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Entry
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- *607047 - ATAXIN 3; ATXN3
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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">*607047</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#evolution">Evolution</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li 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/607047">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<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=ENSG00000066427;t=ENST00000644486" 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=4287" 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=607047" 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="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=ENSG00000066427;t=ENST00000644486" 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_001127696,NM_001127697,NM_001164774,NM_001164776,NM_001164777,NM_001164778,NM_001164779,NM_001164780,NM_001164781,NM_001164782,NM_004993,NM_030660,NR_028453,NR_028454,NR_028455,NR_028456,NR_028457,NR_028458,NR_028459,NR_028460,NR_028461,NR_028462,NR_028463,NR_028464,NR_028465,NR_028466,NR_028467,NR_028468,NR_028469,NR_028470,NR_031765,NR_187583,NR_187584" 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_004993" 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=607047" 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=06131&isoform_id=06131_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/ATXN3" 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/833928,2262195,2262197,2262199,11559486,13518013,13518019,14149092,14149093,21708052,62088198,66267302,119601877,119601878,119601879,119601880,119601881,152112974,189163493,222877354,258613999,258614019,258614023,258614025,258614027,258614029,258614031,258614033,258614035,289517567,289517569,289517571,289517573,289517575,289517579,289517588,289517593,289517596,289517598,289517601,289517604,289517608,289517614,289517622,289517625,289517635,289517637,289517639,289517641,289517643,289517648,289517651,289517655,289517657,289517663,289517668,289517671,289517673,289517675,289517680,289517688,289517692,289517698,289517700,289517702,289517706,289517709,289517711,289517713,289517716,289517720,289517724,289517727,289517729,289517731,289517740,289517744,289517748,289517750,289517752,289517754,289517757,289517761,289517766,289517768,289517771,289517781,289517785,289517788,289517792,289517795,289517805,289517807,289517811,289517813,289517816,289517818,289517821,289517823,289517826,289517828,289517832,289517835,289517837,289517842,289517844,289517849,289517853,289517855,289517858,289517861,289517863,289517865,289517878,289517881,289517885,289517888,289517892,289517895,289517897,289517901,289517903,289517906,289517909,289517911,289517916,289517918,289517920,289517922,289517924,289517929,289517931,289517934,289517937,289517939,289517941,289517943,289517945,289517948,289517950,289517952,289518694,289519132,289519684,289520867,289520870,289520875,289520877,289520880,289520882,289520890,289520893,289520898,289520900,289520903,289520905,289520907,289520911,289520913,289520918,289520921,289520923,289520926,289520928,289520930,289520932,289520934,289520938,289520942,289520945,289520947,289520949,289520953,289520955,289520960,289520962,289520965,289520967,289520969,289520971,289520974,289520976,289520978,289520980,289520982,289520989,289520991,289520994,289520997,289520999,289521001,289521004,289521009,289521011,289521014,289521017,289521019,289521022,289521027,289521031,289521036,289521041,289521043,289521045,289521047,289521051,289521057,311461778,311461780,1316032226,2572523590" 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/P54252" 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=4287" 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=ENSG00000066427;t=ENST00000644486" 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=ATXN3" 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=ATXN3" 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+4287" 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/ATXN3" 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:4287" 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/4287" 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=chr14&hgg_gene=ENST00000644486.2&hgg_start=92044775&hgg_end=92106582&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/atxn3" 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=607047[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=607047[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000066427" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=ATXN3" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=ATXN3" 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=ATXN3" 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=ATXN3&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/PA134971833" 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:7106" 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://www.mousephenotype.org/data/genes/MGI:1099442" 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/ATXN3#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:1099442" 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/4287/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://omia.org/OMIA002473/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=4287" 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=WBGene00006446;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-040426-983" 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:607047" 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://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4287" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=ATXN3&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> 91952008<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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607047
|
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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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ATAXIN 3; ATXN3
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</span>
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</h3>
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</div>
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<div>
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
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</div>
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<div>
|
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<h4>
|
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<span class="mim-font">
|
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AT3<br />
|
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MJD GENE; MJD1<br />
|
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SCA3 GENE
|
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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=ATXN3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ATXN3</a></em></strong>
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/14/466?start=-3&limit=10&highlight=466">14q32.12</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr14:92044775-92106582&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'})">14:92,044,775-92,106,582</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
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{Parkinson disease, late-onset, susceptibility to}
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>ATXN3 has deubiquitinase activity and appears to be a component of the ubiquitin proteasome system. It may also have roles in transcriptional regulation and neuroprotection (summary by <a href="#12" class="mim-tip-reference" title="Haacke, A., Broadley, S. A., Boteva, R., Tzvetkov, N., Hartl, F. U., Breuer, P. <strong>Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3.</strong> Hum. Molec. Genet. 15: 555-568, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407371</a>] [<a href="https://doi.org/10.1093/hmg/ddi472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407371">Haacke et al., 2006</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16407371" 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 identify the gene affected by CAG expansion in Machado-Joseph disease (MJD; <a href="/entry/109150">109150</a>), <a href="#16" class="mim-tip-reference" title="Kawaguchi, Y., Okamoto, T., Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., Kimura, J., Narumiya, S., Kakizuka, A. <strong>CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.</strong> Nature Genet. 8: 221-228, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874163</a>] [<a href="https://doi.org/10.1038/ng1194-221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874163">Kawaguchi et al. (1994)</a> isolated a cDNA with a CAG repeat from a human brain cDNA library using an oligonucleotide probe with 13 CTG repeats, complementary to the CAG repeats. The cDNA, which they designated MJD1, encodes a deduced 359-amino acid protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Goto, J., Watanabe, M., Ichikawa, Y., Yee, S.-B., Ihara, N., Endo, K., Igarashi, S., Takiyama, Y., Gaspar, C., Maciel, P., Tsuji, S., Rouleau, G. A., Kanazawa, I. <strong>Machado-Joseph disease gene products carrying different carboxyl termini.</strong> Neurosci. Res. 28: 373-377, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9274833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9274833</a>] [<a href="https://doi.org/10.1016/s0168-0102(97)00056-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9274833">Goto et al. (1997)</a> obtained 3 ATXN3 cDNAs from a human brain cDNA library. Two of the cDNAs represent an ATXN3 variant that differs from the cDNA reported by <a href="#16" class="mim-tip-reference" title="Kawaguchi, Y., Okamoto, T., Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., Kimura, J., Narumiya, S., Kakizuka, A. <strong>CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.</strong> Nature Genet. 8: 221-228, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874163</a>] [<a href="https://doi.org/10.1038/ng1194-221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874163">Kawaguchi et al. (1994)</a> in splicing of the 3-prime exons, resulting in a different C-terminal sequence in the protein. The third cDNA has a stop codon polymorphism that results in additional C-terminal amino acids. The deduced ATXN3 proteins, which range in size from 360 to 374 amino acids, differ only at their C termini and in the number of glutamines in the polyglutamine (polyQ) tract. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7874163+9274833" 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., Brattig, T., Gossen, M., Riess, O. <strong>Characterization of the rat spinocerebellar ataxia type 3 gene.</strong> Neurogenetics 1: 103-112, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732811</a>] [<a href="https://doi.org/10.1007/s100480050015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10732811">Schmitt et al. (1997)</a> isolated rat Atxn3. They found that the rat and human ATXN3 genes are highly homologous, with an overall sequence identity of approximately 88%. However, the C-terminal end of the putative rat protein differs strongly from the human sequence published by <a href="#16" class="mim-tip-reference" title="Kawaguchi, Y., Okamoto, T., Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., Kimura, J., Narumiya, S., Kakizuka, A. <strong>CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.</strong> Nature Genet. 8: 221-228, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874163</a>] [<a href="https://doi.org/10.1038/ng1194-221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874163">Kawaguchi et al. (1994)</a>. The (CAG)n block in the rat cDNA consists of only 3 interrupted units, suggesting that a long polyQ stretch is not essential for normal function of the Atxn3 protein in rodents. Transcription of rat Atxn3 was detected in most rat tissues, including brain. In human brain sections, <a href="#27" class="mim-tip-reference" title="Schmitt, I., Brattig, T., Gossen, M., Riess, O. <strong>Characterization of the rat spinocerebellar ataxia type 3 gene.</strong> Neurogenetics 1: 103-112, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732811</a>] [<a href="https://doi.org/10.1007/s100480050015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10732811">Schmitt et al. (1997)</a> did not find significantly higher ATXN3 mRNA levels in regions predominantly affected in MJD, suggesting that additional molecules and/or regulatory events are necessary to explain the exclusive degeneration of certain brain areas in MJD. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10732811+7874163" 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 immunohistochemistry of normal and MJD brain, <a href="#23" class="mim-tip-reference" title="Paulson, H. L., Das, S. S., Crino, P. B., Perez, M. K., Patel, S. C., Gotsdiner, D., Fischbeck, K. H., Pittman, R. N. <strong>Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain.</strong> Ann. Neurol. 41: 453-462, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9124802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9124802</a>] [<a href="https://doi.org/10.1002/ana.410410408" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9124802">Paulson et al. (1997)</a> showed that expression of ATXN3 was restricted to a limited subset of neurons, particularly to those in the striatum. In normal and diseased brain and in transfected cells, immunolocalization studies revealed that ATXN3 was predominantly a cytoplasmic protein that localized to neuronal processes as well. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9124802" 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="#28" class="mim-tip-reference" title="Tait, D., Riccio, M., Sittler, A., Scherzinger, E., Santi, S., Ognibene, A., Maraldi, N. M., Lehrach, H., Wanker, E. E. <strong>Ataxin-3 is transported into the nucleus and associates with the nuclear matrix.</strong> Hum. Molec. Genet. 7: 991-997, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9580663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9580663</a>] [<a href="https://doi.org/10.1093/hmg/7.6.991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9580663">Tait et al. (1998)</a> studied the subcellular localization of full-length ataxin-3 protein with a glutamine sequence in the normal range in 2 mammalian cell lines. By immunofluorescence and confocal laser scanning microscopy, and by biochemical subcellular fractionations, they detected the protein predominantly, but not exclusively, in the nucleus. The ataxin-3 present in the nucleus of neuroblastoma cells associated with the inner nuclear matrix. The authors concluded that the ataxin-3 protein, which contains a putative nuclear localization signal very close to the glutamine tract, per se has the ability to be transported into the nucleus and that an expanded glutamine repeat is not essential for this transport. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9580663" 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 Northern blot analysis, <a href="#13" class="mim-tip-reference" title="Ichikawa, Y., Goto, J., Hattori, M., Toyoda, A., Ishii, K., Jeong, S.-Y., Hashida, H., Masuda, N., Ogata, K., Kasai, F., Hirai, M., Maciel, P., Rouleau, G. A., Sakaki, Y., Kanazawa, I. <strong>The genomic structure and expression of MJD, the Machado-Joseph disease gene.</strong> J. Hum. Genet. 46: 413-422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11450850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11450850</a>] [<a href="https://doi.org/10.1007/s100380170060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11450850">Ichikawa et al. (2001)</a> showed that ATXN3 mRNA was ubiquitously expressed in human tissues. They detected at least 4 ATXN3 transcripts of 1.4, 1.8, 4.5, and 7.5 kb and suggested that the different mRNA species probably result from differential splicing and polyadenylation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11450850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Burnett, B., Li, F., Pittman, R. N. <strong>The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity.