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Entry
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- *613004 - HUNTINGTIN; HTT
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- OMIM
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<div class="container hidden-print">
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*613004</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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</li>
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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>
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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="#biochemicalFeatures">Biochemical Features</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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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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</li>
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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/613004">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 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>
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</div>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000197386;t=ENST00000355072" 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=3064" 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=613004" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000197386;t=ENST00000355072" 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_001388492,NM_002111" 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_001388492" 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=613004" 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=00883&isoform_id=00883_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/HTT" 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/398029,454415,794066,794068,840782,4586876,62088592,90903231,119602880,119602881,119602882,119602883,119602884,158254520,209980654,209980656,209980658,209980660,209980662,209980664,209980666,209980668,209980670,209980672,209980674,209980676,209980678,209980680,209980682,209980684,209980686,209980688,209980690,209980692,209980694,209980696,209980698,209980700,209980702,209980706,209980708,209980710,209980714,209980716,209980722,209980724,209980728,209980732,209980734,209980736,296434520,608785750,1933851641,2701656801,2701656803" 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/P42858" 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=3064" 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=ENSG00000197386;t=ENST00000355072" 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=HTT" 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=HTT" 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+3064" 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/HTT" 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:3064" 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/3064" 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=chr4&hgg_gene=ENST00000355072.11&hgg_start=3074681&hgg_end=3243960&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:4851" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/htt" 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=613004[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=613004[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/HTT/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000197386" 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=HTT" 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=HTT" 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=HTT" 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="http://www.LOVD.nl/HTT" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=HTT&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/PA164741646" 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:4851" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0027655.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:96067" 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/HTT#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:96067" 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/3064/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/OMIA000485/" 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=3064" 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=WBGene00009027;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-990415-131" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
|
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</a>
|
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</span>
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</span>
|
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:3064" 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=HTT&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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|
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<a id="title" class="mim-anchor"></a>
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<div>
|
|
<a id="number" class="mim-anchor"></a>
|
|
<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> 58756001<br />
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<strong>ICD10CM:</strong> G10<br />
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<strong>ICD9CM:</strong> 333.4<br />
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">ICD+</a>
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</div>
|
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<div>
|
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<span class="h3">
|
|
<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
|
613004
|
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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>
|
|
<h3>
|
|
<span class="mim-font">
|
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|
HUNTINGTIN; HTT
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</span>
|
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</h3>
|
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</div>
|
|
<div>
|
|
<br />
|
|
</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
|
<div>
|
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<p>
|
|
<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
IT15<br />
|
|
HD GENE
|
|
</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>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=HTT" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">HTT</a></em></strong>
|
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</span>
|
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</p>
|
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</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/4/52?start=-3&limit=10&highlight=52">4p16.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr4:3074681-3243960&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'})">4:3,074,681-3,243,960</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
