRPLA gene product was observed mainly in neuronal cytoplasm. These results demonstrated the existence of the expanded CAG repeat gene product and supported the possibility that the expanded CAG-encoded polyglutamine stretch may participate in the pathologic process of similar trinucleotide repeat diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7647802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Schmitt, I., Epplen, J. T., Riess, O. <strong>Predominant neuronal expression of the gene responsible for dentatorubral-pallidoluysian atrophy (DRPLA) in rat.</strong> Hum. Molec. Genet. 4: 1619-1624, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541849/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541849</a>] [<a href="https://doi.org/10.1093/hmg/4.9.1619" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8541849">Schmitt et al. (1995)</a> isolated the complete coding sequence of the rat DRPLA gene and investigated its expression in different developmental stages of rodent tissues. In rat, the length of the (CAG)n repeat is 7 to 34 repeats with an average of 15, which is mildly reduced in comparison with the human repeats. Northern blot analysis demonstrated that in rodents the gene is already expressed during embryonic development. In addition, the transcript is predominantly represented in neuronal tissues throughout all developmental stages investigated. <a href="#19" class="mim-tip-reference" title="Oyake, M., Onodera, O., Shiroishi, T., Takano, H., Takahashi, Y., Kominami, R., Moriwaki, K., Ikeuchi, T., Igarashi, S., Tanaka, H., Tsuji, S. <strong>Molecular cloning of murine homologue dentatorubral-pallidoluysian atrophy (DRPLA) cDNA: strong conservation of a polymorphic CAG repeat in the murine gene.</strong> Genomics 40: 205-207, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9070948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9070948</a>] [<a href="https://doi.org/10.1006/geno.1996.4522" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9070948">Oyake et al. (1997)</a> cloned a mouse Drpla cDNA and found that the encoded protein is 92% identical to human DRPLA. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9070948+8541849" 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="#28" class="mim-tip-reference" title="Takano, T., Yamanouchi, Y., Nagafuchi, S., Yamada, M. <strong>Assignment of the dentatorubral and pallidoluysian atrophy (DRPLA) gene to 12p13.31 by fluorescence in situ hybridization.</strong> Genomics 32: 171-172, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8786114/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8786114</a>] [<a href="https://doi.org/10.1006/geno.1996.0100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8786114">Takano et al. (1996)</a> assigned the DRPLA gene to chromosome 12p13.31 by fluorescence in situ hybridization. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8786114" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Oyake, M., Onodera, O., Shiroishi, T., Takano, H., Takahashi, Y., Kominami, R., Moriwaki, K., Ikeuchi, T., Igarashi, S., Tanaka, H., Tsuji, S. <strong>Molecular cloning of murine homologue dentatorubral-pallidoluysian atrophy (DRPLA) cDNA: strong conservation of a polymorphic CAG repeat in the murine gene.</strong> Genomics 40: 205-207, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9070948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9070948</a>] [<a href="https://doi.org/10.1006/geno.1996.4522" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9070948">Oyake et al. (1997)</a> mapped the mouse Drpla gene to chromosome 6 by interspecific backcross analysis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9070948" 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="#3" class="mim-tip-reference" title="Burke, J. R., Enghild, J. J., Martin, M. E., Jou, Y.-S., Myers, R. M., Roses, A. D., Vance, J. M., Strittmatter, W. J. <strong>Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH.</strong> Nature Med. 2: 347-350, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8612237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8612237</a>] [<a href="https://doi.org/10.1038/nm0396-347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8612237">Burke et al. (1996)</a> demonstrated that synthetic polyglutamine peptides, DRPLA protein and huntingtin (<a href="/entry/613004">613004</a>) from unaffected individuals with normal-sized polyglutamine tracts bind to glyceraldehyde-3-phosphate dehydrogenase (<a href="/entry/138400">138400</a>). The authors postulated that diseases characterized by the presence of an expanded CAG repeat may share a common metabolic pathogenesis involving GAPD as a functional component. <a href="#22" class="mim-tip-reference" title="Roses, A. D. <strong>From genes to mechanisms to therapies: lessons to be learned from neurological disorders.</strong> Nature Med. 2: 267-269, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8612215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8612215</a>] [<a href="https://doi.org/10.1038/nm0396-267" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8612215">Roses (1996)</a> and <a href="#2" class="mim-tip-reference" title="Barinaga, M. <strong>An intriguing new lead on Huntington's disease.</strong> Science 271: 1233-1234, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8638101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8638101</a>] [<a href="https://doi.org/10.1126/science.271.5253.1233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8638101">Barinaga (1996)</a> reviewed the findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8638101+8612237+8612215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using the yeast 2-hybrid system, <a href="#30" class="mim-tip-reference" title="Wood, J. D., Yuan, J., Margolis, R. L., Colomer, V., Duan, K., Kushi, J., Kaminsky, Z., Kleiderlein, J. J., Jr., Sharp, A. H., Ross, C. A. <strong>Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins.</strong> Molec. Cell. Neurosci. 11: 149-160, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9647693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9647693</a>] [<a href="https://doi.org/10.1006/mcne.1998.0677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9647693">Wood et al. (1998)</a> identified 5 atrophin-1 interacting proteins that bind to atrophin-1 in the vicinity of the polyglutamine tract. Four of the interactions were confirmed using in vitro binding assays. These interactors were found to be similar to huntingtin-interacting proteins, suggesting possible commonality of function between the 2 proteins responsible for the very similar diseases, Huntington disease (HD; <a href="/entry/143100">143100</a>) and DRPLA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9647693" 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="#32" class="mim-tip-reference" title="Zhang, S., Xu, L., Lee, J., Xu, T. <strong>Drosophila Atrophin homolog functions as a transcriptional corepressor in multiple developmental processes.</strong> Cell 108: 45-56, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792320</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00630-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11792320">Zhang et al. (2002)</a> characterized a Drosophila gene encoding an atrophin family protein. Analysis of mutant phenotypes indicated that Drosophila atrophin is required in diverse developmental processes, including early embryonic patterning. Drosophila atrophin genetically interacts with the transcription repressor 'even-skipped' (see <a href="/entry/142991">142991</a>) and is required for its repressive function in vivo. Drosophila atrophin directly binds to even-skipped in vitro. Furthermore, both human atrophin-1 and Drosophila atrophin repress transcription in vivo when tethered to DNA, and poly-Q expansion in atrophin-1 reduces this repressive activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11792320" 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="Okamura-Oho, Y., Miyashita, T., Nagao, K., Shima, S., Ogata, Y., Katada, T., Nishina, H., Yamada, M. <strong>Dentatorubral-pallidoluysian atrophy protein is phosphorylated by c-Jun NH2-terminal kinase.</strong> Hum. Molec. Genet. 12: 1535-1542, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12812981/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12812981</a>] [<a href="https://doi.org/10.1093/hmg/ddg168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12812981">Okamura-Oho et al. (2003)</a> determined that the DRPLA protein is a phosphoprotein and that c-Jun NH2-terminal kinase (JNK; see <a href="/entry/601158">601158</a>) is one of the major factors involved in its phosphorylation. Phosphorylation was demonstrated in a recombinant JNK activation system in vitro and also in overexpressing cells by transfection after JNK activation with osmotic pressure. Phosphorylation of serine-734 in the DRPLA protein was confirmed by a specific antibody raised against the phosphopeptide. Kinetic studies in the JNK recombinant system showed that expanded polyQ slightly reduced the affinity of JNK to the protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12812981" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid screens, coaffinity purification analysis of transfected HEK293 cells, and bioinformatic analysis, <a href="#11" class="mim-tip-reference" title="Lim, J., Hao, T., Shaw, C., Patel, A. J., Szabo, G., Rual, J.-F., Fisk, C. J., Li, N., Smolyar, A., Hill, D. E., Barabasi, A.-L., Vidal, M., Zoghbi, H. Y. <strong>A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.</strong> Cell 125: 801-814, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16713569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16713569</a>] [<a href="https://doi.org/10.1016/j.cell.2006.03.032" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16713569">Lim et al. (2006)</a> developed an interaction network for 54 human proteins involved in 23 inherited ataxias. By database analysis, they expanded the core network to include more distantly related interacting proteins that could function as genetic modifiers. RBPMS (<a href="/entry/601558">601558</a>) was a main hub in the network and interacted with many proteins, including the cerebellar ataxia-associated proteins ATN1 and QK1 (<a href="/entry/609590">609590</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16713569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>Dentatorubral-Pallidoluysian Atrophy</em></strong></p><p>