</strong> Hum. Molec. Genet. 12: 3195-3205, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14559776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14559776</a>] [<a href="https://doi.org/10.1093/hmg/ddg344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14559776">Burnett et al. (2003)</a> stated that the major human AT3 isoform contains an N-terminal deubiquitinating domain, called the Josephin domain, followed by 2 ubiquitin-interacting motifs (UIMs) and a polyQ tract near the C terminus. In some isoforms, the polyQ tract is followed by a third UIM. <a href="#6" class="mim-tip-reference" title="Burnett, B., Li, F., Pittman, R. N. <strong>The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity.</strong> Hum. Molec. Genet. 12: 3195-3205, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14559776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14559776</a>] [<a href="https://doi.org/10.1093/hmg/ddg344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14559776">Burnett et al. (2003)</a> identified a catalytic triad of cys14, his119, and asn134 and other highly conserved residues within the Josephin domain of AT3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14559776" 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="Ichikawa, Y., Goto, J., Hattori, M., Toyoda, A., Ishii, K., Jeong, S.-Y., Hashida, H., Masuda, N., Ogata, K., Kasai, F., Hirai, M., Maciel, P., Rouleau, G. A., Sakaki, Y., Kanazawa, I. <strong>The genomic structure and expression of MJD, the Machado-Joseph disease gene.</strong> J. Hum. Genet. 46: 413-422, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11450850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11450850</a>] [<a href="https://doi.org/10.1007/s100380170060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11450850">Ichikawa et al. (2001)</a> determined that the ATXN3 gene spans 48,240 bp and contains 11 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11450850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By FISH, <a href="#16" class="mim-tip-reference" title="Kawaguchi, Y., Okamoto, T., Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., Kimura, J., Narumiya, S., Kakizuka, A. <strong>CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.</strong> Nature Genet. 8: 221-228, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874163</a>] [<a href="https://doi.org/10.1038/ng1194-221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874163">Kawaguchi et al. (1994)</a> mapped the ATXN3 gene to chromosome 14q32.1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874163" 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>Using a 2-hybrid system, <a href="#30" class="mim-tip-reference" title="Wang, G., Sawai, N., Kotliarova, S., Kanazawa, I., Nukina, N. <strong>Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B.</strong> Hum. Molec. Genet. 9: 1795-1803, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10915768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10915768</a>] [<a href="https://doi.org/10.1093/hmg/9.12.1795" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10915768">Wang et al. (2000)</a> found that ataxin-3 interacted with 2 human homologs of the yeast DNA repair protein RAD23, HHR23A (RAD23A; <a href="/entry/600061">600061</a>) and HHR23B (RAD23B; <a href="/entry/600062">600062</a>). Both normal and mutant ataxin-3 proteins interacted with the ubiquitin-like domain at the N terminus of the HHR23 proteins, which is a motif important for nucleotide excision repair. However, in HEK 293 cells, HHR23A was recruited to intranuclear inclusions formed by the mutant ataxin-3 (see MOLECULAR GENETICS) through its interaction with ataxin-3. The authors suggested that this interaction may be associated with the normal function of ataxin-3, and that some functional abnormality of the HHR23 proteins may exist in MJD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10915768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By combining profile-based sequence analysis with genomewide functional data in model organisms, <a href="#26" class="mim-tip-reference" title="Scheel, H., Tomiuk, S., Hofmann, K. <strong>Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics.</strong> Hum. Molec. Genet. 12: 2845-2852, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12944423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12944423</a>] [<a href="https://doi.org/10.1093/hmg/ddg297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12944423">Scheel et al. (2003)</a> determined that ataxin-3 belongs to a novel group of cysteine proteases and is predicted to be active against ubiquitin chains or related substrates. The catalytic site of this enzyme class is similar to that found in UBP (see USP1; <a href="/entry/603478">603478</a>)- and UCH (see UCHL3; <a href="/entry/603090">603090</a>)-type ubiquitin proteases. They suggested the finding had implications for disease pathogenesis by providing a direct connection between SCA3 and ubiquitin metabolism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12944423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Doss-Pepe, E. W., Stenroos, E. S., Johnson, W. G., Madura, K. <strong>Ataxin-3 interactions with Rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis.</strong> Molec. Cell. Biol. 23: 6469-6483, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12944474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12944474</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12944474[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/10.1128/MCB.23.18.6469-6483.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12944474">Doss-Pepe et al. (2003)</a> showed that both normal and polyQ-expanded human ATXN3 associated with a number of proteasome subunits and with ubiquitinated proteins. Truncation analysis showed that the UIMs of ATXN3 bound polyubiquitin, but other factors in the full-length protein increased the affinity of ATXN3 for polyubiquitin. Both normal and polyQ-expanded ATXN3 inhibited formation of ubiquitin-conjugated histone H2B (see <a href="/entry/609904">609904</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12944474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Burnett, B., Li, F., Pittman, R. N. <strong>The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity.</strong> Hum. Molec. Genet. 12: 3195-3205, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14559776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14559776</a>] [<a href="https://doi.org/10.1093/hmg/ddg344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14559776">Burnett et al. (2003)</a> showed that the UIM domain of AT3 bound ubiquitin chains containing 4 or more ubiquitin units, the chain length required for proteasome degradation. PolyQ-expanded AT3 showed similar binding to ubiquitin chains. Both wildtype and pathologic AT3 also decreased the degree of polyubiquitination of the test protein, iodinated lysosome, suggesting that AT3 is a ubiquitin protease. AT3 was sensitive to a specific ubiquitin protease inhibitor. Mutation of cys14 within the Josephin domain to alanine reduced the ability of AT3 to remove polyubiquitin chains from iodinated lysosome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14559776" 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="Winborn, B. J., Travis, S. M., Todi, S. V., Scaglione, K. M., Xu, P., Williams, A. J., Cohen, R. E., Peng, J., Paulson, H. L. <strong>The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits lys63 linkages in mixed linkage ubiquitin chains.</strong> J. Biol. Chem. 283: 26436-26443, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599482</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599482[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/10.1074/jbc.M803692200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18599482">Winborn et al. (2008)</a> showed that human ATXN3 bound both lys48- and lys63-linked polyubiquitin chains, but preferentially cleaved lys63 linkages. ATXN3 showed greater activity toward mixed-linkage polyubiquitin, cleaving lys63 linkages in chains that contained both lys48 and lys63 linkages. PolyQ expansion did not alter the binding or catalytic properties of ATXN3. The authors concluded that ATXN3 is a mixed-linkage, chain-editing enzyme and that the UIM region of ATXN3 regulates its substrate specificity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18599482" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Mueller, T., Breuer, P., Schmitt, I., Walter, J., Evert, B. O., Wullner, U. <strong>CK2-dependent phosphorylation determines cellular localization and stability of ataxin-3.</strong> Hum. Molec. Genet. 18: 3334-3343, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19542537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19542537</a>] [<a href="https://doi.org/10.1093/hmg/ddp274" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19542537">Mueller et al. (2009)</a> showed that protein casein kinase-2 (CK2; see <a href="/entry/115440">115440</a>)-dependent phosphorylation controlled the nuclear localization, aggregation, and stability of ataxin-3. Ser340 and ser352 within the third ubiquitin-interacting motif of ATXN3 were particularly important for nuclear localization of normal and expanded ATXN3, and mutation of these sites robustly reduced the formation of nuclear inclusions. A putative nuclear leader sequence was not required. ATXN3 associated with CK2-alpha (CSNK2A1; <a href="/entry/115440">115440</a>), and pharmacologic inhibition of CK2 decreased nuclear ATXN3 levels and the formation of nuclear inclusions. ATXN3 shifted to the nucleus upon thermal stress in a CK2-dependent manner, suggesting a key role of CK2-mediated phosphorylation of ATXN3 in SCA3 pathophysiology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19542537" 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="Reina, C. P., Zhong, X., Pittman, R. N. <strong>Proteotoxic stress increases nuclear localization of ataxin-3.</strong> Hum. Molec. Genet. 19: 235-249, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19843543[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/ddp482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19843543">Reina et al. (2010)</a> showed that interactions of ATXN3 with valosin-containing protein (VCP; <a href="/entry/601023">601023</a>) and HHR23B were dynamic and modulated by proteotoxic stresses. Heat shock, a general proteotoxic stress, also induced wildtype and pathogenic ATXN3 to accumulate in the nucleus. Mapping studies showed that 2 regions of ATXN3, the Josephin domain and the C terminus, regulated heat shock-induced nuclear localization. Atxn3-null mouse cells were more sensitive to toxic effects of heat shock, suggesting that ATXN3 had a protective function in the cellular response to heat shock. Oxidative stress also induced nuclear localization of ATXN3; both wildtype and pathogenic ATXN3 accumulated in the nucleus of SCA3 patient fibroblasts following oxidative stress. Heat shock and oxidative stress were the first processes identified that increased nuclear localization of ATXN3. <a href="#25" class="mim-tip-reference" title="Reina, C. P., Zhong, X., Pittman, R. N. <strong>Proteotoxic stress increases nuclear localization of ataxin-3.</strong> Hum. Molec. Genet. 19: 235-249, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19843543[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/ddp482" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19843543">Reina et al. (2010)</a> suggested that the nucleus may be a key site for early pathogenesis of SCA3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19843543" 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="Koch, P., Breuer, P., Peitz, M., Jungverdorben, J., Kesavan, J., Poppe, D., Doerr, J., Ladewig, J., Mertens, J., Tuting, T., Hoffmann, P., Klockgether, T., Evert, B. O., Wullner, U., Brustle, O. <strong>Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease.</strong> Nature 480: 543-546, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22113611/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22113611</a>] [<a href="https://doi.org/10.1038/nature10671" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22113611">Koch et al. (2011)</a> showed that L-glutamate-induced excitation of patient-specific induced pluripotent stem cell (iPSC)-derived neurons initiates calcium-dependent proteolysis of ATXN3 followed by the formation of SDS-insoluble aggregates. This phenotype could be abolished by calpain (see <a href="/entry/114220">114220</a>) inhibition, confirming a key role of this protease in ATXN3 aggregation. Aggregate formation was further dependent on functional sodium and potassium channels as well as ionotropic and voltage-gated calcium channels, and was not observed in iPSCs, fibroblasts, or glia, thereby providing an explanation for the neuron-specific phenotype of Machado-Joseph disease. <a href="#17" class="mim-tip-reference" title="Koch, P., Breuer, P., Peitz, M., Jungverdorben, J., Kesavan, J., Poppe, D., Doerr, J., Ladewig, J., Mertens, J., Tuting, T., Hoffmann, P., Klockgether, T., Evert, B. O., Wullner, U., Brustle, O. <strong>Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease.</strong> Nature 480: 543-546, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22113611/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22113611</a>] [<a href="https://doi.org/10.1038/nature10671" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22113611">Koch et al. (2011)</a> concluded that iPSCs enable the study of aberrant protein processing associated with late-onset neurodegenerative disorders in patient-specific neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22113611" 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 immunoprecipitation analysis and protein pull-down studies, <a href="#3" class="mim-tip-reference" title="Araujo, J., Breuer, P., Dieringer, S., Krauss, S., Dorn, S., Zimmermann, K., Pfeifer, A., Klockgether, T., Wuellner, U., Evert, B. O. <strong>FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3.</strong> Hum. Molec. Genet. 20: 2928-2941, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536589</a>] [<a href="https://doi.org/10.1093/hmg/ddr197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21536589">Araujo et al. (2011)</a> found that endogenous ATXN3 interacted directly with the transcription factor FOXO4 (<a href="/entry/300033">300033</a>) in nuclear extracts of HeLa cells, rat CSM14.1 mesencephalic cells, and mouse brain. The interaction required the N-terminal Josephin domain of ATXN3. Expression of ATXN3 enhanced FOXO4-dependent expression of the antioxidant enzyme SOD2 (<a href="/entry/147460">147460</a>) in a manner independent of ATXN3 deubiquitinase activity. Treatment of HeLa cells with H2O2 induced nuclear translocation of FOXO4 and ATXN3, enhanced binding of FOXO4 and ATXN3 to the SOD2 promoter, and induced SOD2 expression. Coexpression of mutant ATXN3 with an expanded polyglutamine tract or knockdown of ATXN3 via short hairpin RNA reduced FOXO4 nuclear translocation and induction of SOD2. Lymphocytes from SCA3 patients exposed to oxidative stress showed reduced binding of FOXO4 to the SOD2 promoter, concomitant with impaired upregulation of SOD2 and enhanced oxidative cytotoxicity. <a href="#3" class="mim-tip-reference" title="Araujo, J., Breuer, P., Dieringer, S., Krauss, S., Dorn, S., Zimmermann, K., Pfeifer, A., Klockgether, T., Wuellner, U., Evert, B. O. <strong>FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3.</strong> Hum. Molec. Genet. 20: 2928-2941, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536589</a>] [<a href="https://doi.org/10.1093/hmg/ddr197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21536589">Araujo et al. (2011)</a> concluded that ATXN3 stabilizes FOXO4 and acts as a transcriptional coactivator with FOXO4 in the oxidative stress response. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21536589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Ashkenazi, A., Bento, C. F., Ricketts, T., Vicinanza, M., Siddiqi, F., Pavel, M., Squitieri, F., Hardenberg, M. C., Imarisio, S., Menzies, F. M., Rubinsztein, D. C. <strong>Polyglutamine tracts regulate beclin 1-dependent autophagy.</strong> Nature 545: 108-111, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28445460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28445460</a>] [<a href="https://doi.org/10.1038/nature22078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28445460">Ashkenazi et al. (2017)</a> demonstrated that the polyQ domain of ATXN3 enables it to interact with beclin-1 (BECN1; <a href="/entry/604378">604378</a>), a key initiator of autophagy. This interaction allows the deubiquitinase activity of ATXN3 to protect BECN1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by BECN1, was particularly inhibited in ATXN3-depleted human cell lines and mouse primary neurons, and in vivo in mice. This activity of ATXN3 and its polyQ-mediated interaction with BECN1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin (<a href="/entry/613004">613004</a>) exon 1 with an expanded polyQ region, and this impairment was recapitulated in the brains of a mouse model of Huntington disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ATXN3 itself. <a href="#4" class="mim-tip-reference" title="Ashkenazi, A., Bento, C. F., Ricketts, T., Vicinanza, M., Siddiqi, F., Pavel, M., Squitieri, F., Hardenberg, M. C., Imarisio, S., Menzies, F. M., Rubinsztein, D. C. <strong>Polyglutamine tracts regulate beclin 1-dependent autophagy.</strong> Nature 545: 108-111, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28445460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28445460</a>] [<a href="https://doi.org/10.1038/nature22078" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28445460">Ashkenazi et al. (2017)</a> concluded that their data described a specific function for a wildtype polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identified a deleterious function of such mutations distinct from their propensity to aggregate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28445460" 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>CAG Expansion in ATXN3 in Machado-Joseph Disease</em></strong></p><p>