|
|
|
|
</span>
|
|
</p>
|
|
</div>
|
|
|
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|
|
<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=143100,617435" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/4/52?start=-3&limit=10&highlight=52">
|
|
4p16.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Huntington disease
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/143100"> 143100 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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<p>The HTT gene encodes huntingtin, a ubiquitously expressed nuclear protein that binds to a number of transcription factors to regulate transcription. Abnormal expansion of a polyglutamine tract in the N terminus of huntingtin causes Huntington disease (<a href="/entry/143100">143100</a>), a devastating autosomal dominant neurodegenerative disease characterized by motor, psychiatric, and cognitive dysfunction (summary by <a href="#20" class="mim-tip-reference" title="Futter, M., Diekmann, H., Schoenmakers, E., Sadiq, O., Chatterjee, K., Rubinsztein, D. C. <strong>Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors.</strong> J. Med. Genet. 46: 438-446, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19451134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19451134</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19451134[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/10.1136/jmg.2009.066399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19451134">Futter et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19451134" 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 positional cloning and exon amplification of the Huntington disease (HD; <a href="/entry/143100">143100</a>) locus on chromosome 4p16.3, the <a href="#34" class="mim-tip-reference" title="Huntington's Disease Collaborative Research Group. <strong>A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes.</strong> Cell 72: 971-983, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8458085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8458085</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90585-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8458085">Huntington's Disease Collaborative Research Group (1993)</a> identified a novel transcript, designated IT15 (important transcript 15), from human retinal and frontal cortex cDNA libraries. The corresponding gene was predicted to encode a 3,144-residue protein with a molecular mass of 348 kD. The protein was called 'huntingtin' (HTT) (<a href="#32" class="mim-tip-reference" title="Hoogeveen, A. T., Willemsen, R., Meyer, N., de Rooij, K. E., Roos, R. A. C., van Ommen, G.-J. B., Galjaard, H. <strong>Characterization and localization of the Huntington disease gene product.</strong> Hum. Molec. Genet. 2: 2069-2073, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8111375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8111375</a>] [<a href="https://doi.org/10.1093/hmg/2.12.2069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8111375">Hoogeveen et al., 1993</a>). Northern blot analysis detected a 10 to 11-kb transcript in a variety of human tissues. The reading frame was found to contain a polymorphic trinucleotide repeat varying from 11 to 34 CAG copies in normal individuals. This repeat was expanded to a range of 42 to over 66 copies (<a href="#0001">613004.0001</a>) in 1 allele from patients with Huntington disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8458085+8111375" 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="#45" class="mim-tip-reference" title="Lee, J., Park, E. H., Couture, G., Harvey, I., Garneau, P., Pelletier, J. <strong>An upstream open reading frame impedes translation of the huntingtin gene.</strong> Nucleic Acids Res. 30: 5110-5119, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12466534/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12466534</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12466534[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/nar/gkf664" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12466534">Lee et al. (2002)</a> identified an upstream open reading frame (uORF) encoding a 21-amino acid peptide within the 5-prime UTR of the huntingtin gene. This upstream ORF negatively influenced expression from the huntingtin mRNA, perhaps by limiting ribosomal access to downstream initiation sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12466534" 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="Barnes, G. T., Duyao, M. P., Ambrose, C. M., McNeil, S., Perischetti, F., Srinidhi, J., Gusella, J. F., MacDonald, M. E. <strong>Mouse Huntington's disease gene homolog (Hdh).</strong> Somat. Cell Molec. Genet. 20: 87-97, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8009370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8009370</a>] [<a href="https://doi.org/10.1007/BF02290678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8009370">Barnes et al. (1994)</a> found that mouse Htt (It15, Hdh) shares 86% and 91% sequence identity with human HTT DNA and protein, respectively. Despite the overall high level of conservation, the murine gene possesses an imperfect CAG repeat encoding only 7 consecutive glutamines, compared to the 13 to 36 residues that are normal in the human. Although no evidence for polymorphic variation of the CAG repeat was seen in mice, a nearby CCG repeat differed in length by 1 unit between several strains of laboratory mouse and Mus spretus. The absence of a long CAG repeat in the mouse was consistent with the lack of a spontaneous mouse model of HD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8009370" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Baxendale, S., Abdulla, S., Elgar, G., Buck, D., Berks, M., Micklem, G., Durbin, R., Bates, G., Brenner, S., Beck, S., Lehrach, H. <strong>Comparative sequence analysis of the human and pufferfish Huntington's disease genes.</strong> Nature Genet. 10: 67-76, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7647794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7647794</a>] [<a href="https://doi.org/10.1038/ng0595-67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7647794">Baxendale et al. (1995)</a> cloned and sequenced the homolog of the HTT gene in the pufferfish, Fugu rubripes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7647794" 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="#2" class="mim-tip-reference" title="Ambrose, C. M., Duyao, M. P., Barnes, G., Bates, G. P., Lin, C. S., Srinidhi, J., Baxendale, S., Hummerich, H., Lehrach, H., Altherr, M., Wasmuth, J., Buckler, A., Church, D., Housman, D., Berks, M., Micklem, G., Durbin, R., Dodge, A., Read, A., Gusella, J., MacDonald, M. E. <strong>Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat.</strong> Somat. Cell Molec. Genet. 20: 27-38, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8197474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8197474</a>] [<a href="https://doi.org/10.1007/BF02257483" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8197474">Ambrose et al. (1994)</a> found that the HTT gene spans 180 kb and contains 67 exons ranging in size from 48 bp to 341 bp with an average of 138 bp. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8197474" 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="#49" class="mim-tip-reference" title="Lin, B., Nasir, J., Kalchman, M. A., McDonald, H., Zeisler, J., Goldberg, Y. P., Hayden, M. R. <strong>Structural analysis of the 5-prime region of mouse and human Huntington disease genes reveals conservation of putative promoter region and di- and trinucleotide polymorphisms.</strong> Genomics 25: 707-715, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7759106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7759106</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80014-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7759106">Lin et al. (1995)</a> presented a detailed comparison of the sequence of the putative promoter and the organization of the 5-prime genomic region encompassing the first 5 exons of the mouse Htt and human HTT genes. They found 2 dinucleotide (CT) and 1 trinucleotide intronic polymorphism in Htt and an intronic CA polymorphism in HTT. A comparison of 940-bp sequence 5-prime to the putative translation start site revealed a highly conserved region (78.8% nucleotide identity) between the Htt and the HTT gene from mouse nucleotide -56 to -206. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7759106" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Baxendale, S., Abdulla, S., Elgar, G., Buck, D., Berks, M., Micklem, G., Durbin, R., Bates, G., Brenner, S., Beck, S., Lehrach, H. <strong>Comparative sequence analysis of the human and pufferfish Huntington's disease genes.</strong> Nature Genet. 10: 67-76, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7647794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7647794</a>] [<a href="https://doi.org/10.1038/ng0595-67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7647794">Baxendale et al. (1995)</a> found that the Fugu HTT homolog spans only 23 kb of genomic DNA, compared to the 170-kb human gene, and yet all 67 exons are conserved. The first exon, the site of the disease-causing triplet repeat in the human, is highly conserved. However, the glutamine repeat in Fugu consists of only 4 residues. <a href="#7" class="mim-tip-reference" title="Baxendale, S., Abdulla, S., Elgar, G., Buck, D., Berks, M., Micklem, G., Durbin, R., Bates, G., Brenner, S., Beck, S., Lehrach, H. <strong>Comparative sequence analysis of the human and pufferfish Huntington's disease genes.</strong> Nature Genet. 10: 67-76, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7647794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7647794</a>] [<a href="https://doi.org/10.1038/ng0595-67" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7647794">Baxendale et al. (1995)</a> also showed that synteny may be conserved over longer stretches of the 2 genomes. The work described a detailed example of sequence comparison between human and Fugu and illustrated the power of the pufferfish genome as a model system in the analysis of human genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7647794" 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="#27" class="mim-tip-reference" title="Guo, Q., Huang, B., Cheng, J., Seefelder, M., Engler, T., Pfeifer, G., Oeckl, P., Otto, M., Moser, F., Maurer, M., Pautsch, A., Baumeister, W., Fernandez-Busnadiego, R., Kochanek, S. <strong>The cryo-electron microscopy structure of huntingtin.</strong> Nature 555: 117-120, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29466333/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29466333</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29466333[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/nature25502" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29466333">Guo et al. (2018)</a> used cryoelectron microscopy to determine the structure of full-length human HTT in a complex with HTT-associated protein-40 (HAP40; <a href="/entry/305423">305423</a>) to an overall resolution of 4 angstroms. HTT is largely alpha-helical and consists of 3 major domains. The amino- and carboxy-terminal domains contain multiple HEAT repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely alpha-helical and has a tetratricopeptide repeat-like organization. HAP40 binds in a cleft and contacts the 3 HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing the conformation of HTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29466333" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The human HTT gene maps to chromosome 4p16.3 (<a href="#34" class="mim-tip-reference" title="Huntington's Disease Collaborative Research Group. <strong>A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes.</strong> Cell 72: 971-983, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8458085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8458085</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90585-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8458085">Huntington's Disease Collaborative Research Group, 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8458085" 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>Mouse Gene</em></strong></p><p>
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Using DNA markers near the Huntington disease gene on 4p, <a href="#11" class="mim-tip-reference" title="Cheng, S. V., Martin, G. R., Nadeau, J. H., Haines, J. L., Bucan, M., Kozak, C. A., MacDonald, M. E., Lockyer, J. L., Ledley, F. D., Woo, S. L. C., Lehrach, H., Gilliam, T. C., Gusella, J. F. <strong>Synteny on mouse chromosome 5 of homologs for human DNA loci linked to the Huntington disease gene.</strong> Genomics 4: 419-426, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2523855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2523855</a>] [<a href="https://doi.org/10.1016/0888-7543(89)90349-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2523855">Cheng et al. (1989)</a> defined a conserved linkage group on mouse chromosome 5. By linkage analyses using recombinant inbred strains, a standard outcross, and an interspecific backcross, they assigned homologs of 4 anonymous DNA segments and the QDPR gene (<a href="/entry/612676">612676</a>) to mouse chromosome 5 and determined their relationship to previously mapped markers on that autosome. The findings suggested that the murine counterpart of the HD gene may lie between Hx and Emv1. Hx stands for hemimelia-extra toes; the gene lies 6 cM distal to Emv1, an endogenous ecotropic provirus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2523855" 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>From studies of the comparative mapping of the 4p16.3 region in man and mouse, <a href="#1" class="mim-tip-reference" title="Altherr, M. R., Wasmuth, J. J., Seldin, M. F., Nadeau, J. H., Baehr, W., Pittler, S. J. <strong>Chromosome mapping of the rod photoreceptor cGMP phosphodiesterase beta-subunit gene in mouse and human: tight linkage to the Huntington disease region (4p16.3).