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In 22 patients with dentatorubral-pallidoluysian atrophy (DRPLA; <a href="/entry/125370">125370</a>), <a href="#8" class="mim-tip-reference" title="Koide, R., Ikeuchi, T., Onodera, O., Tanaka, H., Igarashi, S., Endo, K., Takahashi, H., Kondo, R., Ishikawa, A., Hayashi, T., Saito, M., Tomoda, A., Miike, T., Naito, H., Ikuta, F., Tsuji, S. <strong>Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA).</strong> Nature Genet. 6: 9-13, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136840</a>] [<a href="https://doi.org/10.1038/ng0194-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8136840">Koide et al. (1994)</a> identified unstable expansion of a CAG unit in the ATN1 gene (<a href="#0001">607462.0001</a>), which they termed B37 after a cDNA clone previously identified by <a href="#10" class="mim-tip-reference" title="Li, S.-H., McInnis, M. G., Margolis, R. L., Antonarakis, S. E., Ross, C. A. <strong>Novel triplet repeat containing genes in human brain: cloning, expression, and length polymorphisms.</strong> Genomics 16: 572-579, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8325628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8325628</a>] [<a href="https://doi.org/10.1006/geno.1993.1232" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8325628">Li et al. (1993)</a>. Each patient was a heterozygote with 1 allele in the normal range (8-25 repeat units) and a second expanded allele with the range of 54-68 repeat units. There were no overlaps in the number of CAG repeat units between control chromosomes and DRPLA chromosomes. In 33 patients with DRPLA from 12 families, <a href="#15" class="mim-tip-reference" title="Nagafuchi, S., Yanagisawa, H., Sato, K., Shirayama, T., Ohsaki, E., Bundo, M., Takeda, T., Tadokoro, K., Kondo, I., Murayama, N., Tanaka, Y., Kikushima, H., Umino, K., Kurosawa, H., Furukawa, T., Nihei, K., Inoue, T., Sano, A., Komure, O., Takahashi, M., Yoshizawa, T., Kanazawa, I., Yamada, M. <strong>Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p.</strong> Nature Genet. 6: 14-18, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136826</a>] [<a href="https://doi.org/10.1038/ng0194-14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8136826">Nagafuchi et al. (1994)</a> identified an expanded CAG repeat in the B37 clone. The repeat size varied from 7-23 in normal individuals and 1 allele was expanded to between 49-75 repeats in affected individuals. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8136840+8136826+8325628" 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>Burke et al. (<a href="#5" class="mim-tip-reference" title="Burke, J. R., Pericak-Vance, M. A., Vance, J. M. <strong>Haw River syndrome (HRS) and dentatorubropallidoluysian atrophy (DRPLA): disorders with an identical trinucleotide repeat expansion but differences in clinical expression and racial frequency. (Abstract)</strong> Am. J. Hum. Genet. 55 (suppl.): A17 only, 1994."None>1994</a>, <a href="#6" class="mim-tip-reference" title="Burke, J. R., Wingfield, M. S., Lewis, K. E., Roses, A. D., Lee, J. E., Hulette, C., Pericak-Vance, M. A., Vance, J. M. <strong>The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family.</strong> Nature Genet. 7: 521-524, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951323</a>] [<a href="https://doi.org/10.1038/ng0894-521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7951323">1994</a>) demonstrated that affected members of the large African American family with Haw River syndrome had the same trinucleotide repeat expansion (<a href="#0001">607462.0001</a>) in the ATN1 gene as that found in DRPLA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7951323" 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>Congenital Hypotonia, Epilepsy, Developmental Delay, and Digital Anomalies</em></strong></p><p>
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In 8 unrelated children with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; <a href="/entry/618494">618494</a>), <a href="#20" class="mim-tip-reference" title="Palmer, E. E., Hong, S., Al Zahrani, F., Hashem, M. O., Aleisa, F. A., Ahmed, H. M. J., Kandula, T., Macintosh, R., Minoche, A. E., Puttick, C., Gayevskiy, V., Drew, A. P., and 31 others. <strong>De novo variants disrupting the HX repeat motif of ATN1 cause a recognizable non-progressive neurocognitive syndrome.</strong> Am. J. Hum. Genet. 104: 542-552, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 778 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30827498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30827498</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30827498">Palmer et al. (2019)</a> identified 8 different de novo heterozygous mutations in exon 7 of the ATN1 gene (see, e.g., <a href="#0002">607462.0002</a>-<a href="#0006">607462.0006</a>), all resulting in substitutions within the highly conserved 16-amino acid histidine-rich 'HX repeat' motif near the C terminus. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. This HX repeat is distal to the expanded repeat responsible for DRPLA. Nuclear magnetic resonance analysis of a synthesized peptide containing 1 of the mutations (H1060Y; <a href="#0005">607462.0005</a>) showed that the mutation resulted in a perturbation of the structural and functional integrity of the HX repeat, and altered zinc-binding properties. Additional functional studies of the variants and studies of patient cells were not performed. However, <a href="#20" class="mim-tip-reference" title="Palmer, E. E., Hong, S., Al Zahrani, F., Hashem, M. O., Aleisa, F. A., Ahmed, H. M. J., Kandula, T., Macintosh, R., Minoche, A. E., Puttick, C., Gayevskiy, V., Drew, A. P., and 31 others. <strong>De novo variants disrupting the HX repeat motif of ATN1 cause a recognizable non-progressive neurocognitive syndrome.</strong> Am. J. Hum. Genet. 104: 542-552, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 778 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30827498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30827498</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30827498">Palmer et al. (2019)</a> noted that de novo disruptions of a similar HX motif in the RERE gene (<a href="/entry/605226">605226</a>) and the AUTS2 gene (<a href="/entry/607270">607270</a>) have been noted in patients with neurocognitive phenotypes. ATN1 also lies within the critical region for Pallister-Killian syndrome (PKS; <a href="/entry/601803">601803</a>), which has an overlapping phenotype. Despite the absence of these variants in gnomAD, all could be classified as 'variants of uncertain significance' according to ACMG guidelines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30827498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#13" class="mim-tip-reference" title="Martins, S., Matama, T., Guimaraes, L., Vale, J., Guimaraes, J., Ramos, L., Coutinho, P., Sequeiros, J., Silveira, I. <strong>Portuguese families with dentatorubropallidoluysian atrophy (DRPLA) share a common haplotype of Asian origin.</strong> Europ. J. Hum. Genet. 11: 808-811, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14512972/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14512972</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201054" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14512972">Martins et al. (2003)</a> stated that DRPLA is prevalent in Japan, but several families of non-Japanese ancestry had been published. To identify the origin of expanded alleles in 4 Portuguese families with DRPLA, they studied 2 intragenic SNPs in introns 1 and 3, in addition to the CAG repeat, of the DRPLA gene. The results showed that all 4 families shared the same haplotype, which was the same as that reported for Japanese DRPLA chromosomes. This haplotype is also the most frequent in Japanese normal alleles, whereas it was rare in Portuguese control chromosomes. The findings supported the suggestion that a founder DRPLA haplotype of Asian origin was introduced in Portugal and is responsible for the frequency of the disease in that country. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14512972" 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>Genetic Anticipation</em></strong></p><p>
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<a href="#8" class="mim-tip-reference" title="Koide, R., Ikeuchi, T., Onodera, O., Tanaka, H., Igarashi, S., Endo, K., Takahashi, H., Kondo, R., Ishikawa, A., Hayashi, T., Saito, M., Tomoda, A., Miike, T., Naito, H., Ikuta, F., Tsuji, S. <strong>Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA).</strong> Nature Genet. 6: 9-13, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136840</a>] [<a href="https://doi.org/10.1038/ng0194-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8136840">Koide et al. (1994)</a> found a good correlation between the size of the (CAG)n repeat expansion and the age of onset. Patients with earlier onset tended to have a phenotype of progressive myoclonic epilepsy and larger expansions. They proposed that the wide variety of clinical manifestations of DRPLA can be explained by the variable unstable expansion of the CAG repeat. Although only 5 cases of paternal transmission and 2 cases of maternal transmission were analyzed, the length of the repeat unit was altered in all cases: the average change in repeat length for paternal transmission was an increase of 4.2 repeats, while that of maternal transmission was a decrease of 1.0 repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8136840" 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="Nagafuchi, S., Yanagisawa, H., Sato, K., Shirayama, T., Ohsaki, E., Bundo, M., Takeda, T., Tadokoro, K., Kondo, I., Murayama, N., Tanaka, Y., Kikushima, H., Umino, K., Kurosawa, H., Furukawa, T., Nihei, K., Inoue, T., Sano, A., Komure, O., Takahashi, M., Yoshizawa, T., Kanazawa, I., Yamada, M. <strong>Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p.</strong> Nature Genet. 6: 14-18, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136826</a>] [<a href="https://doi.org/10.1038/ng0194-14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8136826">Nagafuchi et al. (1994)</a> also found that repeat size correlated closely with age of onset of symptoms and with disease severity. Expansion was usually associated with paternal transmission. <a href="#9" class="mim-tip-reference" title="Komure, O., Sano, A., Nishino, N., Yamauchi, N., Ueno, S., Kondoh, K., Sano, N., Takahashi, M., Murayama, N., Kondo, I., Nagafuchi, S., Yamada, M., Kanazawa, I. <strong>DNA analysis in hereditary dentatorubral-pallidoluysian atrophy: correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation.</strong> Neurology 45: 143-149, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7824105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7824105</a>] [<a href="https://doi.org/10.1212/wnl.45.1.143" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7824105">Komure et al. (1995)</a> analyzed CAG trinucleotide repeats in 71 individuals from 12 Japanese DRPLA pedigrees that included 38 affected individuals. Normal alleles varied from 7 to 23 repeats, whereas affected individuals had from 53 to 88 repeats. Like <a href="#8" class="mim-tip-reference" title="Koide, R., Ikeuchi, T., Onodera, O., Tanaka, H., Igarashi, S., Endo, K., Takahashi, H., Kondo, R., Ishikawa, A., Hayashi, T., Saito, M., Tomoda, A., Miike, T., Naito, H., Ikuta, F., Tsuji, S. <strong>Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA).</strong> Nature Genet. 6: 9-13, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136840</a>] [<a href="https://doi.org/10.1038/ng0194-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8136840">Koide et al. (1994)</a> and <a href="#15" class="mim-tip-reference" title="Nagafuchi, S., Yanagisawa, H., Sato, K., Shirayama, T., Ohsaki, E., Bundo, M., Takeda, T., Tadokoro, K., Kondo, I., Murayama, N., Tanaka, Y., Kikushima, H., Umino, K., Kurosawa, H., Furukawa, T., Nihei, K., Inoue, T., Sano, A., Komure, O., Takahashi, M., Yoshizawa, T., Kanazawa, I., Yamada, M. <strong>Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p.</strong> Nature Genet. 6: 14-18, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136826/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136826</a>] [<a href="https://doi.org/10.1038/ng0194-14" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8136826">Nagafuchi et al. (1994)</a>, they found a significant negative correlation between CAG repeat length and age of onset. In 80% of the paternal transmissions, there was an increase of more than 5 repeats, whereas all the maternal transmissions showed either a decrease or an increase of fewer than 5 repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7824105+8136840+8136826" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Aoki, M., Abe, K., Kameya, T., Watanabe, M., Itoyama, Y. <strong>Maternal anticipation of DRPLA.