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In 8 of 9 patients with clinically diagnosed MJD, <a href="#16" class="mim-tip-reference" title="Kawaguchi, Y., Okamoto, T., Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., Kimura, J., Narumiya, S., Kakizuka, A. <strong>CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.</strong> Nature Genet. 8: 221-228, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874163</a>] [<a href="https://doi.org/10.1038/ng1194-221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874163">Kawaguchi et al. (1994)</a> identified CAG expansions of between 68 to 79 in the ATXN3 gene (<a href="#0001">607047.0001</a>). In normal individuals, the ATXN3 gene was found to contain between 13 and 36 CAG repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874163" 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="Kawaguchi, Y., Okamoto, T., Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., Kimura, J., Narumiya, S., Kakizuka, A. <strong>CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.</strong> Nature Genet. 8: 221-228, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874163</a>] [<a href="https://doi.org/10.1038/ng1194-221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874163">Kawaguchi et al. (1994)</a> found a negative correlation between age of onset and CAG repeat numbers. Southern blot analyses and genomic cloning demonstrated the existence of related genes and raised the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874163" 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>Pathogenic Effects of Polyglutamine Expansion in ATXN3</em></strong></p><p>
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<a href="#24" class="mim-tip-reference" title="Paulson, H. L., Perez, M. K., Trottier, Y., Trojanowski, J. Q., Subramony, S. H., Das, S. S., Vig, P., Mandel, J. L., Fischbeck, K. H., Pittman, R. N. <strong>Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3.</strong> Neuron 19: 333-344, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9292723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9292723</a>] [<a href="https://doi.org/10.1016/s0896-6273(00)80943-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9292723">Paulson et al. (1997)</a> showed that ATXN3 with a polyglutamine sequence in the pathologic range accumulated in ubiquitinated intranuclear inclusions selectively in neurons of affected brain regions. They provided evidence in vitro for a model of disease in which an expanded polyglutamine-containing fragment recruits full-length protein into insoluble aggregates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9292723" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#9" class="mim-tip-reference" title="Evert, B. O., Wullner, U., Schulz, J. B., Weller, M., Groscurth, P., Trottier, Y., Brice, A., Klockgether, T. <strong>High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells.</strong> Hum. Molec. Genet. 8: 1169-1176, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369861</a>] [<a href="https://doi.org/10.1093/hmg/8.7.1169" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10369861">Evert et al. (1999)</a> generated ataxin-3-expressing rat mesencephalic CSM14.1 cells to study the effects of long-term expression of ataxin-3. The isolated stable cell lines provided high level expression of human full-length ataxin-3 with either the normal nonexpanded CAG repeats (SCA3-Q23) or the pathogenic expanded CAG repeats (SCA3-Q70). When cultured at a nonpermissive temperature (39 degrees C), CSM14.1 cells expressing the expanded full-length ataxin-3 developed nuclear inclusion bodies, strong indentations of the nuclear envelope, and cytoplasmic vacuolation, whereas cells expressing the nonexpanded form and control cells did not. The ultrastructural alterations resembled those found in affected neurons of SCA3 patients. Cells with such changes exhibited increased spontaneous nonapoptotic cell death. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Gaspar, C., Jannatipour, M., Dion, P., Laganiere, J., Sequeiros, J., Brais, B., Rouleau, G. A. <strong>CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation.</strong> Hum. Molec. Genet. 9: 1957-1966, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942424</a>] [<a href="https://doi.org/10.1093/hmg/9.13.1957" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10942424">Gaspar et al. (2000)</a> explored the possibility that frameshift mutations in expanded CAG tracts of ATXN3 can generate polyalanine mutant proteins and form intranuclear inclusions. Antisera were raised against a synthetic peptide corresponding to the C terminus of ATXN3, which would result from a frameshift within the CAG repeat motif with an intervening polyalanine stretch. Corresponding proteins were evident in MJD patients by Western blot analysis of lymphoblastoid proteins and in situ hybridization of MJD pontine neurons. Transfection experiments suggested that frameshifts are more likely to occur in longer CAG repeats and that alanine polymers alone may be harmful to cells. The authors suggested that a similar pathogenic mechanism may occur in other CAG repeat disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942424" 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="Toulouse, A., Au-Yeung, F., Gaspar, C., Roussel, J., Dion, P., Rouleau, G. A. <strong>Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts.</strong> Hum. Molec. Genet. 14: 2649-2660, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087686</a>] [<a href="https://doi.org/10.1093/hmg/ddi299" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16087686">Toulouse et al. (2005)</a> established a cellular model of transcript frameshifting of expanded CAG tracts, resulting from ribosomal slippage to the -1 frame exclusively. Ribosomal frameshifting depended on the presence of long CAG tracts, and polyalanine-frameshifted proteins may enhance polyglutamine-associated toxicity, possibly contributing to pathogenesis. Anisomycin, a ribosome-interacting drug that reduces -1 frameshifting, also reduced toxicity, suggesting a therapeutic opportunity for these disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16087686" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#12" class="mim-tip-reference" title="Haacke, A., Broadley, S. A., Boteva, R., Tzvetkov, N., Hartl, F. U., Breuer, P. <strong>Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3.</strong> Hum. Molec. Genet. 15: 555-568, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407371</a>] [<a href="https://doi.org/10.1093/hmg/ddi472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407371">Haacke et al. (2006)</a> found that full-length recombinant human AT3 formed detergent-resistant fibrillar aggregates in vitro with extremely low efficiency, even when it contained a pathogenic polyQ tract of 71 residues (AT3Q71). However, an N-terminally truncated form, called 257cQ71, which began with residue 257 and contained only the C terminus with an expanded polyQ region, readily formed detergent-insoluble aggregates and recruited full-length nonpathogenic AT3Q22 into the aggregates. The efficiency of recruitment increased with expansion of the polyQ stretch. FRET analysis revealed that the interaction of AT3Q22 with the polyQ tract of 257cQ71 caused a conformational change that affected the active-site cysteine within the Josephin domain of AT3Q22. Similar results were found in vivo with transfected mouse neuroblastoma cells: 257cQ71 formed inclusions in almost all cells, and full-length AT3 proteins did not readily aggregate unless coexpressed with 257cQ71. AT3Q71 also formed inclusions, but it appeared to do so following its partial degradation. Use of an engineered protease-sensitive form of AT3 suggested that release of expanded polyQ fragments initiates the formation of cellular inclusions. <a href="#12" class="mim-tip-reference" title="Haacke, A., Broadley, S. A., Boteva, R., Tzvetkov, N., Hartl, F. U., Breuer, P. <strong>Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3.</strong> Hum. Molec. Genet. 15: 555-568, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407371</a>] [<a href="https://doi.org/10.1093/hmg/ddi472" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16407371">Haacke et al. (2006)</a> concluded that recruitment of functional AT3 into aggregates by expanded polyQ-containing fragments reduces cellular AT3 content and thus impairs its function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16407371" 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>Suppression of Mutant ATXN3</em></strong></p><p>
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In animal cell models, <a href="#21" class="mim-tip-reference" title="Miller, V. M., Xia, H., Marrs, G. L., Gouvion, C. M., Lee, G., Davidson, B. L., Paulson, H. L. <strong>Allele-specific silencing of dominant disease genes.</strong> Proc. Nat. Acad. Sci. 100: 7195-7200, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12782788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12782788</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12782788[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1231012100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12782788">Miller et al. (2003)</a> demonstrated that allele-specific silencing of disease genes with small interfering RNA (siRNA) could be achieved by targeting either a linked SNP or the disease mutation directly. They determined that selective targeting of the disease-causing CAG repeat in the ATXN3 gene was not possible and then took advantage of an associated SNP to generate siRNA that exclusively silenced the mutant ATXN3 allele while sparing expression of the wildtype allele. Allele-specific suppression was accomplished with all 3 siRNA delivery approaches in use at the time: in vitro-synthesized duplexes and plasmid and viral expression of short hairpin RNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12782788" 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 vitro, <a href="#19" class="mim-tip-reference" title="Li, Y., Yokota, T., Matsumura, R., Taira, K., Mizusawa, H. <strong>Sequence-dependent and independent inhibition specific for mutant ataxin-3 by small interfering RNA.</strong> Ann. Neurol. 56: 124-129, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15236410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15236410</a>] [<a href="https://doi.org/10.1002/ana.20141" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15236410">Li et al. (2004)</a> found that an siRNA targeted to a C/G polymorphism immediately after the CAG repeat that is expanded in MJD effectively suppressed expression of mutant ataxin-3 (79 repeats) by 96% without significant effect on the wildtype protein. In addition, siRNA decreased cell death by 63 to 76%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15236410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Susceptibility to Late-Onset Parkinson Disease</em></strong></p><p>
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In a family of African descent in which 3 members presented with phenotypic features reminiscent of typical Parkinson disease (<a href="/entry/168600">168600</a>), Gwinn-Hardy et al. (2001) identified pathogenic expansions in the ATXN3 gene. Features suggestive of PD included bradykinesis, facial masking, rigidity, postural instability, shuffling, asymmetric onset, dopamine responsiveness, and lack of atypical features often associated with SCA3. A fourth, mildly symptomatic patient also carried the repeat expansion. The authors suggested that the low numbers of repeats in this family (67-75; normal, 16-34) presenting with parkinsonism may be associated with ethnic background and that evaluation for SCA3 should be considered in similar cases.</p>