</strong> Genomics 12: 750-754, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1315306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1315306</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90305-c" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1315306">Altherr et al. (1992)</a> concluded that the homolog of the HD gene should be located on mouse chromosome 5. <a href="#59" class="mim-tip-reference" title="Nasir, J., Lin, B., Bucan, M., Koizumi, T., Nadeau, J. H., Hayden, M. R. <strong>The murine homologues of the Huntington disease gene (Hdh) and the alpha-adducin gene (Add1) map to mouse chromosome 5 within a region of conserved synteny with human chromosome 4p16.3.</strong> Genomics 22: 198-201, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7959767/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7959767</a>] [<a href="https://doi.org/10.1006/geno.1994.1361" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7959767">Nasir et al. (1994)</a> confirmed this conclusion by using an interspecific backcross to map the murine homolog of IT15 (Hdh) to an area of mouse chromosome 5 that is within the region of conserved synteny with human chromosome 4p16.3. Near the unstable CAG repeat encoding a stretch of polyglutamine that is involved in the pathogenesis of HD, there is a polyproline-encoding CCG repeat that shows more limited allelic variation. <a href="#6" class="mim-tip-reference" title="Barnes, G. T., Duyao, M. P., Ambrose, C. M., McNeil, S., Perischetti, F., Srinidhi, J., Gusella, J. F., MacDonald, M. E. <strong>Mouse Huntington's disease gene homolog (Hdh).</strong> Somat. Cell Molec. Genet. 20: 87-97, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8009370/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8009370</a>] [<a href="https://doi.org/10.1007/BF02290678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8009370">Barnes et al. (1994)</a> used the mouse homolog, Hdh, to map the gene to mouse chromosome 5 in a region devoid of mutations causing any comparable phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7959767+1315306+8009370" 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="#26" class="mim-tip-reference" title="Grosson, C. L. S., MacDonald, M. E., Duyao, M. P., Ambrose, C. M., Roffler-Tarlov, S., Gusella, J. F. <strong>Synteny conservation of the Huntington's disease gene and surrounding loci on mouse chromosome 5.</strong> Mammalian Genome 5: 424-428, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7919654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7919654</a>] [<a href="https://doi.org/10.1007/BF00357002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7919654">Grosson et al. (1994)</a> localized the mouse homologs of the HD gene and 17 other human chromosome 4 loci, including 6 previously unmapped genes, by use of an interspecific cross. All loci mapped in a continuous linkage group on mouse chromosome 5, distal to En2 (engrailed-2; <a href="/entry/131310">131310</a>) and Il6 (interleukin-6; <a href="/entry/147620">147620</a>), the human counterparts of which are located on chromosome 7. The relative order of the loci on human chromosome 4 and mouse chromosome 5 was maintained for the most part. <a href="#26" class="mim-tip-reference" title="Grosson, C. L. S., MacDonald, M. E., Duyao, M. P., Ambrose, C. M., Roffler-Tarlov, S., Gusella, J. F. <strong>Synteny conservation of the Huntington's disease gene and surrounding loci on mouse chromosome 5.</strong> Mammalian Genome 5: 424-428, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7919654/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7919654</a>] [<a href="https://doi.org/10.1007/BF00357002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7919654">Grosson et al. (1994)</a> knew of no phenotypic correspondence between human and mouse mutations mapping to this region of syntenic conservation. The gene that is mutant in achondroplasia (<a href="/entry/100800">100800</a>), namely, fibroblast growth factor receptor-3 (FGFR3; <a href="/entry/134934">134934</a>), was not among the genes mapped. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7919654" 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="#49" class="mim-tip-reference" title="Lin, B., Nasir, J., Kalchman, M. A., McDonald, H., Zeisler, J., Goldberg, Y. P., Hayden, M. R. <strong>Structural analysis of the 5-prime region of mouse and human Huntington disease genes reveals conservation of putative promoter region and di- and trinucleotide polymorphisms.</strong> Genomics 25: 707-715, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7759106/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7759106</a>] [<a href="https://doi.org/10.1016/0888-7543(95)80014-d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7759106">Lin et al. (1995)</a> cloned the mouse Htt gene and showed that it maps to mouse chromosome 5 within a region of conserved synteny with human 4p16.3. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7759106" 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="#32" class="mim-tip-reference" title="Hoogeveen, A. T., Willemsen, R., Meyer, N., de Rooij, K. E., Roos, R. A. C., van Ommen, G.-J. B., Galjaard, H. <strong>Characterization and localization of the Huntington disease gene product.</strong> Hum. Molec. Genet. 2: 2069-2073, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8111375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8111375</a>] [<a href="https://doi.org/10.1093/hmg/2.12.2069" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8111375">Hoogeveen et al. (1993)</a> synthesized oligopeptides corresponding to the C-terminal end of the predicted HD gene product. Immunobiochemical studies with polyclonal antibodies directed against this synthetic peptide revealed the presence of a protein, called huntingtin by them, with a molecular mass of approximately 330 kD in lymphoblastoid cells from normal individuals and patients with Huntington disease. Immunocytochemical studies showed a cytoplasmic localization in various cell types, including neurons. In most of the neuronal cells, the protein was also present in the nucleus. No difference in molecular mass or intracellular localization was found between normal and mutant cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8111375" 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="Dure, L. S., IV, Landwehrmeyer, G. B., Golden, J., McNeil, S. M., Ge, P., Aizawa, H., Huang, Q., Ambrose, C. M., Duyao, M. P., Bird, E. D., DiFiglia, M., Gusella, J. F., MacDonald, M. E., Penney, J. B., Young, A. B., Vonsattel, J.