</strong> Hum. Molec. Genet. 3: 1197-1198, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7981699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7981699</a>] [<a href="https://doi.org/10.1093/hmg/3.7.1197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7981699">Aoki et al. (1994)</a> demonstrated that anticipation with expansion of the CAG repeat can occur through mothers as well as through fathers. They investigated 2 families in which offspring showed progressive myoclonic epilepsy with onset in childhood. In 1 family, patients of the first generation showed mild cerebellar ataxia with onset at 52 to 60 years. A patient of the second generation, the mother, showed severe ataxia with onset in the early thirties. The offspring in the third generation showed mental retardation, convulsions and myoclonus beginning at age 8. <a href="#23" class="mim-tip-reference" title="Sano, A., Yamauchi, N., Kakimoto, Y., Komure, O., Kawai, J., Hazama, F., Kuzume, K., Sano, N., Kondo, I. <strong>Anticipation in hereditary dentatorubral-pallidoluysian atrophy.</strong> Hum. Genet. 93: 699-702, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8005597/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8005597</a>] [<a href="https://doi.org/10.1007/BF00201575" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8005597">Sano et al. (1994)</a> studied 4 families and also demonstrated anticipation. Older-onset patients suffered from cerebellar ataxia with or without dementia, whereas younger-onset patients presented as progressive myoclonus epilepsy syndrome, consisting of mental retardation, dementia, and cerebellar ataxia as well as epilepsy and myoclonus. Anticipation with paternal transmission was significantly greater than with maternal transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7981699+8005597" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Sato, K., Kashihara, K., Okada, S., Ikeuchi, T., Tsuji, S., Shomori, T., Morimoto, K., Hayabara, T. <strong>Does homozygosity advance the onset of dentatorubral-pallidoluysian atrophy?</strong> Neurology 45: 1934-1936, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7477999/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7477999</a>] [<a href="https://doi.org/10.1212/wnl.45.10.1934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7477999">Sato et al. (1995)</a> reported homozygosity for a modest (57-repeat) triplet repeat in a man with early onset of DRPLA at age 17. His parents were first cousins and were neurologically normal at ages 73 and 71, in spite of having 57 CAG repeats in heterozygous state. Four of the proband's sibs died at age 12 with the phenotype of progressive myoclonic epilepsy. These findings supported the hypothesis that the clinical features of DRPLA, like those of Machado-Joseph disease, are influenced by the dosage of expansion of triplet repeats, unlike Huntington disease, in which the homozygous state does not appear to be different clinically from the heterozygous state. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7477999" 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="Norremolle, A., Nielsen, J. E., Sorensen, S. A., Hasholt, L. <strong>Elongated CAG repeats of the B37 gene in a Danish family with dentato-rubro-pallido-luysian atrophy.</strong> Hum. Genet. 95: 313-318, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7868125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7868125</a>] [<a href="https://doi.org/10.1007/BF00225200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7868125">Norremolle et al. (1995)</a> described a Danish family in which affected persons in at least 3 generations had been thought to be suffering from Huntington disease. Because analysis of the huntingtin gene revealed normal alleles and because some of the patients had seizures, they analyzed the B37 gene and found significantly elongated CAG repeats, as had been reported in cases of DRPLA. <a href="#16" class="mim-tip-reference" title="Norremolle, A., Nielsen, J. E., Sorensen, S. A., Hasholt, L. <strong>Elongated CAG repeats of the B37 gene in a Danish family with dentato-rubro-pallido-luysian atrophy.</strong> Hum. Genet. 95: 313-318, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7868125/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7868125</a>] [<a href="https://doi.org/10.1007/BF00225200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7868125">Norremolle et al. (1995)</a> reported that affected persons with almost identical repeat lengths presented very different symptoms. Both expansion and contraction in paternal transmission was observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7868125" 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="Ikeuchi, T., Igarashi, S., Takiyama, Y., Onodera, O., Oyake, M., Takano, H., Koide, R., Tanaka, H., Tsuji, S. <strong>Non-mendelian transmission in dentatorubral-pallidoluysian atrophy and Machado-Joseph disease: the mutant allele is preferentially transmitted in male meiosis.</strong> Am. J. Hum. Genet. 58: 730-733, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644735</a>]" pmid="8644735">Ikeuchi et al. (1996)</a> analyzed the segregation patterns of 411 transmissions of 24 DRPLA pedigrees and 80 transmissions in 7 Machado-Joseph disease (MJD; <a href="/entry/109150">109150</a>) pedigrees, with the diagnoses confirmed by molecular testing. Significant distortions in favor of transmission of the mutant alleles were found in male meiosis, where the mutant alleles were transmitted to 62% of all offspring in DRPLA (P less than 0.01) and 73% in MJD (P less than 0.01). The results were considered consistent with meiotic drive in both disorders. The authors commented that since more prominent meiotic instability of the length of the CAG trinucleotide repeats is observed in male meiosis than in female meiosis and since meiotic drive is observed only in male meiosis, these results raised the possibility that a common molecular mechanism underlies the meiotic drive and the meiotic instability in male meiosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8644735" 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>On the basis of studies in an extensively affected Tennessee family, <a href="#21" class="mim-tip-reference" title="Potter, N. T. <strong>The relationship between (CAG)n repeat number and age of onset in a family with dentatorubral-pallidoluysian atrophy (DRPLA): diagnostic implications of confirmatory and predictive testing.</strong> J. Med. Genet. 33: 168-170, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8929958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8929958</a>] [<a href="https://doi.org/10.1136/jmg.33.2.168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8929958">Potter (1996)</a> emphasized the intrafamilial variability and lack of close correlation between age of onset and (CAG)n repeat number in this disease. The studies were done on DNA derived from leukocytes; tissue-specific instability (somatic mosaicism) has been reported in DRPLA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8929958" 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="#29" class="mim-tip-reference" title="Takiyama, Y., Sakoe, K., Amaike, M., Soutome, M., Ogawa, T., Nakano, I., Nishizawa, M. <strong>Single sperm analysis of the CAG repeats in the gene for dentatorubral-pallidoluysian atrophy (DRPLA): the instability of the CAG repeats in the DRPLA gene is prominent among the CAG repeat diseases.</strong> Hum. Molec. Genet. 8: 453-457, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949204</a>] [<a href="https://doi.org/10.1093/hmg/8.3.453" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9949204">Takiyama et al. (1999)</a> determined the CAG repeat size in 427 single sperm from 2 men with DRPLA. The mean variance of the change in the CAG repeat size in sperm from the DRPLA patients (288.0) was larger than any variances of the CAG repeat size in sperm from patients with Machado-Joseph disease (38.5), Huntington disease (69.0), and spinal and bulbar muscular atrophy (16.3; <a href="/entry/313200">313200</a>), which is consistent with the clinical observation that the genetic anticipation on the paternal transmission of DRPLA is the most prominent among CAG repeat diseases. The variance was different in the 2 patients (51.0 vs 524.9, P greater than 0.0001). The segregation ratio of normal to expanded allele sperm was 1:1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9949204" 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>To investigate the molecular mechanisms underlying CAG repeat instability, <a href="#26" class="mim-tip-reference" title="Sato, T., Oyake, M., Nakamura, K., Nakao, K., Fukusima, Y., Onodera, O., Igarashi, S., Takano, H., Kikugawa, K., Ishida, Y., Shimohata, T., Koide, R., and 15 others. <strong>Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients.</strong> Hum. Molec. Genet. 8: 99-106, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9887337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9887337</a>] [<a href="https://doi.org/10.1093/hmg/8.1.99" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9887337">Sato et al. (1999)</a> established 3 transgenic lines, each harboring a single copy of a full-length human mutant DRPLA gene carrying a CAG repeat expansion. These transgenic mice exhibited an age-dependent increase (+0.31 per year) in male transmission and an age-dependent contraction (-1.21 per year) in female transmission. Similar tendencies in intergenerational instabilities were also observed in human DRPLA parent-offspring pairs. The intergenerational instabilities of the CAG repeats may be interpreted as being derived from the instability occurring during continuous cell division of spermatogonia in the male, and that occurring during the period of meiotic arrest in the female. The transgenic mice also exhibited an age-dependent increase in the degree of somatic mosaicism that occurred in a cell lineage-dependent manner, with the size range of CAG repeats being smaller in the cerebellum than in other tissues, including the cerebrum, which was consistent with observations in autopsied tissues of DRPLA patients. Thus, the transgenic mice described by <a href="#26" class="mim-tip-reference" title="Sato, T., Oyake, M., Nakamura, K., Nakao, K., Fukusima, Y., Onodera, O., Igarashi, S., Takano, H., Kikugawa, K., Ishida, Y., Shimohata, T., Koide, R., and 15 others. <strong>Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients.</strong> Hum. Molec. Genet. 8: 99-106, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9887337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9887337</a>] [<a href="https://doi.org/10.1093/hmg/8.1.99" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9887337">Sato et al. (1999)</a> exhibited age-dependent intergenerational and somatic instabilities of expanded CAG repeats comparable with those observed in human DRPLA patients, and should therefore serve as good models for investigating the molecular mechanisms of instabilities of CAG repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9887337" 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 comparing transgenic mice bearing either full-length atrophin-1 or partial huntingtin trans-proteins to wildtype, <a href="#12" class="mim-tip-reference" title="Luthi-Carter, R., Strand, A. D., Hanson, S. A., Kooperberg, C., Schilling, G., La Spada, A. R., Merry, D. E., Young, A. B., Ross, C. A., Borchelt, D. R., Olson, J. M. <strong>Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington's disease mouse models reveal context-independent effects.