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<p>By comparing wildtype haplotypes encompassing the ATXN3 CAG repeat in 431 chromosomes of European, Asian, and African origin, <a href="#20" class="mim-tip-reference" title="Martins, S., Calafell, F., Wong, V. C. N., Sequeiros, J., Amorim, A. <strong>A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus.</strong> Europ. J. Hum. Genet. 14: 932-940, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16724006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16724006</a>] [<a href="https://doi.org/10.1038/sj.ejhg.5201643" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16724006">Martins et al. (2006)</a> concluded that the main mutation mechanism occurring in the evolution of the polymorphic CAG repeat is a multistep process resulting from gene conversion or DNA slippage, as opposed to a stepwise process. The 4 most frequent haplotypes showed a bimodal CAG repeat length frequency distribution, particularly in the European population, and genetic distances among all the alleles from each population did not reflect allele size differences. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16724006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#7" class="mim-tip-reference" title="Cemal, C. K., Carroll, C. J., Lawrence, L., Lowrie, M. B., Ruddle, P., Al-Mahdawi, S., King, R. H. M., Pook, M. A., Huxley, C., Chamberlain, S. <strong>YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit.</strong> Hum. Molec. Genet. 11: 1075-1094, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11978767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11978767</a>] [<a href="https://doi.org/10.1093/hmg/11.9.1075" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11978767">Cemal et al. (2002)</a> generated transgenic mice by introducing pathologic ATXN3 alleles with polyglutamine tract lengths of 64, 67, 72, 76, and 84 repeats, as well as the wildtype with 15 repeats. The mice with expanded alleles demonstrated a mild and slowly progressive cerebellar deficit, manifesting as early as 4 weeks of age. As the disease progressed, pelvic elevation became markedly flattened and was accompanied by hypotonia and motor and sensory loss. Neuronal intranuclear inclusion formation and cell loss was prominent in the pontine and dentate nuclei, with variable cell loss in other regions of the cerebellum from 4 weeks of age. Peripheral nerve demyelination and axonal loss was also detected in symptomatic mice from 26 weeks of age. In contrast, transgenic mice carrying the wildtype (CAG)15 allele of the ATXN3 locus appeared completely normal at 20 months. Disease severity increased with the level of expression of the expanded protein and the size of the repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11978767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Boy, J., Schmidt, T., Wolburg, H., Mack, A., Nuber, S., Bottcher, M., Schmitt, I., Holzmann, C., Zimmermann, F., Servadio, A., Riess, O. <strong>Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3.</strong> Hum. Molec. Genet. 18: 4282-4295, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19666958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19666958</a>] [<a href="https://doi.org/10.1093/hmg/ddp381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19666958">Boy et al. (2009)</a> generated a conditional mouse model of SCA3. Transgenic mice developed a progressive neurologic phenotype characterized by neuronal dysfunction in the cerebellum, reduced anxiety, hyperactivity, impaired performance on the rotarod test, and lower body weight gain. When mutant ataxin-3 expression was turned off in symptomatic mice in an early disease state, the transgenic mice were indistinguishable from negative controls after 5 months of treatment. <a href="#5" class="mim-tip-reference" title="Boy, J., Schmidt, T., Wolburg, H., Mack, A., Nuber, S., Bottcher, M., Schmitt, I., Holzmann, C., Zimmermann, F., Servadio, A., Riess, O. <strong>Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3.</strong> Hum. Molec. Genet. 18: 4282-4295, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19666958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19666958</a>] [<a href="https://doi.org/10.1093/hmg/ddp381" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19666958">Boy et al. (2009)</a> concluded that reducing the production of pathogenic ataxin-3 may be a promising approach to treat SCA3, provided that such treatment is applied before irreversible damage has taken place and that it is continued for a sufficiently long time. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19666958" 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="Alves, S., Nascimento-Ferreira, I., Dufour, N., Hassig, R., Auregan, G., Nobrega, C., Brouillet, E., Hantraye, P., Pedroso de Lima, M. C., Deglon, N., Pereira de Almeida, L. <strong>Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3?</strong> Hum. Molec. Genet. 19: 2380-2394, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20308049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20308049</a>] [<a href="https://doi.org/10.1093/hmg/ddq111" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20308049">Alves et al. (2010)</a> both overexpressed and silenced wildtype ATX3 in the rat model of MJD developed by <a href="#2" class="mim-tip-reference" title="Alves, S., Regulier, E., Nascimento-Ferreira, I., Hassig, R., Dufour, N., Koeppen, A., Carvalho, A. L., Simoes, S., Pedroso de Lima, M. C., Brouillet, E., Gould, V. C., Deglon, N., de Almeida, L. P. <strong>Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease.</strong> Hum. Molec. Genet. 17: 2071-2083, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385100</a>] [<a href="https://doi.org/10.1093/hmg/ddn106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18385100">Alves et al. (2008)</a>. They found that overexpression of wildtype ATX3 did not protect against MJD pathology, that knockdown of wildtype ATX3 did not aggravate MJD pathology, and that non-allele-specific silencing of ataxin-3 strongly reduced neuropathology. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20308049+18385100" 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>Transgenic Drosophila Models of Machado-Joseph Disease</em></strong></p><p>
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<a href="#31" class="mim-tip-reference" title="Warrick, J. M., Morabito, L. M., Bilen, J., Gordesky-Gold, B., Faust, L. Z., Paulson, H. L., Bonini, N. M. <strong>Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism.</strong> Molec. Cell 18: 37-48, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15808507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15808507</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.02.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15808507">Warrick et al. (2005)</a> expressed normal and pathogenic forms of human ATXN3 in Drosophila and found that the normal activity of ATXN3 mitigated polyQ-induced neurodegeneration. When both normal and pathogenic proteins were expressed together throughout the nervous system, flies lived longer and showed improved brain cortical structure compared with flies expressing only the pathogenic protein. Normal ATXN3 reduced accumulation of pathogenic ATXN3 and of other polyQ disease proteins. Mutations in the ubiquitin interaction motif or in the ubiquitin protease domain of ATXN3 abrogated the protective effect. Protection also required proteasome activity, indicating that the normal function of ATXN3 requires the ubiquitin pathway of protein quality control. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15808507" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Jung, J., Bonini, N. <strong>CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease.</strong> Science 315: 1857-1859, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332375</a>] [<a href="https://doi.org/10.1126/science.1139517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17332375">Jung and Bonini (2007)</a> showed that a transgenic Drosophila model for spinocerebellar ataxia type 3 recapitulated key features of human CAG repeat instability, including large repeat changes and strong expansion bias. Instability was dramatically enhanced by transcription and modulated by nuclear excision repair and CREB-binding protein (<a href="/entry/600140">600140</a>), a histone acetyltransferase whose decreased activity contributes to polyglutamine disease. Pharmacologic treatment normalized acetylation-suppressed instability. Thus, <a href="#14" class="mim-tip-reference" title="Jung, J., Bonini, N. <strong>CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease.</strong> Science 315: 1857-1859, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332375</a>] [<a href="https://doi.org/10.1126/science.1139517" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17332375">Jung and Bonini (2007)</a> concluded that toxic consequences of pathogenic polyglutamine protein may include enhancing repeat instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17332375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Li, L.-B., Yu, Z., Teng, X., Bonini, N. M. <strong>RNA toxicity is a component of ataxin-3 degeneration in Drosophila.</strong> Nature 453: 1107-1111, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18449188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18449188</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18449188[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18449188">Li et al. (2008)</a> provided evidence of a pathogenic role for ATXN3 CAG repeat RNA in polyQ toxicity. In a screen for modifiers of polyQ degeneration induced by ATXN3 in a transgenic Drosophila model, the authors isolated an upregulation allele of muscleblind (see MBNL1; <a href="/entry/606516">606516</a>), a gene implicated in the RNA toxicity of CUG expansion diseases. Upregulation of muscleblind enhanced ATXN3 toxicity. Altering the ATXN3 repeat sequence to an interrupted CAACAG repeat within the polyQ-encoding region resulted in dramatically mitigated toxicity in flies. Expressing an untranslated CAG repeat of pathogenic length in flies resulted neuronal degeneration. <a href="#18" class="mim-tip-reference" title="Li, L.-B., Yu, Z., Teng, X., Bonini, N. M. <strong>RNA toxicity is a component of ataxin-3 degeneration in Drosophila.</strong> Nature 453: 1107-1111, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18449188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18449188</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18449188[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature06909" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18449188">Li et al. (2008)</a> concluded that these studies reveal a role for RNA in polyQ toxicity, highlighting common components in RNA-based and polyQ protein-based trinucleotide repeat expansion diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18449188" 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>To gain insight into the significance of ataxin-3 cleavage, <a href="#15" class="mim-tip-reference" title="Jung, J., Xu, K., Lessing, D., Bonini, N. M. <strong>Preventing ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3.</strong> Hum. Molec. Genet. 18: 4843-4852, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19783548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19783548</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19783548[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/ddp456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19783548">Jung et al. (2009)</a> developed a Drosophila SL2 cell-based model as well as transgenic fly models of SCA3. Ataxin-3 protein cleavage was conserved in the fly and may be caspase-dependent as reported previously. Comparison of flies expressing either wildtype or caspase-site mutant proteins indicated that ataxin-3 cleavage enhanced neuronal loss in vivo. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19783548" 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>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=607047[MIM]" class="btn btn-default mim-tip-hint" role="button" 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>
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<strong>.0001 MACHADO-JOSEPH DISEASE</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">rs193922928 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs193922928;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=rs193922928" 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=rs193922928" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>Machado-Joseph disease (<a href="/entry/109150">109150</a>), also known as spinocerebellar ataxia-3, results from an expansion of a (CAG)n repeat in the ATXN3 gene. In normal individuals, the gene contains between 13 and 36 CAG repeats, whereas most patients with clinically diagnosed MJD and all of the affected members of a family with clinical and pathologic MJD showed expansion of the repeat number in the range of 68 to 79 copies (<a href="#16" class="mim-tip-reference" title="Kawaguchi, Y., Okamoto, T., Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., Kimura, J., Narumiya, S., Kakizuka, A. <strong>CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.</strong> Nature Genet. 8: 221-228, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874163</a>] [<a href="https://doi.org/10.1038/ng1194-221" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7874163">Kawaguchi et al., 1994</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Susceptibility to Late-Onset Parkinson Disease</p><p>In a family of African descent in which 3 members presented with phenotypic features reminiscent of typical Parkinson disease (<a href="/entry/168600">168600</a>), Gwinn-Hardy et al. (2001) identified pathogenic expansions in the ATXN3 gene. Features suggestive of PD included bradykinesis, facial masking, rigidity, postural instability, shuffling, asymmetric onset, dopamine responsiveness, and lack of atypical features often associated with SCA3. A fourth, mildly symptomatic patient also carried the repeat expansion. The authors suggested that the low numbers of repeats in this family (67-75; normal, 16-34) presenting with parkinsonism may be associated with ethnic background and that evaluation for SCA3 should be considered in similar cases.</p>
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Hum. Molec. Genet. 19: 2380-2394, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20308049/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20308049</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20308049" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Alves, S., Regulier, E., Nascimento-Ferreira, I., Hassig, R., Dufour, N., Koeppen, A., Carvalho, A. L., Simoes, S., Pedroso de Lima, M. C., Brouillet, E., Gould, V. C., Deglon, N., de Almeida, L. P.
|
|
<strong>Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease.</strong>
|
|
Hum. Molec. Genet. 17: 2071-2083, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18385100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18385100</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18385100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddn106" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
<a id="Araujo2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Araujo, J., Breuer, P., Dieringer, S., Krauss, S., Dorn, S., Zimmermann, K., Pfeifer, A., Klockgether, T., Wuellner, U., Evert, B. O.
|
|
<strong>FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3.</strong>
|
|
Hum. Molec. Genet. 20: 2928-2941, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21536589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21536589</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21536589" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddr197" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
<a id="Ashkenazi2017" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ashkenazi, A., Bento, C. F., Ricketts, T., Vicinanza, M., Siddiqi, F., Pavel, M., Squitieri, F., Hardenberg, M. C., Imarisio, S., Menzies, F. M., Rubinsztein, D. C.
|
|
<strong>Polyglutamine tracts regulate beclin 1-dependent autophagy.</strong>
|
|
Nature 545: 108-111, 2017.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28445460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28445460</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28445460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature22078" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="5" class="mim-anchor"></a>
|
|
<a id="Boy2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Boy, J., Schmidt, T., Wolburg, H., Mack, A., Nuber, S., Bottcher, M., Schmitt, I., Holzmann, C., Zimmermann, F., Servadio, A., Riess, O.
|
|
<strong>Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3.</strong>
|
|
Hum. Molec. Genet. 18: 4282-4295, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19666958/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19666958</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19666958" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddp381" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="6" class="mim-anchor"></a>
|
|
<a id="Burnett2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Burnett, B., Li, F., Pittman, R. N.
|
|
<strong>The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity.</strong>
|
|
Hum. Molec. Genet. 12: 3195-3205, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14559776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14559776</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14559776" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddg344" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
|
<a id="Cemal2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Cemal, C. K., Carroll, C. J., Lawrence, L., Lowrie, M. B., Ruddle, P., Al-Mahdawi, S., King, R. H. M., Pook, M. A., Huxley, C., Chamberlain, S.
|
|
<strong>YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit.</strong>
|
|
Hum. Molec. Genet. 11: 1075-1094, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11978767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11978767</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11978767" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/11.9.1075" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
|
<a id="Doss-Pepe2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Doss-Pepe, E. W., Stenroos, E. S., Johnson, W. G., Madura, K.