-P. <strong>IT15 gene expression in fetal human brain.</strong> Brain Res. 659: 33-41, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7820679/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7820679</a>] [<a href="https://doi.org/10.1016/0006-8993(94)90860-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7820679">Dure et al. (1994)</a> examined the in situ hybridization of riboprobes specific for the IT15 gene against normal human fetal and adult brains. In both types of specimen, the autoradiographic signal correlated strongly with cell number except in the germinal matrix and white matter where there is a significant proportion of glial cells. This suggested that IT15 expression is predominantly neuronal. However, there was no predominance of IT15 expression in the striatum of the fetal brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7820679" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The wide expression of the HTT transcript does not correlate with the pattern of neuropathology in the disease. To study the huntingtin protein, <a href="#76" class="mim-tip-reference" title="Trottier, Y., Devys, D., Imbert, G., Saudou, F., An, I., Lutz, Y., Weber, C., Agid, Y., Hirsch, E. C., Mandel, J.-L. <strong>Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form.</strong> Nature Genet. 10: 104-110, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7647777/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7647777</a>] [<a href="https://doi.org/10.1038/ng0595-104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7647777">Trottier et al. (1995)</a> generated monoclonal antibodies against 4 different regions of the protein. On Western blots, these monoclonals detected the huntingtin protein of approximately 350 kD in various human cell lines and in neural and nonneural rodent tissues. A doublet protein was detected in cell lines from HD patients, corresponding to the mutant and normal huntingtin. Immunohistochemical studies in the human brain, using 2 of these antibodies, detected huntingtin in perikarya of some neurons, neuropils, and varicosities. Huntingtin was also visualized as punctate staining likely to represent nerve endings. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7647777" 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="Gutekunst, C.-A., Levey, A. I., Heilman, C. J., Whaley, W. L., Yi, H., Nash, N. R., Rees, H. D., Madden, J. J., Hersch, S. M. <strong>Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies.</strong> Proc. Nat. Acad. Sci. 92: 8710-8714, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7568002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7568002</a>] [<a href="https://doi.org/10.1073/pnas.92.19.8710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7568002">Gutekunst et al. (1995)</a> used both polyclonal and monoclonal antifusion protein antibodies to identify native huntingtin in rat, monkey, and human. Western blots revealed a protein with the expected molecular weight that is present in the soluble fraction of rat and monkey brain tissues and lymphoblastoid cell lines from control cases. Immunocytochemistry indicated that huntingtin is located in neurons throughout the brain, with the highest levels evident in larger neurons. In the human striatum, huntingtin was enriched in a patch-like distribution, potentially corresponding to the first areas affected in HD. Subcellular localization of huntingtin was consistent with a cytosolic protein primarily found in somatodendritic regions. Huntingtin appears to be associated particularly with microtubules, although some is also associated with synaptic vesicles. On the basis of the localization of huntingtin in association with microtubules, <a href="#29" class="mim-tip-reference" title="Gutekunst, C.-A., Levey, A. I., Heilman, C. J., Whaley, W. L., Yi, H., Nash, N. R., Rees, H. D., Madden, J. J., Hersch, S. M. <strong>Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies.</strong> Proc. Nat. Acad. Sci. 92: 8710-8714, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7568002/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7568002</a>] [<a href="https://doi.org/10.1073/pnas.92.19.8710" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7568002">Gutekunst et al. (1995)</a> speculated that the mutation impairs the cytoskeletal anchoring or transport of mitochondria, vesicles, or other organelles or molecules. Lymphoblastoid cell lines from juvenile-onset heterozygote HD cases showed expression of both normal and mutant huntingtin; increasing repeat expansion leads to lower levels of the mutant protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7568002" 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="#48" class="mim-tip-reference" title="Li, X.-J., Li, S.-H., Sharp, A. H., Nucifora, F. C., Jr., Schilling, G., Lanahan, A., Worley, P., Snyder, S. H., Ross, C. A. <strong>A huntingtin-associated protein enriched in brain and implications for pathology.</strong> Nature 378: 398-402, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7477378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7477378</a>] [<a href="https://doi.org/10.1038/378398a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7477378">Li et al. (1995)</a> described a huntingtin-associated protein (HAP1; <a href="/entry/600947">600947</a>), which is enriched in brain. The authors found that binding of HAP1 to huntingtin was enhanced by an expanded polyglutamine repeat. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7477378" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#15" class="mim-tip-reference" title="De Rooij, K. E., Dorsman, J. C., Smoor, M. A., den Dunnen, J. T., Van Ommen, G.-J. B. <strong>Subcellular localization of the Huntington's disease gene product in cell lines by immunofluorescence and biochemical subcellular fractionation.</strong> Hum. Molec. Genet. 5: 1093-1099, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8842726/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8842726</a>] [<a href="https://doi.org/10.1093/hmg/5.8.1093" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8842726">De Rooij et al. (1996)</a> used affinity-purified antibodies to analyze the subcellular location of huntingtin. In mouse embryonic fibroblasts, human skin fibroblasts, and mouse neuroblastoma cells, they detected huntingtin in the cytoplasm and the nucleus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8842726" 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="Burke, J. R., Enghild, J. J., Martin, M. E., Jou, Y.