</strong> Hum. Molec. Genet. 11: 1927-1937, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12165555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12165555</a>] [<a href="https://doi.org/10.1093/hmg/11.17.1927" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12165555">Luthi-Carter et al. (2002)</a> reported that there was considerable overlap in the alteration of gene expression between the 2 models, at least in the cerebellum. The authors concluded that polyglutamine-induced changes may be independent of their protein context. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12165555" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Sato, T., Miura, M., Yamada, M., Yoshida, T., Wood, J. D., Yazawa, I., Masuda, M., Suzuki, T., Shin, R.-M., Yau, H.-J., Liu, F.-C., Shimohata, T., Onodera, O., Ross, C. A., Katsuki, M., Takahashi, H., Kano, M., Aosaki, T., Tsuji, S. <strong>Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice.</strong> Hum. Molec. Genet. 18: 723-736, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19039037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19039037</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19039037[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19039037">Sato et al. (2009)</a> generated a DRPLA Q129 mouse resulting from en masse expansion of the 76 CAG repeat in a Q76 mouse breeding program. Only the Q129 mice exhibited devastating progressive neurologic phenotypes similar to those of juvenile-onset DRPLA patients. Electrophysiologic studies demonstrated age-dependent and region-specific presynaptic dysfunction in the globus pallidus and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells and decreased currents through AMPA receptors (see <a href="/entry/138248">138248</a>) and GABA-A (see <a href="/entry/137160">137160</a>) receptors in CA1 neurons were also observed. The Q129 mice developed progressive brain atrophy but no obvious neuronal loss, associated with massive neuronal intranuclear accumulation (NIA) of mutant proteins with expanded polyQ stretches starting on postnatal day 4, whereas NIA in the Q76 mice appeared later with regional specificity to the vulnerable regions of DRPLA. Expression profile analysis demonstrated age-dependent downregulation of genes, including those relevant to synaptic functions and CREB (<a href="/entry/123810">123810</a>)-dependent genes. <a href="#25" class="mim-tip-reference" title="Sato, T., Miura, M., Yamada, M., Yoshida, T., Wood, J. D., Yazawa, I., Masuda, M., Suzuki, T., Shin, R.-M., Yau, H.-J., Liu, F.-C., Shimohata, T., Onodera, O., Ross, C. A., Katsuki, M., Takahashi, H., Kano, M., Aosaki, T., Tsuji, S. <strong>Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice.</strong> Hum. Molec. Genet. 18: 723-736, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19039037/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19039037</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19039037[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddn403" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19039037">Sato et al. (2009)</a> suggested that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that the age-dependent NIA is associated with nuclear dysfunction including transcriptional dysregulations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19039037" 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 22 patients with dentatorubral-pallidoluysian atrophy (DRPLA; <a href="/entry/125370">125370</a>), <a href="#8" class="mim-tip-reference" title="Koide, R., Ikeuchi, T., Onodera, O., Tanaka, H., Igarashi, S., Endo, K., Takahashi, H., Kondo, R., Ishikawa, A., Hayashi, T., Saito, M., Tomoda, A., Miike, T., Naito, H., Ikuta, F., Tsuji, S. <strong>Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA).</strong> Nature Genet. 6: 9-13, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136840</a>] [<a href="https://doi.org/10.1038/ng0194-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8136840">Koide et al. (1994)</a> identified unstable expansion of a CAG unit in the DRPLA gene, which they termed B37 after a cDNA clone previously identified by <a href="#10" class="mim-tip-reference" title="Li, S.-H., McInnis, M. G., Margolis, R. L., Antonarakis, S. E., Ross, C. A. <strong>Novel triplet repeat containing genes in human brain: cloning, expression, and length polymorphisms.</strong> Genomics 16: 572-579, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8325628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8325628</a>] [<a href="https://doi.org/10.1006/geno.1993.1232" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8325628">Li et al. (1993)</a>. Each patient was a heterozygote with 1 allele in the normal range (8-25 repeat units) and a second expanded allele with the range of 54-68 repeat units. There were no overlaps in the number of CAG repeat units between control chromosomes and DRPLA chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8136840+8325628" 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>Burke et al. (<a href="#5" class="mim-tip-reference" title="Burke, J. R., Pericak-Vance, M. A., Vance, J. M. <strong>Haw River syndrome (HRS) and dentatorubropallidoluysian atrophy (DRPLA): disorders with an identical trinucleotide repeat expansion but differences in clinical expression and racial frequency. (Abstract)</strong> Am. J. Hum. Genet. 55 (suppl.): A17 only, 1994."None>1994</a>, <a href="#6" class="mim-tip-reference" title="Burke, J. R., Wingfield, M. S., Lewis, K. E., Roses, A. D., Lee, J. E., Hulette, C., Pericak-Vance, M. A., Vance, J. M. <strong>The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family.</strong> Nature Genet. 7: 521-524, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951323</a>] [<a href="https://doi.org/10.1038/ng0894-521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7951323">1994</a>) demonstrated that affected members of the large African American family with Haw River syndrome had a trinucleotide repeat expansion in the ATN1 gene that was identical to that found in DRPLA, a frequent disorder in Japanese but rare in Europeans. In addition to the difference in racial frequency, the clinical expression and pathology of Haw River syndrome differed from that of the disease as observed in the Japanese: seizures were a consistent feature, there was no myoclonus, basal ganglion calcification was common, and neuronal loss was prominent in the globus pallidus. Burke et al. (<a href="#5" class="mim-tip-reference" title="Burke, J. R., Pericak-Vance, M. A., Vance, J. M. <strong>Haw River syndrome (HRS) and dentatorubropallidoluysian atrophy (DRPLA): disorders with an identical trinucleotide repeat expansion but differences in clinical expression and racial frequency. (Abstract)</strong> Am. J. Hum. Genet. 55 (suppl.): A17 only, 1994."None>1994</a>, <a href="#4" class="mim-tip-reference" title="Burke, J. R., Ikeuchi, T., Koide, R., Tsuji, S., Yamada, M., Pericak-Vance, M. A., Vance, J. M. <strong>Dentatorubral-pallidoluysian atrophy and Haw River syndrome. (Letter)</strong> Lancet 344: 1711-1712, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7996992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7996992</a>] [<a href="https://doi.org/10.1016/s0140-6736(94)90497-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7996992">1994</a>) suggested that the difference in racial frequency is probably due to differences in the repeat size. The frequency of the repeat allele of intermediate size was very low in Europeans, somewhat higher in African Americans, and relatively high (5-10%) in Japanese. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7951323+7996992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 CONGENITAL HYPOTONIA, EPILEPSY, DEVELOPMENTAL DELAY, AND DIGITAL ANOMALIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555144357 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555144357;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1555144357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1555144357" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 3-year-old boy of Argentinian descent (patient 1) with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; <a href="/entry/618494">618494</a>), <a href="#20" class="mim-tip-reference" title="Palmer, E. E., Hong, S., Al Zahrani, F., Hashem, M. O., Aleisa, F. A., Ahmed, H. M. J., Kandula, T., Macintosh, R., Minoche, A. E., Puttick, C., Gayevskiy, V., Drew, A. P., and 31 others. <strong>De novo variants disrupting the HX repeat motif of ATN1 cause a recognizable non-progressive neurocognitive syndrome.</strong> Am. J. Hum. Genet. 104: 542-552, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 778 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30827498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30827498</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30827498">Palmer et al. (2019)</a> identified a de novo heterozygous c.3160C-A transversion in exon 7 of the ATN1 gene, resulting in a his1054-to-asn (H1054N) substitution at a highly conserved His residue in the 16-amino acid 'HX repeat' motif near the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30827498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555144358 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555144358;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1555144358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1555144358" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 1-year-old boy of Hispanic descent (patient 2) with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; <a href="/entry/618494">618494</a>), <a href="#20" class="mim-tip-reference" title="Palmer, E. E., Hong, S., Al Zahrani, F., Hashem, M. O., Aleisa, F. A., Ahmed, H. M. J., Kandula, T., Macintosh, R., Minoche, A. E., Puttick, C., Gayevskiy, V., Drew, A. P., and 31 others. <strong>De novo variants disrupting the HX repeat motif of ATN1 cause a recognizable non-progressive neurocognitive syndrome.</strong> Am. J. Hum. Genet. 104: 542-552, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 778 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30827498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30827498</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30827498">Palmer et al. (2019)</a> identified a de novo heterozygous c.3172C-T transition in exon 7 of the ATN1 gene, resulting in a his1058-to-tyr (H1058Y) substitution at a highly conserved His residue in the 16-amino acid 'HX repeat' motif near the C terminus. The mutation which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30827498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1064795494 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1064795494;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1064795494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1064795494" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000482562 OR RCV000787319" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000482562, RCV000787319" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000482562...</a>