|
|
<strong>Ataxin-3 interactions with Rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis.</strong>
|
|
Molec. Cell. Biol. 23: 6469-6483, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12944474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12944474</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12944474[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12944474" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1128/MCB.23.18.6469-6483.2003" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="9" class="mim-anchor"></a>
|
|
<a id="Evert1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Evert, B. O., Wullner, U., Schulz, J. B., Weller, M., Groscurth, P., Trottier, Y., Brice, A., Klockgether, T.
|
|
<strong>High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells.</strong>
|
|
Hum. Molec. Genet. 8: 1169-1176, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10369861/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10369861</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10369861" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/8.7.1169" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="10" class="mim-anchor"></a>
|
|
<a id="Gaspar2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Gaspar, C., Jannatipour, M., Dion, P., Laganiere, J., Sequeiros, J., Brais, B., Rouleau, G. A.
|
|
<strong>CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation.</strong>
|
|
Hum. Molec. Genet. 9: 1957-1966, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10942424/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10942424</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10942424" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/9.13.1957" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="11" class="mim-anchor"></a>
|
|
<a id="Goto1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Goto, J., Watanabe, M., Ichikawa, Y., Yee, S.-B., Ihara, N., Endo, K., Igarashi, S., Takiyama, Y., Gaspar, C., Maciel, P., Tsuji, S., Rouleau, G. A., Kanazawa, I.
|
|
<strong>Machado-Joseph disease gene products carrying different carboxyl termini.</strong>
|
|
Neurosci. Res. 28: 373-377, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9274833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9274833</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9274833" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0168-0102(97)00056-4" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Haacke2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Haacke, A., Broadley, S. A., Boteva, R., Tzvetkov, N., Hartl, F. U., Breuer, P.
|
|
<strong>Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3.</strong>
|
|
Hum. Molec. Genet. 15: 555-568, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16407371/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16407371</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16407371" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddi472" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Ichikawa2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ichikawa, Y., Goto, J., Hattori, M., Toyoda, A., Ishii, K., Jeong, S.-Y., Hashida, H., Masuda, N., Ogata, K., Kasai, F., Hirai, M., Maciel, P., Rouleau, G. A., Sakaki, Y., Kanazawa, I.
|
|
<strong>The genomic structure and expression of MJD, the Machado-Joseph disease gene.</strong>
|
|
J. Hum. Genet. 46: 413-422, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11450850/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11450850</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11450850" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1007/s100380170060" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Jung2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Jung, J., Bonini, N.
|
|
<strong>CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease.</strong>
|
|
Science 315: 1857-1859, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332375</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17332375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1139517" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Jung2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Jung, J., Xu, K., Lessing, D., Bonini, N. M.
|
|
<strong>Preventing ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3.</strong>
|
|
Hum. Molec. Genet. 18: 4843-4852, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19783548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19783548</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19783548[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19783548" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1093/hmg/ddp456" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Kawaguchi1994" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Kawaguchi, Y., Okamoto, T., Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., Kimura, J., Narumiya, S., Kakizuka, A.
|
|
<strong>CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.</strong>
|
|
Nature Genet. 8: 221-228, 1994.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7874163/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7874163</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7874163" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ng1194-221" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Koch2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Koch, P., Breuer, P., Peitz, M., Jungverdorben, J., Kesavan, J., Poppe, D., Doerr, J., Ladewig, J., Mertens, J., Tuting, T., Hoffmann, P., Klockgether, T., Evert, B. O., Wullner, U., Brustle, O.
|
|
<strong>Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease.</strong>
|
|
Nature 480: 543-546, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22113611/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22113611</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22113611" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/nature10671" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="Li2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Li, L.-B., Yu, Z., Teng, X., Bonini, N. M.
|
|
<strong>RNA toxicity is a component of ataxin-3 degeneration in Drosophila.</strong>
|
|
Nature 453: 1107-1111, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18449188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18449188</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18449188[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18449188" 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/nature06909" target="_blank">Full Text</a>]
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|
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|
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|
|
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|
|
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|
|
<a id="Li2004" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Li, Y., Yokota, T., Matsumura, R., Taira, K., Mizusawa, H.
|
|
<strong>Sequence-dependent and independent inhibition specific for mutant ataxin-3 by small interfering RNA.</strong>
|
|
Ann. Neurol. 56: 124-129, 2004.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15236410/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15236410</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15236410" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
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[<a href="https://doi.org/10.1002/ana.20141" target="_blank">Full Text</a>]
|
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|
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|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Martins2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Martins, S., Calafell, F., Wong, V. C. N., Sequeiros, J., Amorim, A.
|
|
<strong>A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus.</strong>
|
|
Europ. J. Hum. Genet. 14: 932-940, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16724006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16724006</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16724006" 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/sj.ejhg.5201643" target="_blank">Full Text</a>]
|
|
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|
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|
|
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|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Miller2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Miller, V. M., Xia, H., Marrs, G. L., Gouvion, C. M., Lee, G., Davidson, B. L., Paulson, H. L.
|
|
<strong>Allele-specific silencing of dominant disease genes.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 7195-7200, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12782788/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12782788</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12782788[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12782788" 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/10.1073/pnas.1231012100" target="_blank">Full Text</a>]
|
|
|
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|
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|
|
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|
|
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|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Mueller2009" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Mueller, T., Breuer, P., Schmitt, I., Walter, J., Evert, B. O., Wullner, U.
|
|
<strong>CK2-dependent phosphorylation determines cellular localization and stability of ataxin-3.</strong>
|
|
Hum. Molec. Genet. 18: 3334-3343, 2009.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19542537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19542537</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19542537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
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|
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|
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[<a href="https://doi.org/10.1093/hmg/ddp274" target="_blank">Full Text</a>]
|
|
|
|
|
|
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|
|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Paulson1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Paulson, H. L., Das, S. S., Crino, P. B., Perez, M. K., Patel, S. C., Gotsdiner, D., Fischbeck, K. H., Pittman, R. N.
|
|
<strong>Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain.</strong>
|
|
Ann. Neurol. 41: 453-462, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9124802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9124802</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9124802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
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|
|
[<a href="https://doi.org/10.1002/ana.410410408" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Paulson1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Paulson, H. L., Perez, M. K., Trottier, Y., Trojanowski, J. Q., Subramony, S. H., Das, S. S., Vig, P., Mandel, J. L., Fischbeck, K. H., Pittman, R. N.
|
|
<strong>Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3.</strong>
|
|
Neuron 19: 333-344, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9292723/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9292723</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9292723" 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/s0896-6273(00)80943-5" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="25" class="mim-anchor"></a>
|
|
<a id="Reina2010" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Reina, C. P., Zhong, X., Pittman, R. N.
|
|
<strong>Proteotoxic stress increases nuclear localization of ataxin-3.</strong>
|
|
Hum. Molec. Genet. 19: 235-249, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19843543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19843543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19843543[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19843543" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
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|
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|
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[<a href="https://doi.org/10.1093/hmg/ddp482" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="26" class="mim-anchor"></a>
|
|
<a id="Scheel2003" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Scheel, H., Tomiuk, S., Hofmann, K.
|
|
<strong>Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics.</strong>
|
|
Hum. Molec. Genet. 12: 2845-2852, 2003.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12944423/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12944423</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12944423" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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|
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[<a href="https://doi.org/10.1093/hmg/ddg297" target="_blank">Full Text</a>]
|
|
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|
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</p>
|
|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="27" class="mim-anchor"></a>
|
|
<a id="Schmitt1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schmitt, I., Brattig, T., Gossen, M., Riess, O.
|
|
<strong>Characterization of the rat spinocerebellar ataxia type 3 gene.</strong>
|
|
Neurogenetics 1: 103-112, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10732811/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10732811</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10732811" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
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|
|
[<a href="https://doi.org/10.1007/s100480050015" target="_blank">Full Text</a>]
|
|
|
|
|
|
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|
|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="28" class="mim-anchor"></a>
|
|
<a id="Tait1998" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Tait, D., Riccio, M., Sittler, A., Scherzinger, E., Santi, S., Ognibene, A., Maraldi, N. M., Lehrach, H., Wanker, E. E.
|
|
<strong>Ataxin-3 is transported into the nucleus and associates with the nuclear matrix.</strong>
|
|
Hum. Molec. Genet. 7: 991-997, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9580663/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9580663</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9580663" 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/7.6.991" target="_blank">Full Text</a>]
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|
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|
|
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|
|
|
|
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|
|
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|
|
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|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Toulouse, A., Au-Yeung, F., Gaspar, C., Roussel, J., Dion, P., Rouleau, G. A.
|
|
<strong>Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts.</strong>
|
|
Hum. Molec. Genet. 14: 2649-2660, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16087686/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16087686</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16087686" 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/ddi299" target="_blank">Full Text</a>]
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|
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|
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|
|
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|
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|
|
<div class="">
|
|
<p class="mim-text-font">
|
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Wang, G., Sawai, N., Kotliarova, S., Kanazawa, I., Nukina, N.
|
|
<strong>Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B.</strong>
|
|
Hum. Molec. Genet. 9: 1795-1803, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10915768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10915768</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10915768" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/9.12.1795" target="_blank">Full Text</a>]
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|
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|
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|
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|
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Warrick, J. M., Morabito, L. M., Bilen, J., Gordesky-Gold, B., Faust, L. Z., Paulson, H. L., Bonini, N. M.
|
|
<strong>Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism.</strong>
|
|
Molec. Cell 18: 37-48, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15808507/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15808507</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15808507" 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.molcel.2005.02.030" target="_blank">Full Text</a>]
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|
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Winborn, B. J., Travis, S. M., Todi, S. V., Scaglione, K. M., Xu, P., Williams, A. J., Cohen, R. E., Peng, J., Paulson, H. L.