-S., Myers, R. M., Roses, A. D., Vance, J. M., Strittmatter, W. J. <strong>Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH.</strong> Nature Med. 2: 347-350, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8612237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8612237</a>] [<a href="https://doi.org/10.1038/nm0396-347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8612237">Burke et al. (1996)</a> described the isolation of a protein present in brain homogenates that bound to a synthetic 60-glutamine peptide (such as that found in huntingtin). Eighteen amino acids of this protein were found to be identical to the N terminus of glyceraldehyde-3-phosphate dehydrogenase (GAPD, or GAPDH; <a href="/entry/138400">138400</a>). GAPD was also found to bind to another protein with a polyglutamine tract, namely the DRPLA protein, atrophin-1 (<a href="/entry/607462">607462</a>). <a href="#8" class="mim-tip-reference" title="Burke, J. R., Enghild, J. J., Martin, M. E., Jou, Y.-S., Myers, R. M., Roses, A. D., Vance, J. M., Strittmatter, W. J. <strong>Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH.</strong> Nature Med. 2: 347-350, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8612237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8612237</a>] [<a href="https://doi.org/10.1038/nm0396-347" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8612237">Burke et al. (1996)</a> demonstrated that synthetic polyglutamine peptides, DRPLA protein, and huntingtin from unaffected individuals with normal-sized polyglutamine tracts bind to GAPD. GAPD had also been shown to bind to RNA, ATP, calcyclin (<a href="/entry/114110">114110</a>), actin (see <a href="/entry/102610">102610</a>), tubulin (see <a href="/entry/191130">191130</a>) and amyloid precursor protein (<a href="/entry/104760">104760</a>). On the basis of their findings, the authors postulated that disease characterized by the presence of an expanded CAG repeat, which share a common mode of heritability, may also share a common metabolic pathogenesis involving GAPD as a functional component. Both <a href="#65" class="mim-tip-reference" title="Roses, A. D. <strong>From genes to mechanisms to therapies: lessons to be learned from neurological disorders.</strong> Nature Med. 2: 267-269, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8612215/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8612215</a>] [<a href="https://doi.org/10.1038/nm0396-267" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8612215">Roses (1996)</a> and <a href="#5" class="mim-tip-reference" title="Barinaga, M. <strong>An intriguing new lead on Huntington's disease.</strong> Science 271: 1233-1234, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8638101/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8638101</a>] [<a href="https://doi.org/10.1126/science.271.5253.1233" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8638101">Barinaga (1996)</a> reviewed these findings. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8638101+8612237+8612215" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In human lymphoblastoid cells, <a href="#38" class="mim-tip-reference" title="Kahlem, P., Green, H., Djian, P. <strong>Transglutaminase action imitates Huntington's disease: selective polymerization of huntingtin containing expanded polyglutamine.</strong> Molec. Cell 1: 595-601, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660943</a>] [<a href="https://doi.org/10.1016/s1097-2765(00)80059-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9660943">Kahlem et al. (1998)</a> showed that huntingtin is a substrate of transglutaminase (see, e.g., TGM1; <a href="/entry/190195">190195</a>) in vitro and that the rate constant of the reaction increases with length of the polyglutamine over a range of an order of magnitude. As a result, huntingtin with expanded polyglutamine is preferentially incorporated into polymers. Both disappearance of huntingtin with expanded polyglutamine and its replacement by polymeric forms are prevented by inhibitors of transglutaminase. The effect of transglutaminase therefore duplicates the changes in the affected parts of the brain. In the presence of either tissue or brain transglutaminase, monomeric huntingtin bearing a polyglutamine expansion formed polymers much more rapidly than one with a short polyglutamine sequence. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9660943" 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="#84" class="mim-tip-reference" title="Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B. R., Goffredo, D., Conti, L., MacDonald, M. E., Friedlander, R. M., Silani, V., Hayden, M. R., Timmusk, T., Sipione, S., Cattaneo, E. <strong>Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease.</strong> Science 293: 493-498, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11408619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11408619</a>] [<a href="https://doi.org/10.1126/science.1059581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11408619">Zuccato et al. (2001)</a> demonstrated that wildtype huntingtin upregulates transcription of brain-derived neurotrophic factor (BDNF; <a href="/entry/113505">113505</a>), a prosurvival factor produced by cortical neurons that is necessary for survival of striatal neurons in the brain. <a href="#84" class="mim-tip-reference" title="Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B. R., Goffredo, D., Conti, L., MacDonald, M. E., Friedlander, R. M., Silani, V., Hayden, M. R., Timmusk, T., Sipione, S., Cattaneo, E. <strong>Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease.</strong> Science 293: 493-498, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11408619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11408619</a>] [<a href="https://doi.org/10.1126/science.1059581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11408619">Zuccato et al. (2001)</a> showed that this beneficial activity of huntingtin is lost when the protein becomes mutated, resulting in decreased production of cortical BDNF. This leads to insufficient neurotrophic support for striatal neurons, which then die. <a href="#84" class="mim-tip-reference" title="Zuccato, C., Ciammola, A., Rigamonti, D., Leavitt, B. R., Goffredo, D., Conti, L., MacDonald, M. E., Friedlander, R. M., Silani, V., Hayden, M. R., Timmusk, T., Sipione, S., Cattaneo, E. <strong>Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease.</strong> Science 293: 493-498, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11408619/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11408619</a>] [<a href="https://doi.org/10.1126/science.1059581" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11408619">Zuccato et al. (2001)</a> suggested that restoring wildtype huntingtin activity and increasing BDNF production may be therapeutic approaches for treating HD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11408619" 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="#39" class="mim-tip-reference" title="Kegel, K. B., Meloni, A. R., Yi, Y., Kim, Y. J., Doyle, E., Cuiffo, B. G., Sapp, E., Wang, Y., Qin, Z.