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<p>In a 5-year-old girl of Hispanic descent (patient 3) with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; <a href="/entry/618494">618494</a>), <a href="#20" class="mim-tip-reference" title="Palmer, E. E., Hong, S., Al Zahrani, F., Hashem, M. O., Aleisa, F. A., Ahmed, H. M. J., Kandula, T., Macintosh, R., Minoche, A. E., Puttick, C., Gayevskiy, V., Drew, A. P., and 31 others. <strong>De novo variants disrupting the HX repeat motif of ATN1 cause a recognizable non-progressive neurocognitive syndrome.</strong> Am. J. Hum. Genet. 104: 542-552, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 778 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30827498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30827498</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30827498">Palmer et al. (2019)</a> identified a de novo heterozygous 6-bp insertion (c.3177_3178insAACCTG) in exon 7 of the ATN1 gene, resulting in a Ser1059_His1060insAsnLeu substitution in the highly conserved 16-amino acid 'HX repeat' motif near the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30827498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs797044566 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs797044566;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs797044566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs797044566" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000171467 OR RCV000787320" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000171467, RCV000787320" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000171467...</a>
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<p>In a 9-year-old girl of Saudi descent (patient 5) with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; <a href="/entry/618494">618494</a>), <a href="#20" class="mim-tip-reference" title="Palmer, E. E., Hong, S., Al Zahrani, F., Hashem, M. O., Aleisa, F. A., Ahmed, H. M. J., Kandula, T., Macintosh, R., Minoche, A. E., Puttick, C., Gayevskiy, V., Drew, A. P., and 31 others. <strong>De novo variants disrupting the HX repeat motif of ATN1 cause a recognizable non-progressive neurocognitive syndrome.</strong> Am. J. Hum. Genet. 104: 542-552, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 778 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30827498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30827498</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30827498">Palmer et al. (2019)</a> identified a de novo heterozygous c.3178C-T transition in exon 7 of the ATN1 gene, resulting in a his1060-to-tyr (H1060Y) substitution at a highly conserved His residue in the 16-amino acid 'HX repeat' motif near the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Nuclear magnetic resonance analysis of a synthesized peptide containing the H1060Y variant showed that the mutation resulted in a perturbation of the structural and functional integrity of the HX repeat, and altered zinc-binding properties. Additional functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30827498" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 CONGENITAL HYPOTONIA, EPILEPSY, DEVELOPMENTAL DELAY, AND DIGITAL ANOMALIES</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1565569158 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1565569158;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1565569158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1565569158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000779621 OR RCV000787321" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000779621, RCV000787321" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000779621...</a>
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<p>In a French girl (patient 8) who died at 2 months of age with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; <a href="/entry/618494">618494</a>), <a href="#20" class="mim-tip-reference" title="Palmer, E. E., Hong, S., Al Zahrani, F., Hashem, M. O., Aleisa, F. A., Ahmed, H. M. J., Kandula, T., Macintosh, R., Minoche, A. E., Puttick, C., Gayevskiy, V., Drew, A. P., and 31 others. <strong>De novo variants disrupting the HX repeat motif of ATN1 cause a recognizable non-progressive neurocognitive syndrome.</strong> Am. J. Hum. Genet. 104: 542-552, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 778 only, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30827498/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30827498</a>] [<a href="https://doi.org/10.1016/j.ajhg.2019.01.013" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30827498">Palmer et al. (2019)</a> identified a de novo heterozygous c.3185A-G transition in exon 7 of the ATN1 gene, resulting in a his1062-to-arg (H1062R) substitution at a highly conserved His residue in the 16-amino acid 'HX repeat' motif near the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. The patient had previously been reported by <a href="#14" class="mim-tip-reference" title="Mosca, A.-L., Laurent, N., Guibaud, L., Callier, P., Thauvin-Robinet, C., Mugneret, F., Huet, F., Grimaldi, M., Gouyon, J.-B., Sandre, D., Faivre, L. <strong>Polymicrogyria, cerebellar vermis hypoplasia, severe facial dysmorphism and cleft palate: a new syndrome?</strong> Europ. J. Med. Genet. 50: 48-53, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17067864/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17067864</a>] [<a href="https://doi.org/10.1016/j.ejmg.2006.08.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17067864">Mosca et al. (2007)</a>. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17067864+30827498" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<ol>
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<a id="Aoki1994" class="mim-anchor"></a>
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Aoki, M., Abe, K., Kameya, T., Watanabe, M., Itoyama, Y.
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<strong>Maternal anticipation of DRPLA.</strong>
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Hum. Molec. Genet. 3: 1197-1198, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7981699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7981699</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7981699" 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/3.7.1197" target="_blank">Full Text</a>]
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<a id="Barinaga1996" class="mim-anchor"></a>
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Barinaga, M.
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<strong>An intriguing new lead on Huntington's disease.</strong>
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Science 271: 1233-1234, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8638101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8638101</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8638101" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.271.5253.1233" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Burke1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Burke, J. R., Enghild, J. J., Martin, M. E., Jou, Y.-S., Myers, R. M., Roses, A. D., Vance, J. M., Strittmatter, W. J.
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<strong>Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH.</strong>
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Nature Med. 2: 347-350, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8612237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8612237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8612237" 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/nm0396-347" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Burke1994" class="mim-anchor"></a>
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Burke, J. R., Ikeuchi, T., Koide, R., Tsuji, S., Yamada, M., Pericak-Vance, M. A., Vance, J. M.
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<strong>Dentatorubral-pallidoluysian atrophy and Haw River syndrome. (Letter)</strong>
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Lancet 344: 1711-1712, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7996992/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7996992</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7996992" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0140-6736(94)90497-9" target="_blank">Full Text</a>]
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<a id="Burke1994" class="mim-anchor"></a>
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Burke, J. R., Pericak-Vance, M. A., Vance, J. M.
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<strong>Haw River syndrome (HRS) and dentatorubropallidoluysian atrophy (DRPLA): disorders with an identical trinucleotide repeat expansion but differences in clinical expression and racial frequency. (Abstract)</strong>
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Am. J. Hum. Genet. 55 (suppl.): A17 only, 1994.
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<a id="Burke1994" class="mim-anchor"></a>
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Burke, J. R., Wingfield, M. S., Lewis, K. E., Roses, A. D., Lee, J. E., Hulette, C., Pericak-Vance, M. A., Vance, J. M.
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<strong>The Haw River syndrome: dentatorubropallidoluysian atrophy (DRPLA) in an African-American family.</strong>
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Nature Genet. 7: 521-524, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7951323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7951323</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7951323" 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/ng0894-521" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Ikeuchi1996" class="mim-anchor"></a>
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Ikeuchi, T., Igarashi, S., Takiyama, Y., Onodera, O., Oyake, M., Takano, H., Koide, R., Tanaka, H., Tsuji, S.
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<strong>Non-mendelian transmission in dentatorubral-pallidoluysian atrophy and Machado-Joseph disease: the mutant allele is preferentially transmitted in male meiosis.</strong>
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Am. J. Hum. Genet. 58: 730-733, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8644735/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8644735</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8644735" 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="8" class="mim-anchor"></a>
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<a id="Koide1994" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Koide, R., Ikeuchi, T., Onodera, O., Tanaka, H., Igarashi, S., Endo, K., Takahashi, H., Kondo, R., Ishikawa, A., Hayashi, T., Saito, M., Tomoda, A., Miike, T., Naito, H., Ikuta, F., Tsuji, S.
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<strong>Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA).</strong>
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Nature Genet. 6: 9-13, 1994.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8136840/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8136840</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8136840" 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/ng0194-9" target="_blank">Full Text</a>]
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<a id="9" class="mim-anchor"></a>
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<a id="Komure1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Komure, O., Sano, A., Nishino, N., Yamauchi, N., Ueno, S., Kondoh, K., Sano, N., Takahashi, M., Murayama, N., Kondo, I., Nagafuchi, S., Yamada, M., Kanazawa, I.