|
|
<strong>The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits lys63 linkages in mixed linkage ubiquitin chains.</strong>
|
|
J. Biol. Chem. 283: 26436-26443, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18599482/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18599482</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18599482[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18599482" 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/10.1074/jbc.M803692200" target="_blank">Full Text</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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Ada Hamosh - updated : 04/03/2018
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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 : 08/05/2013<br>Patricia A. Hartz - updated : 4/10/2013<br>Ada Hamosh - updated : 2/7/2012<br>George E. Tiller - updated : 12/29/2010<br>George E. Tiller - updated : 11/1/2010<br>George E. Tiller - updated : 10/4/2010<br>George E. Tiller - updated : 7/7/2010<br>Patricia A. Hartz - updated : 12/8/2009<br>Patricia A. Hartz - updated : 11/11/2009<br>George E. Tiller - updated : 12/9/2008<br>Ada Hamosh - updated : 7/9/2008<br>Ada Hamosh - updated : 4/12/2007<br>Cassandra L. Kniffin - updated : 9/25/2006<br>George E. Tiller - updated : 1/31/2006<br>Patricia A. Hartz - updated : 5/4/2005<br>Cassandra L. Kniffin - updated : 7/27/2004<br>Victor A. McKusick - updated : 7/14/2003<br>George E. Tiller - updated : 12/16/2002
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Cassandra L. Kniffin : 6/19/2002
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 11/01/2019
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alopez : 04/03/2018<br>alopez : 08/05/2013<br>alopez : 8/5/2013<br>mgross : 4/10/2013<br>mgross : 1/29/2013<br>alopez : 2/8/2012<br>terry : 2/7/2012<br>wwang : 1/11/2011<br>terry : 12/29/2010<br>ckniffin : 11/16/2010<br>alopez : 11/5/2010<br>terry : 11/1/2010<br>wwang : 10/21/2010<br>terry : 10/4/2010<br>terry : 9/9/2010<br>wwang : 7/21/2010<br>terry : 7/7/2010<br>mgross : 1/12/2010<br>terry : 12/8/2009<br>mgross : 11/16/2009<br>terry : 11/11/2009<br>wwang : 12/9/2008<br>wwang : 7/17/2008<br>terry : 7/9/2008<br>alopez : 4/13/2007<br>terry : 4/12/2007<br>wwang : 9/26/2006<br>ckniffin : 9/25/2006<br>wwang : 2/7/2006<br>terry : 1/31/2006<br>mgross : 6/6/2005<br>terry : 5/4/2005<br>tkritzer : 11/8/2004<br>tkritzer : 7/28/2004<br>ckniffin : 7/27/2004<br>tkritzer : 7/23/2003<br>terry : 7/14/2003<br>cwells : 12/16/2002<br>carol : 6/21/2002<br>ckniffin : 6/21/2002
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<span class="mim-font">
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<strong>*</strong> 607047
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ATAXIN 3; ATXN3
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<em>Alternative titles; symbols</em>
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AT3<br />
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MJD GENE; MJD1<br />
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SCA3 GENE
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<strong><em>HGNC Approved Gene Symbol: ATXN3</em></strong>
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<strong>SNOMEDCT:</strong> 91952008;
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Cytogenetic location: 14q32.12
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Genomic coordinates <span class="small">(GRCh38)</span> : 14:92,044,775-92,106,582 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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14q32.12
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{Parkinson disease, late-onset, susceptibility to}
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168600
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Autosomal dominant; Multifactorial
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3
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Machado-Joseph disease
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109150
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>ATXN3 has deubiquitinase activity and appears to be a component of the ubiquitin proteasome system. It may also have roles in transcriptional regulation and neuroprotection (summary by Haacke et al., 2006). </p>
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<strong>Cloning and Expression</strong>
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<p>To identify the gene affected by CAG expansion in Machado-Joseph disease (MJD; 109150), Kawaguchi et al. (1994) isolated a cDNA with a CAG repeat from a human brain cDNA library using an oligonucleotide probe with 13 CTG repeats, complementary to the CAG repeats. The cDNA, which they designated MJD1, encodes a deduced 359-amino acid protein. </p><p>Goto et al. (1997) obtained 3 ATXN3 cDNAs from a human brain cDNA library. Two of the cDNAs represent an ATXN3 variant that differs from the cDNA reported by Kawaguchi et al. (1994) in splicing of the 3-prime exons, resulting in a different C-terminal sequence in the protein. The third cDNA has a stop codon polymorphism that results in additional C-terminal amino acids. The deduced ATXN3 proteins, which range in size from 360 to 374 amino acids, differ only at their C termini and in the number of glutamines in the polyglutamine (polyQ) tract. </p><p>Schmitt et al. (1997) isolated rat Atxn3. They found that the rat and human ATXN3 genes are highly homologous, with an overall sequence identity of approximately 88%. However, the C-terminal end of the putative rat protein differs strongly from the human sequence published by Kawaguchi et al. (1994). The (CAG)n block in the rat cDNA consists of only 3 interrupted units, suggesting that a long polyQ stretch is not essential for normal function of the Atxn3 protein in rodents. Transcription of rat Atxn3 was detected in most rat tissues, including brain. In human brain sections, Schmitt et al. (1997) did not find significantly higher ATXN3 mRNA levels in regions predominantly affected in MJD, suggesting that additional molecules and/or regulatory events are necessary to explain the exclusive degeneration of certain brain areas in MJD. </p><p>Using immunohistochemistry of normal and MJD brain, Paulson et al. (1997) showed that expression of ATXN3 was restricted to a limited subset of neurons, particularly to those in the striatum. In normal and diseased brain and in transfected cells, immunolocalization studies revealed that ATXN3 was predominantly a cytoplasmic protein that localized to neuronal processes as well. </p><p>Tait et al. (1998) studied the subcellular localization of full-length ataxin-3 protein with a glutamine sequence in the normal range in 2 mammalian cell lines. By immunofluorescence and confocal laser scanning microscopy, and by biochemical subcellular fractionations, they detected the protein predominantly, but not exclusively, in the nucleus. The ataxin-3 present in the nucleus of neuroblastoma cells associated with the inner nuclear matrix. The authors concluded that the ataxin-3 protein, which contains a putative nuclear localization signal very close to the glutamine tract, per se has the ability to be transported into the nucleus and that an expanded glutamine repeat is not essential for this transport. </p><p>Using Northern blot analysis, Ichikawa et al. (2001) showed that ATXN3 mRNA was ubiquitously expressed in human tissues. They detected at least 4 ATXN3 transcripts of 1.4, 1.8, 4.5, and 7.5 kb and suggested that the different mRNA species probably result from differential splicing and polyadenylation. </p><p>Burnett et al. (2003) stated that the major human AT3 isoform contains an N-terminal deubiquitinating domain, called the Josephin domain, followed by 2 ubiquitin-interacting motifs (UIMs) and a polyQ tract near the C terminus. In some isoforms, the polyQ tract is followed by a third UIM. Burnett et al. (2003) identified a catalytic triad of cys14, his119, and asn134 and other highly conserved residues within the Josephin domain of AT3. </p>
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<strong>Gene Structure</strong>
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<p>Ichikawa et al. (2001) determined that the ATXN3 gene spans 48,240 bp and contains 11 exons. </p>
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<strong>Mapping</strong>
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<p>By FISH, Kawaguchi et al. (1994) mapped the ATXN3 gene to chromosome 14q32.1. </p>
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<strong>Gene Function</strong>
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<p>Using a 2-hybrid system, Wang et al. (2000) found that ataxin-3 interacted with 2 human homologs of the yeast DNA repair protein RAD23, HHR23A (RAD23A; 600061) and HHR23B (RAD23B; 600062). Both normal and mutant ataxin-3 proteins interacted with the ubiquitin-like domain at the N terminus of the HHR23 proteins, which is a motif important for nucleotide excision repair. However, in HEK 293 cells, HHR23A was recruited to intranuclear inclusions formed by the mutant ataxin-3 (see MOLECULAR GENETICS) through its interaction with ataxin-3. The authors suggested that this interaction may be associated with the normal function of ataxin-3, and that some functional abnormality of the HHR23 proteins may exist in MJD. </p><p>By combining profile-based sequence analysis with genomewide functional data in model organisms, Scheel et al. (2003) determined that ataxin-3 belongs to a novel group of cysteine proteases and is predicted to be active against ubiquitin chains or related substrates. The catalytic site of this enzyme class is similar to that found in UBP (see USP1; 603478)- and UCH (see UCHL3; 603090)-type ubiquitin proteases. They suggested the finding had implications for disease pathogenesis by providing a direct connection between SCA3 and ubiquitin metabolism. </p><p>Doss-Pepe et al. (2003) showed that both normal and polyQ-expanded human ATXN3 associated with a number of proteasome subunits and with ubiquitinated proteins. Truncation analysis showed that the UIMs of ATXN3 bound polyubiquitin, but other factors in the full-length protein increased the affinity of ATXN3 for polyubiquitin. Both normal and polyQ-expanded ATXN3 inhibited formation of ubiquitin-conjugated histone H2B (see 609904). </p><p>Burnett et al. (2003) showed that the UIM domain of AT3 bound ubiquitin chains containing 4 or more ubiquitin units, the chain length required for proteasome degradation. PolyQ-expanded AT3 showed similar binding to ubiquitin chains. Both wildtype and pathologic AT3 also decreased the degree of polyubiquitination of the test protein, iodinated lysosome, suggesting that AT3 is a ubiquitin protease. AT3 was sensitive to a specific ubiquitin protease inhibitor. Mutation of cys14 within the Josephin domain to alanine reduced the ability of AT3 to remove polyubiquitin chains from iodinated lysosome. </p><p>Winborn et al. (2008) showed that human ATXN3 bound both lys48- and lys63-linked polyubiquitin chains, but preferentially cleaved lys63 linkages. ATXN3 showed greater activity toward mixed-linkage polyubiquitin, cleaving lys63 linkages in chains that contained both lys48 and lys63 linkages. PolyQ expansion did not alter the binding or catalytic properties of ATXN3. The authors concluded that ATXN3 is a mixed-linkage, chain-editing enzyme and that the UIM region of ATXN3 regulates its substrate specificity. </p><p>Mueller et al. (2009) showed that protein casein kinase-2 (CK2; see 115440)-dependent phosphorylation controlled the nuclear localization, aggregation, and stability of ataxin-3. Ser340 and ser352 within the third ubiquitin-interacting motif of ATXN3 were particularly important for nuclear localization of normal and expanded ATXN3, and mutation of these sites robustly reduced the formation of nuclear inclusions. A putative nuclear leader sequence was not required. ATXN3 associated with CK2-alpha (CSNK2A1; 115440), and pharmacologic inhibition of CK2 decreased nuclear ATXN3 levels and the formation of nuclear inclusions. ATXN3 shifted to the nucleus upon thermal stress in a CK2-dependent manner, suggesting a key role of CK2-mediated phosphorylation of ATXN3 in SCA3 pathophysiology. </p><p>Reina et al. (2010) showed that interactions of ATXN3 with valosin-containing protein (VCP; 601023) and HHR23B were dynamic and modulated by proteotoxic stresses. Heat shock, a general proteotoxic stress, also induced wildtype and pathogenic ATXN3 to accumulate in the nucleus. Mapping studies showed that 2 regions of ATXN3, the Josephin domain and the C terminus, regulated heat shock-induced nuclear localization. Atxn3-null mouse cells were more sensitive to toxic effects of heat shock, suggesting that ATXN3 had a protective function in the cellular response to heat shock. Oxidative stress also induced nuclear localization of ATXN3; both wildtype and pathogenic ATXN3 accumulated in the nucleus of SCA3 patient fibroblasts following oxidative stress. Heat shock and oxidative stress were the first processes identified that increased nuclear localization of ATXN3. Reina et al. (2010) suggested that the nucleus may be a key site for early pathogenesis of SCA3. </p><p>Koch et al. (2011) showed that L-glutamate-induced excitation of patient-specific induced pluripotent stem cell (iPSC)-derived neurons initiates calcium-dependent proteolysis of ATXN3 followed by the formation of SDS-insoluble aggregates. This phenotype could be abolished by calpain (see 114220) inhibition, confirming a key role of this protease in ATXN3 aggregation. Aggregate formation was further dependent on functional sodium and potassium channels as well as ionotropic and voltage-gated calcium channels, and was not observed in iPSCs, fibroblasts, or glia, thereby providing an explanation for the neuron-specific phenotype of Machado-Joseph disease. Koch et al. (2011) concluded that iPSCs enable the study of aberrant protein processing associated with late-onset neurodegenerative disorders in patient-specific neurons. </p><p>Using immunoprecipitation analysis and protein pull-down studies, Araujo et al. (2011) found that endogenous ATXN3 interacted directly with the transcription factor FOXO4 (300033) in nuclear extracts of HeLa cells, rat CSM14.1 mesencephalic cells, and mouse brain. The interaction required the N-terminal Josephin domain of ATXN3. Expression of ATXN3 enhanced FOXO4-dependent expression of the antioxidant enzyme SOD2 (147460) in a manner independent of ATXN3 deubiquitinase activity. Treatment of HeLa cells with H2O2 induced nuclear translocation of FOXO4 and ATXN3, enhanced binding of FOXO4 and ATXN3 to the SOD2 promoter, and induced SOD2 expression. Coexpression of mutant ATXN3 with an expanded polyglutamine tract or knockdown of ATXN3 via short hairpin RNA reduced FOXO4 nuclear translocation and induction of SOD2. Lymphocytes from SCA3 patients exposed to oxidative stress showed reduced binding of FOXO4 to the SOD2 promoter, concomitant with impaired upregulation of SOD2 and enhanced oxidative cytotoxicity. Araujo et al. (2011) concluded that ATXN3 stabilizes FOXO4 and acts as a transcriptional coactivator with FOXO4 in the oxidative stress response. </p><p>Ashkenazi et al. (2017) demonstrated that the polyQ domain of ATXN3 enables it to interact with beclin-1 (BECN1; 604378), a key initiator of autophagy. This interaction allows the deubiquitinase activity of ATXN3 to protect BECN1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by BECN1, was particularly inhibited in ATXN3-depleted human cell lines and mouse primary neurons, and in vivo in mice. This activity of ATXN3 and its polyQ-mediated interaction with BECN1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin (613004) exon 1 with an expanded polyQ region, and this impairment was recapitulated in the brains of a mouse model of Huntington disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ATXN3 itself. Ashkenazi et al. (2017) concluded that their data described a specific function for a wildtype polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identified a deleterious function of such mutations distinct from their propensity to aggregate. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>CAG Expansion in ATXN3 in Machado-Joseph Disease</em></strong></p><p>