-H., Chen, J. D., Nevins, J. R., Aronin, N., DiFiglia, M. <strong>Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription.</strong> J. Biol. Chem. 277: 7466-7476, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11739372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11739372</a>] [<a href="https://doi.org/10.1074/jbc.M103946200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11739372">Kegel et al. (2002)</a> demonstrated localization of huntingtin to subnuclear compartments, including speckles, promyelocytic leukemia protein bodies, and nucleoli, in normal and HD human fibroblasts and in mouse neurons. Western blot analysis showed that purified nuclei had low levels of full-length huntingtin compared with the cytoplasm, but contained high levels of N- and C-terminal huntingtin fragments, which tightly bound to the nuclear matrix. Full-length huntingtin coimmunoprecipitated with the transcriptional CTBP1 (<a href="/entry/602618">602618</a>) protein, and polyglutamine expansion in huntingtin reduced this interaction. Full-length wildtype and mutant huntingtin repressed transcription when targeted to DNA, but truncated N-terminal wildtype huntingtin did not, suggesting that proteolysis of huntingtin in the nucleus may normally occur in cells to terminate or modulate huntingtin function. However, truncated N-terminal mutant huntingtin retained the ability to repress transcription, suggesting an abnormal gain of function. <a href="#39" class="mim-tip-reference" title="Kegel, K. B., Meloni, A. R., Yi, Y., Kim, Y. J., Doyle, E., Cuiffo, B. G., Sapp, E., Wang, Y., Qin, Z.-H., Chen, J. D., Nevins, J. R., Aronin, N., DiFiglia, M. <strong>Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription.</strong> J. Biol. Chem. 277: 7466-7476, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11739372/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11739372</a>] [<a href="https://doi.org/10.1074/jbc.M103946200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11739372">Kegel et al. (2002)</a> suggested that wildtype huntingtin may function in the nucleus in the assembly of nuclear matrix-bound protein complexes involved with transcriptional repression and RNA processing. Proteolysis of mutant huntingtin may disrupt nuclear functions by altering protein complex interactions and inappropriately repressing transcription in HD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11739372" 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 live-cell time-lapse video microscopy, <a href="#80" class="mim-tip-reference" title="Xia, J., Lee, D. H., Taylor, J., Vandelft, M., Truant, R. <strong>Huntingtin contains a highly conserved nuclear export signal.</strong> Hum. Molec. Genet. 12: 1393-1403, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12783847/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12783847</a>] [<a href="https://doi.org/10.1093/hmg/ddg156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12783847">Xia et al. (2003)</a> visualized polyglutamine-mediated aggregation and transient nuclear localization of huntingtin over time in a striatal cell line. A classic nuclear localization signal could not be detected in the huntingtin amino acid sequence, but a nuclear export signal (NES) in the carboxy terminus of huntingtin was discovered. Leptomycin B treatment of clonal striatal cells enhanced the nuclear localization of huntingtin, and a mutant NES huntingtin displayed increased nuclear localization, indicating that huntingtin can shuttle to and from the nucleus. The huntingtin NES is strictly conserved among all huntingtin proteins from diverse species. This export signal may be important in Huntington disease because this fragment of huntingtin is proteolytically cleaved during HD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12783847" 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="#85" class="mim-tip-reference" title="Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B. R., Hayden, M. R., Timmusk, T., Rigamonti, D., Cattaneo, E. <strong>Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.</strong> Nature Genet. 35: 76-83, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881722</a>] [<a href="https://doi.org/10.1038/ng1219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12881722">Zuccato et al. (2003)</a> showed that the neuron-restrictive silencer element (NRSE) is the target of wildtype huntingtin activity on BDNF promoter II. Wildtype huntingtin inhibits the silencing activity of the NRSE, increasing transcription of BDNF. <a href="#85" class="mim-tip-reference" title="Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B. R., Hayden, M. R., Timmusk, T., Rigamonti, D., Cattaneo, E. <strong>Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.</strong> Nature Genet. 35: 76-83, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881722</a>] [<a href="https://doi.org/10.1038/ng1219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12881722">Zuccato et al. (2003)</a> showed that this effect occurs through cytoplasmic sequestering of repressor element-1 transcription factor/neuron-restrictive silencer factor (REST/NRSF; <a href="/entry/600571">600571</a>), the transcription factor that binds to NRSE. In contrast, aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. Wildtype huntingtin coimmunoprecipitates with REST/NRSF, and less immunoprecipitated material is found in brain tissue with Huntington disease. <a href="#85" class="mim-tip-reference" title="Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B. R., Hayden, M. R., Timmusk, T., Rigamonti, D., Cattaneo, E. <strong>Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.</strong> Nature Genet. 35: 76-83, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881722</a>] [<a href="https://doi.org/10.1038/ng1219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12881722">Zuccato et al. (2003)</a> also reported that wildtype huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype. Consistently, loss of expression of NRSE-controlled neuronal genes was shown in cells, mice, and human brain with Huntington disease. <a href="#85" class="mim-tip-reference" title="Zuccato, C., Tartari, M., Crotti, A., Goffredo, D., Valenza, M., Conti, L., Cataudella, T., Leavitt, B. R., Hayden, M. R., Timmusk, T., Rigamonti, D., Cattaneo, E. <strong>Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes.</strong> Nature Genet. 