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<strong>DNA analysis in hereditary dentatorubral-pallidoluysian atrophy: correlation between CAG repeat length and phenotypic variation and the molecular basis of anticipation.</strong>
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Neurology 45: 143-149, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7824105/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7824105</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7824105" 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.45.1.143" target="_blank">Full Text</a>]
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<a id="10" class="mim-anchor"></a>
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<a id="Li1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Li, S.-H., McInnis, M. G., Margolis, R. L., Antonarakis, S. E., Ross, C. A.
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<strong>Novel triplet repeat containing genes in human brain: cloning, expression, and length polymorphisms.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8325628/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8325628</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8325628" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1993.1232" target="_blank">Full Text</a>]
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<a id="Lim2006" class="mim-anchor"></a>
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Lim, J., Hao, T., Shaw, C., Patel, A. J., Szabo, G., Rual, J.-F., Fisk, C. J., Li, N., Smolyar, A., Hill, D. E., Barabasi, A.-L., Vidal, M., Zoghbi, H. Y.
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<strong>A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration.</strong>
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Cell 125: 801-814, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16713569/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16713569</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16713569" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2006.03.032" target="_blank">Full Text</a>]
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<a id="Luthi-Carter2002" class="mim-anchor"></a>
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<div class="">
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Luthi-Carter, R., Strand, A. D., Hanson, S. A., Kooperberg, C., Schilling, G., La Spada, A. R., Merry, D. E., Young, A. B., Ross, C. A., Borchelt, D. R., Olson, J. M.
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<strong>Polyglutamine and transcription: gene expression changes shared by DRPLA and Huntington's disease mouse models reveal context-independent effects.</strong>
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Hum. Molec. Genet. 11: 1927-1937, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12165555/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12165555</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12165555" 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/11.17.1927" target="_blank">Full Text</a>]
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<a id="Martins2003" class="mim-anchor"></a>
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Martins, S., Matama, T., Guimaraes, L., Vale, J., Guimaraes, J., Ramos, L., Coutinho, P., Sequeiros, J., Silveira, I.
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<strong>Portuguese families with dentatorubropallidoluysian atrophy (DRPLA) share a common haplotype of Asian origin.</strong>
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Europ. J. Hum. Genet. 11: 808-811, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9949204/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9949204</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9949204" 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/8.3.453" target="_blank">Full Text</a>]
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</p>
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</li>
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<li>
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<a id="30" class="mim-anchor"></a>
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<a id="Wood1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wood, J. D., Yuan, J., Margolis, R. L., Colomer, V., Duan, K., Kushi, J., Kaminsky, Z., Kleiderlein, J. J., Jr., Sharp, A. H., Ross, C. A.
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<strong>Atrophin-1, the DRPLA gene product, interacts with two families of WW domain-containing proteins.</strong>
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Molec. Cell. Neurosci. 11: 149-160, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9647693/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9647693</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9647693" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/mcne.1998.0677" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="31" class="mim-anchor"></a>
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<a id="Yazawa1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yazawa, I., Nukina, N., Hashida, H., Goto, J., Yamada, M., Kanazawa, I.
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<strong>Abnormal gene product identified in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) brain.</strong>
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Nature Genet. 10: 99-103, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7647802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7647802</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7647802" 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/ng0595-99" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="32" class="mim-anchor"></a>
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<a id="Zhang2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zhang, S., Xu, L., Lee, J., Xu, T.
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<strong>Drosophila Atrophin homolog functions as a transcriptional corepressor in multiple developmental processes.</strong>
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Cell 108: 45-56, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11792320/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11792320</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11792320" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(01)00630-4" target="_blank">Full Text</a>]
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</ol>
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<a id="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 07/03/2019
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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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George E. Tiller - updated : 8/10/2009<br>Patricia A. Hartz - updated : 1/15/2009<br>George E. Tiller - updated : 4/25/2005<br>Victor A. McKusick - updated : 11/13/2003<br>George E. Tiller - updated : 7/9/2003
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</span>
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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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Cassandra L. Kniffin : 1/6/2003
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</span>
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 10/31/2019
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</span>
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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 : 07/15/2019<br>carol : 07/12/2019<br>ckniffin : 07/03/2019<br>terry : 05/11/2010<br>carol : 9/15/2009<br>wwang : 8/21/2009<br>terry : 8/10/2009<br>carol : 2/9/2009<br>carol : 2/5/2009<br>carol : 1/29/2009<br>mgross : 1/15/2009<br>mgross : 1/15/2009<br>tkritzer : 4/25/2005<br>tkritzer : 11/19/2003<br>terry : 11/13/2003<br>cwells : 7/9/2003<br>carol : 1/24/2003<br>carol : 1/24/2003<br>ckniffin : 1/7/2003
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</span>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 607462
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</span>
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</h3>
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<div>
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<h3>
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<span class="mim-font">
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ATROPHIN 1; ATN1
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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<div>
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<h4>
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<span class="mim-font">
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DRPLA GENE; DRPLA
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</span>
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</h4>
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<div>
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<br />
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: ATN1</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> 68116008;
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</span>
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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: 12p13.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 12:6,924,459-6,942,321 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="2">
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<span class="mim-font">
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12p13.31
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</span>
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</td>
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<td>
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<span class="mim-font">
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Congenital hypotonia, epilepsy, developmental delay, and digital anomalies
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</span>
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</td>
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<td>
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<span class="mim-font">
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618494
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</td>
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<span class="mim-font">
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Dentatorubral-pallidoluysian atrophy
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</td>
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<td>
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<span class="mim-font">
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125370
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The ATN1 gene encodes atrophin-1, a member of a class of evolutionarily conserved transcriptional corepressors involved in nuclear signaling. ATN1 is believed to play a role as a nuclear transcriptional regulator important for brain and other organ system development (summary by Palmer et al., 2019). </p>
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<div>
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<br />
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</div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>In the search for a candidate gene for dentatorubral-pallidoluysian atrophy (DRPLA; 125370), an inherited neurodegenerative disorder that demonstrates genetic anticipation characteristic of unstable expansion of trinucleotide repeats, Koide et al. (1994) searched a catalog of genes expressed in human brain identified by Li et al. (1993) that contained trinucleotide repeats. One of these, B37, which was known to map to chromosome 12, was examined and found to show CAG repeat expansion (607462.0001) in 22 individuals with DRPLA. By screening adult human occipital cortex and fetal human brain cDNA libraries, Onodera et al. (1995) isolated a full-length DRPLA cDNA encoding a deduced 1,185-amino acid protein with a predicted molecular mass of 125 kD. The (CAG)n repeat that is expanded in patients with DRPLA is located at position 1462 and is predicted to code for a polyglutamine tract. There was high heterozygosity of the length of the polyglutamine tract, ranging from 8 to 35 repeat units in 140 normal chromosomes. Northern blot analysis revealed a 4.7-kb transcript that is widely expressed in various tissues, including heart, lung, kidney, placenta, skeletal muscle, and brain. </p><p>Using antibodies against a synthetic peptide corresponding to the sequence of the C-terminus of the DRPLA gene product, Yazawa et al. (1995) identified the DRPLA gene product in normal human brains as a protein of approximately 190 kD. They also found a larger protein of approximately 205 kD specifically in DRPLA brains. Immunohistochemically, the DRPLA gene product was observed mainly in neuronal cytoplasm. These results demonstrated the existence of the expanded CAG repeat gene product and supported the possibility that the expanded CAG-encoded polyglutamine stretch may participate in the pathologic process of similar trinucleotide repeat diseases. </p><p>Schmitt et al. (1995) isolated the complete coding sequence of the rat DRPLA gene and investigated its expression in different developmental stages of rodent tissues. In rat, the length of the (CAG)n repeat is 7 to 34 repeats with an average of 15, which is mildly reduced in comparison with the human repeats. Northern blot analysis demonstrated that in rodents the gene is already expressed during embryonic development. In addition, the transcript is predominantly represented in neuronal tissues throughout all developmental stages investigated. Oyake et al. (1997) cloned a mouse Drpla cDNA and found that the encoded protein is 92% identical to human DRPLA. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Mapping</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p>Takano et al. (1996) assigned the DRPLA gene to chromosome 12p13.31 by fluorescence in situ hybridization. </p><p>Oyake et al. (1997) mapped the mouse Drpla gene to chromosome 6 by interspecific backcross analysis. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Function</strong>