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In 8 of 9 patients with clinically diagnosed MJD, Kawaguchi et al. (1994) identified CAG expansions of between 68 to 79 in the ATXN3 gene (607047.0001). In normal individuals, the ATXN3 gene was found to contain between 13 and 36 CAG repeats. </p><p>Kawaguchi et al. (1994) found a negative correlation between age of onset and CAG repeat numbers. Southern blot analyses and genomic cloning demonstrated the existence of related genes and raised the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD. </p><p><strong><em>Pathogenic Effects of Polyglutamine Expansion in ATXN3</em></strong></p><p>
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Paulson et al. (1997) showed that ATXN3 with a polyglutamine sequence in the pathologic range accumulated in ubiquitinated intranuclear inclusions selectively in neurons of affected brain regions. They provided evidence in vitro for a model of disease in which an expanded polyglutamine-containing fragment recruits full-length protein into insoluble aggregates. </p><p>Evert et al. (1999) generated ataxin-3-expressing rat mesencephalic CSM14.1 cells to study the effects of long-term expression of ataxin-3. The isolated stable cell lines provided high level expression of human full-length ataxin-3 with either the normal nonexpanded CAG repeats (SCA3-Q23) or the pathogenic expanded CAG repeats (SCA3-Q70). When cultured at a nonpermissive temperature (39 degrees C), CSM14.1 cells expressing the expanded full-length ataxin-3 developed nuclear inclusion bodies, strong indentations of the nuclear envelope, and cytoplasmic vacuolation, whereas cells expressing the nonexpanded form and control cells did not. The ultrastructural alterations resembled those found in affected neurons of SCA3 patients. Cells with such changes exhibited increased spontaneous nonapoptotic cell death. </p><p>Gaspar et al. (2000) explored the possibility that frameshift mutations in expanded CAG tracts of ATXN3 can generate polyalanine mutant proteins and form intranuclear inclusions. Antisera were raised against a synthetic peptide corresponding to the C terminus of ATXN3, which would result from a frameshift within the CAG repeat motif with an intervening polyalanine stretch. Corresponding proteins were evident in MJD patients by Western blot analysis of lymphoblastoid proteins and in situ hybridization of MJD pontine neurons. Transfection experiments suggested that frameshifts are more likely to occur in longer CAG repeats and that alanine polymers alone may be harmful to cells. The authors suggested that a similar pathogenic mechanism may occur in other CAG repeat disorders. </p><p>Toulouse et al. (2005) established a cellular model of transcript frameshifting of expanded CAG tracts, resulting from ribosomal slippage to the -1 frame exclusively. Ribosomal frameshifting depended on the presence of long CAG tracts, and polyalanine-frameshifted proteins may enhance polyglutamine-associated toxicity, possibly contributing to pathogenesis. Anisomycin, a ribosome-interacting drug that reduces -1 frameshifting, also reduced toxicity, suggesting a therapeutic opportunity for these disorders. </p><p>Haacke et al. (2006) found that full-length recombinant human AT3 formed detergent-resistant fibrillar aggregates in vitro with extremely low efficiency, even when it contained a pathogenic polyQ tract of 71 residues (AT3Q71). However, an N-terminally truncated form, called 257cQ71, which began with residue 257 and contained only the C terminus with an expanded polyQ region, readily formed detergent-insoluble aggregates and recruited full-length nonpathogenic AT3Q22 into the aggregates. The efficiency of recruitment increased with expansion of the polyQ stretch. FRET analysis revealed that the interaction of AT3Q22 with the polyQ tract of 257cQ71 caused a conformational change that affected the active-site cysteine within the Josephin domain of AT3Q22. Similar results were found in vivo with transfected mouse neuroblastoma cells: 257cQ71 formed inclusions in almost all cells, and full-length AT3 proteins did not readily aggregate unless coexpressed with 257cQ71. AT3Q71 also formed inclusions, but it appeared to do so following its partial degradation. Use of an engineered protease-sensitive form of AT3 suggested that release of expanded polyQ fragments initiates the formation of cellular inclusions. Haacke et al. (2006) concluded that recruitment of functional AT3 into aggregates by expanded polyQ-containing fragments reduces cellular AT3 content and thus impairs its function. </p><p><strong><em>Suppression of Mutant ATXN3</em></strong></p><p>
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In animal cell models, Miller et al. (2003) demonstrated that allele-specific silencing of disease genes with small interfering RNA (siRNA) could be achieved by targeting either a linked SNP or the disease mutation directly. They determined that selective targeting of the disease-causing CAG repeat in the ATXN3 gene was not possible and then took advantage of an associated SNP to generate siRNA that exclusively silenced the mutant ATXN3 allele while sparing expression of the wildtype allele. Allele-specific suppression was accomplished with all 3 siRNA delivery approaches in use at the time: in vitro-synthesized duplexes and plasmid and viral expression of short hairpin RNA. </p><p>In vitro, Li et al. (2004) found that an siRNA targeted to a C/G polymorphism immediately after the CAG repeat that is expanded in MJD effectively suppressed expression of mutant ataxin-3 (79 repeats) by 96% without significant effect on the wildtype protein. In addition, siRNA decreased cell death by 63 to 76%. </p><p><strong><em>Susceptibility to Late-Onset Parkinson Disease</em></strong></p><p>
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In a family of African descent in which 3 members presented with phenotypic features reminiscent of typical Parkinson disease (168600), Gwinn-Hardy et al. (2001) identified pathogenic expansions in the ATXN3 gene. Features suggestive of PD included bradykinesis, facial masking, rigidity, postural instability, shuffling, asymmetric onset, dopamine responsiveness, and lack of atypical features often associated with SCA3. A fourth, mildly symptomatic patient also carried the repeat expansion. The authors suggested that the low numbers of repeats in this family (67-75; normal, 16-34) presenting with parkinsonism may be associated with ethnic background and that evaluation for SCA3 should be considered in similar cases.</p>
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</span>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Evolution</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By comparing wildtype haplotypes encompassing the ATXN3 CAG repeat in 431 chromosomes of European, Asian, and African origin, Martins et al. (2006) concluded that the main mutation mechanism occurring in the evolution of the polymorphic CAG repeat is a multistep process resulting from gene conversion or DNA slippage, as opposed to a stepwise process. The 4 most frequent haplotypes showed a bimodal CAG repeat length frequency distribution, particularly in the European population, and genetic distances among all the alleles from each population did not reflect allele size differences. </p>
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</span>
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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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<span class="mim-text-font">
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<p><strong><em>Transgenic Rodent Models of Machado-Joseph Disease</em></strong></p><p>
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Cemal et al. (2002) generated transgenic mice by introducing pathologic ATXN3 alleles with polyglutamine tract lengths of 64, 67, 72, 76, and 84 repeats, as well as the wildtype with 15 repeats. The mice with expanded alleles demonstrated a mild and slowly progressive cerebellar deficit, manifesting as early as 4 weeks of age. As the disease progressed, pelvic elevation became markedly flattened and was accompanied by hypotonia and motor and sensory loss. Neuronal intranuclear inclusion formation and cell loss was prominent in the pontine and dentate nuclei, with variable cell loss in other regions of the cerebellum from 4 weeks of age. Peripheral nerve demyelination and axonal loss was also detected in symptomatic mice from 26 weeks of age. In contrast, transgenic mice carrying the wildtype (CAG)15 allele of the ATXN3 locus appeared completely normal at 20 months. Disease severity increased with the level of expression of the expanded protein and the size of the repeat. </p><p>Boy et al. (2009) generated a conditional mouse model of SCA3. Transgenic mice developed a progressive neurologic phenotype characterized by neuronal dysfunction in the cerebellum, reduced anxiety, hyperactivity, impaired performance on the rotarod test, and lower body weight gain. When mutant ataxin-3 expression was turned off in symptomatic mice in an early disease state, the transgenic mice were indistinguishable from negative controls after 5 months of treatment. Boy et al. (2009) concluded that reducing the production of pathogenic ataxin-3 may be a promising approach to treat SCA3, provided that such treatment is applied before irreversible damage has taken place and that it is continued for a sufficiently long time. </p><p>Alves et al. (2010) both overexpressed and silenced wildtype ATX3 in the rat model of MJD developed by Alves et al. (2008). They found that overexpression of wildtype ATX3 did not protect against MJD pathology, that knockdown of wildtype ATX3 did not aggravate MJD pathology, and that non-allele-specific silencing of ataxin-3 strongly reduced neuropathology. </p><p><strong><em>Transgenic Drosophila Models of Machado-Joseph Disease</em></strong></p><p>
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Warrick et al. (2005) expressed normal and pathogenic forms of human ATXN3 in Drosophila and found that the normal activity of ATXN3 mitigated polyQ-induced neurodegeneration. When both normal and pathogenic proteins were expressed together throughout the nervous system, flies lived longer and showed improved brain cortical structure compared with flies expressing only the pathogenic protein. Normal ATXN3 reduced accumulation of pathogenic ATXN3 and of other polyQ disease proteins. Mutations in the ubiquitin interaction motif or in the ubiquitin protease domain of ATXN3 abrogated the protective effect. Protection also required proteasome activity, indicating that the normal function of ATXN3 requires the ubiquitin pathway of protein quality control. </p><p>Jung and Bonini (2007) showed that a transgenic Drosophila model for spinocerebellar ataxia type 3 recapitulated key features of human CAG repeat instability, including large repeat changes and strong expansion bias. Instability was dramatically enhanced by transcription and modulated by nuclear excision repair and CREB-binding protein (600140), a histone acetyltransferase whose decreased activity contributes to polyglutamine disease. Pharmacologic treatment normalized acetylation-suppressed instability. Thus, Jung and Bonini (2007) concluded that toxic consequences of pathogenic polyglutamine protein may include enhancing repeat instability. </p><p>Li et al. (2008) provided evidence of a pathogenic role for ATXN3 CAG repeat RNA in polyQ toxicity. In a screen for modifiers of polyQ degeneration induced by ATXN3 in a transgenic Drosophila model, the authors isolated an upregulation allele of muscleblind (see MBNL1; 606516), a gene implicated in the RNA toxicity of CUG expansion diseases. Upregulation of muscleblind enhanced ATXN3 toxicity. Altering the ATXN3 repeat sequence to an interrupted CAACAG repeat within the polyQ-encoding region resulted in dramatically mitigated toxicity in flies. Expressing an untranslated CAG repeat of pathogenic length in flies resulted neuronal degeneration. Li et al. (2008) concluded that these studies reveal a role for RNA in polyQ toxicity, highlighting common components in RNA-based and polyQ protein-based trinucleotide repeat expansion diseases. </p><p>To gain insight into the significance of ataxin-3 cleavage, Jung et al. (2009) developed a Drosophila SL2 cell-based model as well as transgenic fly models of SCA3. Ataxin-3 protein cleavage was conserved in the fly and may be caspase-dependent as reported previously. Comparison of flies expressing either wildtype or caspase-site mutant proteins indicated that ataxin-3 cleavage enhanced neuronal loss in vivo. </p>
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</span>
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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>1 Selected Example):</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 MACHADO-JOSEPH DISEASE</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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PARKINSON DISEASE, LATE-ONSET, SUSCEPTIBILITY TO, INCLUDED
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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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ATXN3, (CAG)n REPEAT EXPANSION
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<br />
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SNP: rs193922928,
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ClinVar: RCV000003729, RCV000003730
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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>Machado-Joseph disease (109150), also known as spinocerebellar ataxia-3, results from an expansion of a (CAG)n repeat in the ATXN3 gene. In normal individuals, the gene contains between 13 and 36 CAG repeats, whereas most patients with clinically diagnosed MJD and all of the affected members of a family with clinical and pathologic MJD showed expansion of the repeat number in the range of 68 to 79 copies (Kawaguchi et al., 1994). </p><p>Susceptibility to Late-Onset Parkinson Disease</p><p>In a family of African descent in which 3 members presented with phenotypic features reminiscent of typical Parkinson disease (168600), Gwinn-Hardy et al. (2001) identified pathogenic expansions in the ATXN3 gene. Features suggestive of PD included bradykinesis, facial masking, rigidity, postural instability, shuffling, asymmetric onset, dopamine responsiveness, and lack of atypical features often associated with SCA3. A fourth, mildly symptomatic patient also carried the repeat expansion. The authors suggested that the low numbers of repeats in this family (67-75; normal, 16-34) presenting with parkinsonism may be associated with ethnic background and that evaluation for SCA3 should be considered in similar cases.</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>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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Alves, S., Nascimento-Ferreira, I., Dufour, N., Hassig, R., Auregan, G., Nobrega, C., Brouillet, E., Hantraye, P., Pedroso de Lima, M. C., Deglon, N., Pereira de Almeida, L.
|
|
<strong>Silencing ataxin-3 mitigates degeneration in a rat model of Machado-Joseph disease: no role for wild-type ataxin-3?</strong>
|
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Hum. Molec. Genet. 19: 2380-2394, 2010.
|
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|
|
|
|
[PubMed: 20308049]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddq111]
|
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|
|
|
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</p>
|
|
</li>
|
|
|
|
<li>
|
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<p class="mim-text-font">
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Alves, S., Regulier, E., Nascimento-Ferreira, I., Hassig, R., Dufour, N., Koeppen, A., Carvalho, A. L., Simoes, S., Pedroso de Lima, M. C., Brouillet, E., Gould, V. C., Deglon, N., de Almeida, L. P.
|
|
<strong>Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease.</strong>
|
|
Hum. Molec. Genet. 17: 2071-2083, 2008.
|
|
|
|
|
|
[PubMed: 18385100]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddn106]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Araujo, J., Breuer, P., Dieringer, S., Krauss, S., Dorn, S., Zimmermann, K., Pfeifer, A., Klockgether, T., Wuellner, U., Evert, B. O.
|
|
<strong>FOXO4-dependent upregulation of superoxide dismutase-2 in response to oxidative stress is impaired in spinocerebellar ataxia type 3.</strong>
|
|
Hum. Molec. Genet. 20: 2928-2941, 2011.
|
|
|
|
|
|
[PubMed: 21536589]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddr197]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ashkenazi, A., Bento, C. F., Ricketts, T., Vicinanza, M., Siddiqi, F., Pavel, M., Squitieri, F., Hardenberg, M. C., Imarisio, S., Menzies, F. M., Rubinsztein, D. C.
|
|
<strong>Polyglutamine tracts regulate beclin 1-dependent autophagy.</strong>
|
|
Nature 545: 108-111, 2017.
|
|
|
|
|
|
[PubMed: 28445460]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature22078]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Boy, J., Schmidt, T., Wolburg, H., Mack, A., Nuber, S., Bottcher, M., Schmitt, I., Holzmann, C., Zimmermann, F., Servadio, A., Riess, O.
|
|
<strong>Reversibility of symptoms in a conditional mouse model of spinocerebellar ataxia type 3.</strong>
|
|
Hum. Molec. Genet. 18: 4282-4295, 2009.
|
|
|
|
|
|
[PubMed: 19666958]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp381]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Burnett, B., Li, F., Pittman, R. N.
|
|
<strong>The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity.</strong>
|
|
Hum. Molec. Genet. 12: 3195-3205, 2003.
|
|
|
|
|
|
[PubMed: 14559776]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddg344]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Cemal, C. K., Carroll, C. J., Lawrence, L., Lowrie, M. B., Ruddle, P., Al-Mahdawi, S., King, R. H. M., Pook, M. A., Huxley, C., Chamberlain, S.
|
|
<strong>YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit.</strong>
|
|
Hum. Molec. Genet. 11: 1075-1094, 2002.
|
|
|
|
|
|
[PubMed: 11978767]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/11.9.1075]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Doss-Pepe, E. W., Stenroos, E. S., Johnson, W. G., Madura, K.
|
|
<strong>Ataxin-3 interactions with Rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis.</strong>
|
|
Molec. Cell. Biol. 23: 6469-6483, 2003.
|
|
|
|
|
|
[PubMed: 12944474]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1128/MCB.23.18.6469-6483.2003]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Evert, B. O., Wullner, U., Schulz, J. B., Weller, M., Groscurth, P., Trottier, Y., Brice, A., Klockgether, T.
|
|
<strong>High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells.</strong>
|
|
Hum. Molec. Genet. 8: 1169-1176, 1999.
|
|
|
|
|
|
[PubMed: 10369861]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/8.7.1169]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gaspar, C., Jannatipour, M., Dion, P., Laganiere, J., Sequeiros, J., Brais, B., Rouleau, G. A.
|
|
<strong>CAG tract of MJD-1 may be prone to frameshifts causing polyalanine accumulation.</strong>
|
|
Hum. Molec. Genet. 9: 1957-1966, 2000.
|
|
|
|
|
|
[PubMed: 10942424]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/9.13.1957]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Goto, J., Watanabe, M., Ichikawa, Y., Yee, S.-B., Ihara, N., Endo, K., Igarashi, S., Takiyama, Y., Gaspar, C., Maciel, P., Tsuji, S., Rouleau, G. A., Kanazawa, I.
|
|
<strong>Machado-Joseph disease gene products carrying different carboxyl termini.</strong>
|
|
Neurosci. Res. 28: 373-377, 1997.
|
|
|
|
|
|
[PubMed: 9274833]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0168-0102(97)00056-4]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Haacke, A., Broadley, S. A., Boteva, R., Tzvetkov, N., Hartl, F. U., Breuer, P.
|
|
<strong>Proteolytic cleavage of polyglutamine-expanded ataxin-3 is critical for aggregation and sequestration of non-expanded ataxin-3.</strong>
|
|
Hum. Molec. Genet. 15: 555-568, 2006.
|
|
|
|
|
|
[PubMed: 16407371]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddi472]
|
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|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
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Ichikawa, Y., Goto, J., Hattori, M., Toyoda, A., Ishii, K., Jeong, S.-Y., Hashida, H., Masuda, N., Ogata, K., Kasai, F., Hirai, M., Maciel, P., Rouleau, G. A., Sakaki, Y., Kanazawa, I.
|
|
<strong>The genomic structure and expression of MJD, the Machado-Joseph disease gene.</strong>
|
|
J. Hum. Genet. 46: 413-422, 2001.
|
|
|
|
|
|
[PubMed: 11450850]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s100380170060]
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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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Jung, J., Bonini, N.
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<strong>CREB-binding protein modulates repeat instability in a Drosophila model for polyQ disease.</strong>
|
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Science 315: 1857-1859, 2007.
|
|
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|
|
|
[PubMed: 17332375]
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|
|
|
|
[Full Text: https://doi.org/10.1126/science.1139517]
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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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Jung, J., Xu, K., Lessing, D., Bonini, N. M.
|
|
<strong>Preventing ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3.</strong>
|
|
Hum. Molec. Genet. 18: 4843-4852, 2009.
|
|
|
|
|
|
[PubMed: 19783548]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp456]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Kawaguchi, Y., Okamoto, T., Taniwaki, M., Aizawa, M., Inoue, M., Katayama, S., Kawakami, H., Nakamura, S., Nishimura, M., Akiguchi, I., Kimura, J., Narumiya, S., Kakizuka, A.
|
|
<strong>CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1.</strong>
|
|
Nature Genet. 8: 221-228, 1994.
|
|
|
|
|
|
[PubMed: 7874163]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng1194-221]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Koch, P., Breuer, P., Peitz, M., Jungverdorben, J., Kesavan, J., Poppe, D., Doerr, J., Ladewig, J., Mertens, J., Tuting, T., Hoffmann, P., Klockgether, T., Evert, B. O., Wullner, U., Brustle, O.
|
|
<strong>Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease.</strong>
|
|
Nature 480: 543-546, 2011.
|
|
|
|
|
|
[PubMed: 22113611]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature10671]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Li, L.-B., Yu, Z., Teng, X., Bonini, N. M.
|
|
<strong>RNA toxicity is a component of ataxin-3 degeneration in Drosophila.</strong>
|
|
Nature 453: 1107-1111, 2008.
|
|
|
|
|
|
[PubMed: 18449188]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/nature06909]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Li, Y., Yokota, T., Matsumura, R., Taira, K., Mizusawa, H.
|
|
<strong>Sequence-dependent and independent inhibition specific for mutant ataxin-3 by small interfering RNA.</strong>
|
|
Ann. Neurol. 56: 124-129, 2004.
|
|
|
|
|
|
[PubMed: 15236410]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.20141]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Martins, S., Calafell, F., Wong, V. C. N., Sequeiros, J., Amorim, A.
|
|
<strong>A multistep mutation mechanism drives the evolution of the CAG repeat at MJD/SCA3 locus.</strong>
|
|
Europ. J. Hum. Genet. 14: 932-940, 2006.
|
|
|
|
|
|
[PubMed: 16724006]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.ejhg.5201643]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Miller, V. M., Xia, H., Marrs, G. L., Gouvion, C. M., Lee, G., Davidson, B. L., Paulson, H. L.
|
|
<strong>Allele-specific silencing of dominant disease genes.</strong>
|
|
Proc. Nat. Acad. Sci. 100: 7195-7200, 2003.
|
|
|
|
|
|
[PubMed: 12782788]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.1231012100]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Mueller, T., Breuer, P., Schmitt, I., Walter, J., Evert, B. O., Wullner, U.
|
|
<strong>CK2-dependent phosphorylation determines cellular localization and stability of ataxin-3.</strong>
|
|
Hum. Molec. Genet. 18: 3334-3343, 2009.
|
|
|
|
|
|
[PubMed: 19542537]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp274]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Paulson, H. L., Das, S. S., Crino, P. B., Perez, M. K., Patel, S. C., Gotsdiner, D., Fischbeck, K. H., Pittman, R. N.
|
|
<strong>Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain.</strong>
|
|
Ann. Neurol. 41: 453-462, 1997.
|
|
|
|
|
|
[PubMed: 9124802]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ana.410410408]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Paulson, H. L., Perez, M. K., Trottier, Y., Trojanowski, J. Q., Subramony, S. H., Das, S. S., Vig, P., Mandel, J. L., Fischbeck, K. H., Pittman, R. N.
|
|
<strong>Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3.</strong>
|
|
Neuron 19: 333-344, 1997.
|
|
|
|
|
|
[PubMed: 9292723]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0896-6273(00)80943-5]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Reina, C. P., Zhong, X., Pittman, R. N.
|
|
<strong>Proteotoxic stress increases nuclear localization of ataxin-3.</strong>
|
|
Hum. Molec. Genet. 19: 235-249, 2010.
|
|
|
|
|
|
[PubMed: 19843543]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddp482]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Scheel, H., Tomiuk, S., Hofmann, K.
|
|
<strong>Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics.</strong>
|
|
Hum. Molec. Genet. 12: 2845-2852, 2003.
|
|
|
|
|
|
[PubMed: 12944423]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddg297]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schmitt, I., Brattig, T., Gossen, M., Riess, O.
|
|
<strong>Characterization of the rat spinocerebellar ataxia type 3 gene.</strong>
|
|
Neurogenetics 1: 103-112, 1997.
|
|
|
|
|
|
[PubMed: 10732811]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1007/s100480050015]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Tait, D., Riccio, M., Sittler, A., Scherzinger, E., Santi, S., Ognibene, A., Maraldi, N. M., Lehrach, H., Wanker, E. E.
|
|
<strong>Ataxin-3 is transported into the nucleus and associates with the nuclear matrix.</strong>
|
|
Hum. Molec. Genet. 7: 991-997, 1998.
|
|
|
|
|
|
[PubMed: 9580663]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/7.6.991]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Toulouse, A., Au-Yeung, F., Gaspar, C., Roussel, J., Dion, P., Rouleau, G. A.
|
|
<strong>Ribosomal frameshifting on MJD-1 transcripts with long CAG tracts.</strong>
|
|
Hum. Molec. Genet. 14: 2649-2660, 2005.
|
|
|
|
|
|
[PubMed: 16087686]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddi299]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Wang, G., Sawai, N., Kotliarova, S., Kanazawa, I., Nukina, N.
|
|
<strong>Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B.</strong>
|
|
Hum. Molec. Genet. 9: 1795-1803, 2000.
|
|
|
|
|
|
[PubMed: 10915768]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/9.12.1795]
|
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|
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|
|
</p>
|
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</li>
|
|
|
|
<li>
|
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<p class="mim-text-font">
|
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Warrick, J. M., Morabito, L. M., Bilen, J., Gordesky-Gold, B., Faust, L. Z., Paulson, H. L., Bonini, N. M.
|
|
<strong>Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism.</strong>
|
|
Molec. Cell 18: 37-48, 2005.
|
|
|
|
|
|
[PubMed: 15808507]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.molcel.2005.02.030]
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</p>
|
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</li>
|
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<li>
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|
|
<strong>The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits lys63 linkages in mixed linkage ubiquitin chains.</strong>
|
|
J. Biol. Chem. 283: 26436-26443, 2008.
|
|
|
|
|
|
[PubMed: 18599482]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1074/jbc.M803692200]
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