|
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
|
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<p>Burke et al. (1996) demonstrated that synthetic polyglutamine peptides, DRPLA protein and huntingtin (613004) from unaffected individuals with normal-sized polyglutamine tracts bind to glyceraldehyde-3-phosphate dehydrogenase (138400). The authors postulated that diseases characterized by the presence of an expanded CAG repeat may share a common metabolic pathogenesis involving GAPD as a functional component. Roses (1996) and Barinaga (1996) reviewed the findings. </p><p>Using the yeast 2-hybrid system, Wood et al. (1998) identified 5 atrophin-1 interacting proteins that bind to atrophin-1 in the vicinity of the polyglutamine tract. Four of the interactions were confirmed using in vitro binding assays. These interactors were found to be similar to huntingtin-interacting proteins, suggesting possible commonality of function between the 2 proteins responsible for the very similar diseases, Huntington disease (HD; 143100) and DRPLA. </p><p>Zhang et al. (2002) characterized a Drosophila gene encoding an atrophin family protein. Analysis of mutant phenotypes indicated that Drosophila atrophin is required in diverse developmental processes, including early embryonic patterning. Drosophila atrophin genetically interacts with the transcription repressor 'even-skipped' (see 142991) and is required for its repressive function in vivo. Drosophila atrophin directly binds to even-skipped in vitro. Furthermore, both human atrophin-1 and Drosophila atrophin repress transcription in vivo when tethered to DNA, and poly-Q expansion in atrophin-1 reduces this repressive activity. </p><p>Okamura-Oho et al. (2003) determined that the DRPLA protein is a phosphoprotein and that c-Jun NH2-terminal kinase (JNK; see 601158) is one of the major factors involved in its phosphorylation. Phosphorylation was demonstrated in a recombinant JNK activation system in vitro and also in overexpressing cells by transfection after JNK activation with osmotic pressure. Phosphorylation of serine-734 in the DRPLA protein was confirmed by a specific antibody raised against the phosphopeptide. Kinetic studies in the JNK recombinant system showed that expanded polyQ slightly reduced the affinity of JNK to the protein. </p><p>Using yeast 2-hybrid screens, coaffinity purification analysis of transfected HEK293 cells, and bioinformatic analysis, Lim et al. (2006) developed an interaction network for 54 human proteins involved in 23 inherited ataxias. By database analysis, they expanded the core network to include more distantly related interacting proteins that could function as genetic modifiers. RBPMS (601558) was a main hub in the network and interacted with many proteins, including the cerebellar ataxia-associated proteins ATN1 and QK1 (609590). </p>
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</span>
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<div>
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<br />
|
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
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</span>
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</h4>
|
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</div>
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<span class="mim-text-font">
|
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<p><strong><em>Dentatorubral-Pallidoluysian Atrophy</em></strong></p><p>
|
|
In 22 patients with dentatorubral-pallidoluysian atrophy (DRPLA; 125370), Koide et al. (1994) identified unstable expansion of a CAG unit in the ATN1 gene (607462.0001), which they termed B37 after a cDNA clone previously identified by Li et al. (1993). Each patient was a heterozygote with 1 allele in the normal range (8-25 repeat units) and a second expanded allele with the range of 54-68 repeat units. There were no overlaps in the number of CAG repeat units between control chromosomes and DRPLA chromosomes. In 33 patients with DRPLA from 12 families, Nagafuchi et al. (1994) identified an expanded CAG repeat in the B37 clone. The repeat size varied from 7-23 in normal individuals and 1 allele was expanded to between 49-75 repeats in affected individuals. </p><p>Burke et al. (1994, 1994) demonstrated that affected members of the large African American family with Haw River syndrome had the same trinucleotide repeat expansion (607462.0001) in the ATN1 gene as that found in DRPLA. </p><p><strong><em>Congenital Hypotonia, Epilepsy, Developmental Delay, and Digital Anomalies</em></strong></p><p>
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In 8 unrelated children with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; 618494), Palmer et al. (2019) identified 8 different de novo heterozygous mutations in exon 7 of the ATN1 gene (see, e.g., 607462.0002-607462.0006), all resulting in substitutions within the highly conserved 16-amino acid histidine-rich 'HX repeat' motif near the C terminus. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. This HX repeat is distal to the expanded repeat responsible for DRPLA. Nuclear magnetic resonance analysis of a synthesized peptide containing 1 of the mutations (H1060Y; 607462.0005) showed that the mutation resulted in a perturbation of the structural and functional integrity of the HX repeat, and altered zinc-binding properties. Additional functional studies of the variants and studies of patient cells were not performed. However, Palmer et al. (2019) noted that de novo disruptions of a similar HX motif in the RERE gene (605226) and the AUTS2 gene (607270) have been noted in patients with neurocognitive phenotypes. ATN1 also lies within the critical region for Pallister-Killian syndrome (PKS; 601803), which has an overlapping phenotype. Despite the absence of these variants in gnomAD, all could be classified as 'variants of uncertain significance' according to ACMG guidelines. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Genotype/Phenotype Correlations</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Martins et al. (2003) stated that DRPLA is prevalent in Japan, but several families of non-Japanese ancestry had been published. To identify the origin of expanded alleles in 4 Portuguese families with DRPLA, they studied 2 intragenic SNPs in introns 1 and 3, in addition to the CAG repeat, of the DRPLA gene. The results showed that all 4 families shared the same haplotype, which was the same as that reported for Japanese DRPLA chromosomes. This haplotype is also the most frequent in Japanese normal alleles, whereas it was rare in Portuguese control chromosomes. The findings supported the suggestion that a founder DRPLA haplotype of Asian origin was introduced in Portugal and is responsible for the frequency of the disease in that country. </p><p><strong><em>Genetic Anticipation</em></strong></p><p>
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Koide et al. (1994) found a good correlation between the size of the (CAG)n repeat expansion and the age of onset. Patients with earlier onset tended to have a phenotype of progressive myoclonic epilepsy and larger expansions. They proposed that the wide variety of clinical manifestations of DRPLA can be explained by the variable unstable expansion of the CAG repeat. Although only 5 cases of paternal transmission and 2 cases of maternal transmission were analyzed, the length of the repeat unit was altered in all cases: the average change in repeat length for paternal transmission was an increase of 4.2 repeats, while that of maternal transmission was a decrease of 1.0 repeat. </p><p>Nagafuchi et al. (1994) also found that repeat size correlated closely with age of onset of symptoms and with disease severity. Expansion was usually associated with paternal transmission. Komure et al. (1995) analyzed CAG trinucleotide repeats in 71 individuals from 12 Japanese DRPLA pedigrees that included 38 affected individuals. Normal alleles varied from 7 to 23 repeats, whereas affected individuals had from 53 to 88 repeats. Like Koide et al. (1994) and Nagafuchi et al. (1994), they found a significant negative correlation between CAG repeat length and age of onset. In 80% of the paternal transmissions, there was an increase of more than 5 repeats, whereas all the maternal transmissions showed either a decrease or an increase of fewer than 5 repeats. </p><p>Aoki et al. (1994) demonstrated that anticipation with expansion of the CAG repeat can occur through mothers as well as through fathers. They investigated 2 families in which offspring showed progressive myoclonic epilepsy with onset in childhood. In 1 family, patients of the first generation showed mild cerebellar ataxia with onset at 52 to 60 years. A patient of the second generation, the mother, showed severe ataxia with onset in the early thirties. The offspring in the third generation showed mental retardation, convulsions and myoclonus beginning at age 8. Sano et al. (1994) studied 4 families and also demonstrated anticipation. Older-onset patients suffered from cerebellar ataxia with or without dementia, whereas younger-onset patients presented as progressive myoclonus epilepsy syndrome, consisting of mental retardation, dementia, and cerebellar ataxia as well as epilepsy and myoclonus. Anticipation with paternal transmission was significantly greater than with maternal transmission. </p><p>Sato et al. (1995) reported homozygosity for a modest (57-repeat) triplet repeat in a man with early onset of DRPLA at age 17. His parents were first cousins and were neurologically normal at ages 73 and 71, in spite of having 57 CAG repeats in heterozygous state. Four of the proband's sibs died at age 12 with the phenotype of progressive myoclonic epilepsy. These findings supported the hypothesis that the clinical features of DRPLA, like those of Machado-Joseph disease, are influenced by the dosage of expansion of triplet repeats, unlike Huntington disease, in which the homozygous state does not appear to be different clinically from the heterozygous state. </p><p>Norremolle et al. (1995) described a Danish family in which affected persons in at least 3 generations had been thought to be suffering from Huntington disease. Because analysis of the huntingtin gene revealed normal alleles and because some of the patients had seizures, they analyzed the B37 gene and found significantly elongated CAG repeats, as had been reported in cases of DRPLA. Norremolle et al. (1995) reported that affected persons with almost identical repeat lengths presented very different symptoms. Both expansion and contraction in paternal transmission was observed. </p><p>Ikeuchi et al. (1996) analyzed the segregation patterns of 411 transmissions of 24 DRPLA pedigrees and 80 transmissions in 7 Machado-Joseph disease (MJD; 109150) pedigrees, with the diagnoses confirmed by molecular testing. Significant distortions in favor of transmission of the mutant alleles were found in male meiosis, where the mutant alleles were transmitted to 62% of all offspring in DRPLA (P less than 0.01) and 73% in MJD (P less than 0.01). The results were considered consistent with meiotic drive in both disorders. The authors commented that since more prominent meiotic instability of the length of the CAG trinucleotide repeats is observed in male meiosis than in female meiosis and since meiotic drive is observed only in male meiosis, these results raised the possibility that a common molecular mechanism underlies the meiotic drive and the meiotic instability in male meiosis. </p><p>On the basis of studies in an extensively affected Tennessee family, Potter (1996) emphasized the intrafamilial variability and lack of close correlation between age of onset and (CAG)n repeat number in this disease. The studies were done on DNA derived from leukocytes; tissue-specific instability (somatic mosaicism) has been reported in DRPLA. </p><p>Takiyama et al. (1999) determined the CAG repeat size in 427 single sperm from 2 men with DRPLA. The mean variance of the change in the CAG repeat size in sperm from the DRPLA patients (288.0) was larger than any variances of the CAG repeat size in sperm from patients with Machado-Joseph disease (38.5), Huntington disease (69.0), and spinal and bulbar muscular atrophy (16.3; 313200), which is consistent with the clinical observation that the genetic anticipation on the paternal transmission of DRPLA is the most prominent among CAG repeat diseases. The variance was different in the 2 patients (51.0 vs 524.9, P greater than 0.0001). The segregation ratio of normal to expanded allele sperm was 1:1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To investigate the molecular mechanisms underlying CAG repeat instability, Sato et al. (1999) established 3 transgenic lines, each harboring a single copy of a full-length human mutant DRPLA gene carrying a CAG repeat expansion. These transgenic mice exhibited an age-dependent increase (+0.31 per year) in male transmission and an age-dependent contraction (-1.21 per year) in female transmission. Similar tendencies in intergenerational instabilities were also observed in human DRPLA parent-offspring pairs. The intergenerational instabilities of the CAG repeats may be interpreted as being derived from the instability occurring during continuous cell division of spermatogonia in the male, and that occurring during the period of meiotic arrest in the female. The transgenic mice also exhibited an age-dependent increase in the degree of somatic mosaicism that occurred in a cell lineage-dependent manner, with the size range of CAG repeats being smaller in the cerebellum than in other tissues, including the cerebrum, which was consistent with observations in autopsied tissues of DRPLA patients. Thus, the transgenic mice described by Sato et al. (1999) exhibited age-dependent intergenerational and somatic instabilities of expanded CAG repeats comparable with those observed in human DRPLA patients, and should therefore serve as good models for investigating the molecular mechanisms of instabilities of CAG repeats. </p><p>In comparing transgenic mice bearing either full-length atrophin-1 or partial huntingtin trans-proteins to wildtype, Luthi-Carter et al. (2002) reported that there was considerable overlap in the alteration of gene expression between the 2 models, at least in the cerebellum. The authors concluded that polyglutamine-induced changes may be independent of their protein context. </p><p>Sato et al. (2009) generated a DRPLA Q129 mouse resulting from en masse expansion of the 76 CAG repeat in a Q76 mouse breeding program. Only the Q129 mice exhibited devastating progressive neurologic phenotypes similar to those of juvenile-onset DRPLA patients. Electrophysiologic studies demonstrated age-dependent and region-specific presynaptic dysfunction in the globus pallidus and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells and decreased currents through AMPA receptors (see 138248) and GABA-A (see 137160) receptors in CA1 neurons were also observed. The Q129 mice developed progressive brain atrophy but no obvious neuronal loss, associated with massive neuronal intranuclear accumulation (NIA) of mutant proteins with expanded polyQ stretches starting on postnatal day 4, whereas NIA in the Q76 mice appeared later with regional specificity to the vulnerable regions of DRPLA. Expression profile analysis demonstrated age-dependent downregulation of genes, including those relevant to synaptic functions and CREB (123810)-dependent genes. Sato et al. (2009) suggested that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that the age-dependent NIA is associated with nuclear dysfunction including transcriptional dysregulations. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>6 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATN1, (CAG)n REPEAT EXPANSION
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<br />
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ClinVar: RCV000003333
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 22 patients with dentatorubral-pallidoluysian atrophy (DRPLA; 125370), Koide et al. (1994) identified unstable expansion of a CAG unit in the DRPLA gene, which they termed B37 after a cDNA clone previously identified by Li et al. (1993). Each patient was a heterozygote with 1 allele in the normal range (8-25 repeat units) and a second expanded allele with the range of 54-68 repeat units. There were no overlaps in the number of CAG repeat units between control chromosomes and DRPLA chromosomes. </p><p>Burke et al. (1994, 1994) demonstrated that affected members of the large African American family with Haw River syndrome had a trinucleotide repeat expansion in the ATN1 gene that was identical to that found in DRPLA, a frequent disorder in Japanese but rare in Europeans. In addition to the difference in racial frequency, the clinical expression and pathology of Haw River syndrome differed from that of the disease as observed in the Japanese: seizures were a consistent feature, there was no myoclonus, basal ganglion calcification was common, and neuronal loss was prominent in the globus pallidus. Burke et al. (1994, 1994) suggested that the difference in racial frequency is probably due to differences in the repeat size. The frequency of the repeat allele of intermediate size was very low in Europeans, somewhat higher in African Americans, and relatively high (5-10%) in Japanese. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CONGENITAL HYPOTONIA, EPILEPSY, DEVELOPMENTAL DELAY, AND DIGITAL ANOMALIES</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATN1, HIS1054ASN
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<br />
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SNP: rs1555144357,
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ClinVar: RCV000659259, RCV000787317
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 3-year-old boy of Argentinian descent (patient 1) with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; 618494), Palmer et al. (2019) identified a de novo heterozygous c.3160C-A transversion in exon 7 of the ATN1 gene, resulting in a his1054-to-asn (H1054N) substitution at a highly conserved His residue in the 16-amino acid 'HX repeat' motif near the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0003 CONGENITAL HYPOTONIA, EPILEPSY, DEVELOPMENTAL DELAY, AND DIGITAL ANOMALIES</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATN1, HIS1058TYR
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<br />
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SNP: rs1555144358,
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ClinVar: RCV000659260, RCV000787318, RCV003335528
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a 1-year-old boy of Hispanic descent (patient 2) with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; 618494), Palmer et al. (2019) identified a de novo heterozygous c.3172C-T transition in exon 7 of the ATN1 gene, resulting in a his1058-to-tyr (H1058Y) substitution at a highly conserved His residue in the 16-amino acid 'HX repeat' motif near the C terminus. The mutation which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 CONGENITAL HYPOTONIA, EPILEPSY, DEVELOPMENTAL DELAY, AND DIGITAL ANOMALIES</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATN1, 6-BP INS, 3177AACCTG
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<br />
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SNP: rs1064795494,
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ClinVar: RCV000482562, RCV000787319
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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|
<p>In a 5-year-old girl of Hispanic descent (patient 3) with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; 618494), Palmer et al. (2019) identified a de novo heterozygous 6-bp insertion (c.3177_3178insAACCTG) in exon 7 of the ATN1 gene, resulting in a Ser1059_His1060insAsnLeu substitution in the highly conserved 16-amino acid 'HX repeat' motif near the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 CONGENITAL HYPOTONIA, EPILEPSY, DEVELOPMENTAL DELAY, AND DIGITAL ANOMALIES</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATN1, HIS1060TYR
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<br />
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SNP: rs797044566,
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ClinVar: RCV000171467, RCV000787320
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 9-year-old girl of Saudi descent (patient 5) with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; 618494), Palmer et al. (2019) identified a de novo heterozygous c.3178C-T transition in exon 7 of the ATN1 gene, resulting in a his1060-to-tyr (H1060Y) substitution at a highly conserved His residue in the 16-amino acid 'HX repeat' motif near the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. Nuclear magnetic resonance analysis of a synthesized peptide containing the H1060Y variant showed that the mutation resulted in a perturbation of the structural and functional integrity of the HX repeat, and altered zinc-binding properties. Additional functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 CONGENITAL HYPOTONIA, EPILEPSY, DEVELOPMENTAL DELAY, AND DIGITAL ANOMALIES</strong>
|
|
</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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ATN1, HIS1062ARG
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<br />
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SNP: rs1565569158,
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ClinVar: RCV000779621, RCV000787321
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a French girl (patient 8) who died at 2 months of age with congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA; 618494), Palmer et al. (2019) identified a de novo heterozygous c.3185A-G transition in exon 7 of the ATN1 gene, resulting in a his1062-to-arg (H1062R) substitution at a highly conserved His residue in the 16-amino acid 'HX repeat' motif near the C terminus. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the gnomAD database. The patient had previously been reported by Mosca et al. (2007). Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
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Aoki, M., Abe, K., Kameya, T., Watanabe, M., Itoyama, Y.
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<strong>Maternal anticipation of DRPLA.</strong>
|
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Hum. Molec. Genet. 3: 1197-1198, 1994.
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[PubMed: 7981699]
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[Full Text: https://doi.org/10.1093/hmg/3.7.1197]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Barinaga, M.
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<strong>An intriguing new lead on Huntington's disease.</strong>
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Science 271: 1233-1234, 1996.
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[PubMed: 8638101]
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[Full Text: https://doi.org/10.1126/science.271.5253.1233]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Burke, J. R., Enghild, J. J., Martin, M. E., Jou, Y.-S., Myers, R. M., Roses, A. D., Vance, J. M., Strittmatter, W. J.
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|
<strong>Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH.</strong>
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|
Nature Med. 2: 347-350, 1996.
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[PubMed: 8612237]
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[Full Text: https://doi.org/10.1038/nm0396-347]
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</p>
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</li>
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<li>
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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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</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 : 07/03/2019<br>George E. Tiller - updated : 8/10/2009<br>Patricia A. Hartz - updated : 1/15/2009<br>George E. Tiller - updated : 4/25/2005<br>Victor A. McKusick - updated : 11/13/2003<br>George E. Tiller - updated : 7/9/2003
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</span>
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</div>
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</div>
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Creation Date:
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