35: 76-83, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12881722/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12881722</a>] [<a href="https://doi.org/10.1038/ng1219" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12881722">Zuccato et al. (2003)</a> concluded that wildtype huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. The findings indicated a novel mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12881722" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Gauthier, L. R., Charrin, B. C., Borrell-Pages, M., Dompierre, J. P., Rangone, H., Cordelieres, F. P., De Mey, J., MacDonald, M. E., Lebmann, V., Humbert, S., Saudou, F. <strong>Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules.</strong> Cell 118: 127-138, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15242649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15242649</a>] [<a href="https://doi.org/10.1016/j.cell.2004.06.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15242649">Gauthier et al. (2004)</a> showed that huntingtin specifically enhances vesicular transport of BDNF along microtubules. They determined that huntingtin-mediated transport involves HAP1 and the p150(Glued) (DCTN1; <a href="/entry/601143">601143</a>) subunit of dynactin, an essential component of molecular motors. BDNF transport was attenuated both in the disease context and by reducing the levels of wildtype huntingtin. The alteration of the huntingtin/HAP1/p150(Glued) complex correlated with reduced association of motor proteins with microtubules. The polyglutamine-huntingtin-induced transport deficit resulted in the loss of neurotrophic support and neuronal toxicity. <a href="#21" class="mim-tip-reference" title="Gauthier, L. R., Charrin, B. C., Borrell-Pages, M., Dompierre, J. P., Rangone, H., Cordelieres, F. P., De Mey, J., MacDonald, M. E., Lebmann, V., Humbert, S., Saudou, F. <strong>Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules.</strong> Cell 118: 127-138, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15242649/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15242649</a>] [<a href="https://doi.org/10.1016/j.cell.2004.06.018" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15242649">Gauthier et al. (2004)</a> concluded that a key role of huntingtin is to promote BDNF transport and suggested that loss of this function might contribute to pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15242649" 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 yeast 1-hybrid and DNase footprint analyses, <a href="#74" class="mim-tip-reference" title="Tanaka, K., Shouguchi-Miyata, J., Miyamoto, N., Ikeda, J. <strong>Novel nuclear shuttle proteins, HDBP1 and HDBP2, bind to neuronal cell-specific cis-regulatory element in the promoter for the human Huntington's disease gene.</strong> J. Biol. Chem. 279: 7275-7286, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14625278/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14625278</a>] [<a href="https://doi.org/10.1074/jbc.M310726200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14625278">Tanaka et al. (2004)</a> identified 2 proteins, HDBP1 (SLC2A4RG; <a href="/entry/609493">609493</a>) and HDBP2 (ZNF395; <a href="/entry/609494">609494</a>), that bound a 7-bp consensus sequence (GCCGGCG) in the HTT promoter. Mutation of the 7-bp consensus sequence abolished HTT promoter function in a human neuronal cell line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14625278" 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 an antibody specific for HTT phosphorylated on ser421, <a href="#77" class="mim-tip-reference" title="Warby, S. C., Chan, E. Y., Metzler, M., Gan, L., Singaraja, R. R., Crocker, S. F., Robertson, H. A., Hayden, M. R. <strong>Huntingtin phosphorylation on serine 421 is significantly reduced in the striatum and by polyglutamine expansion in vivo.</strong> Hum. Molec. Genet. 14: 1569-1577, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15843398/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15843398</a>] [<a href="https://doi.org/10.1093/hmg/ddi165" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15843398">Warby et al. (2005)</a> demonstrated that HTT phosphorylation was present at significant levels under normal physiologic conditions in human and mouse brain. Htt phosphorylation showed a regional distribution with highest levels in the cerebellum, less in the cortex, and least in the striatum. In cell cultures and in YAC transgenic mice, endogenous phosphorylation of polyglutamine-expanded HTT was significantly reduced relative to wildtype HTT. The presence and pattern of significant HTT phosphorylation in the brain suggested to the authors that this dynamic posttranslational modification may be important for the regulation of HTT and may contribute to the selective neurodegeneration seen in HD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15843398" 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="#62" class="mim-tip-reference" title="Ralser, M., Nonhoff, U., Albrecht, M., Lengauer, T., Wanker, E. E., Lehrach, H., Krobitsch, S. <strong>Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways.</strong> Hum. Molec. Genet. 14: 2893-2909, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115810</a>] [<a href="https://doi.org/10.1093/hmg/ddi321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115810">Ralser et al. (2005)</a> demonstrated that ataxin-2 (<a href="/entry/601517">601517</a>) interacted with endophilin-A1 (SH3GL2; <a href="/entry/604465">604465</a>) and endophilin-A3 (SH3GL3; <a href="/entry/603362">603362</a>). In a yeast model system, expression of ataxin-2 as well as both endophilin proteins was toxic for yeast lacking Sac6, which encodes fimbrin (PLS3; <a href="/entry/300131">300131</a>), a protein involved in actin filament organization and endocytotic processes. Expression of huntingtin was also toxic in Sac6-null yeast. These effects could be suppressed by simultaneous expression of 1 of the 2 human fimbrin orthologs, L-plastin (LCP1; <a href="/entry/153430">153430</a>) or T-plastin (PLS3). Ataxin-2 associated with L- and T-plastin, and overexpression of ataxin-2 led to accumulation of T-plastin in mammalian cells. <a href="#62" class="mim-tip-reference" title="Ralser, M., Nonhoff, U., Albrecht, M., Lengauer, T., Wanker, E. E., Lehrach, H., Krobitsch, S. <strong>Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways.</strong> Hum. Molec. Genet. 14: 2893-2909, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16115810/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16115810</a>] [<a href="https://doi.org/10.1093/hmg/ddi321" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16115810">Ralser et al. (2005)</a> suggested an interplay between ataxin-2, endophilin proteins, and huntingtin in plastin-associated cellular pathways. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16115810" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Cornett, J., Cao, F., Wang, C.-E., Ross, C. A., Bates, G. P., Li, S.-H., Li, X.-J. <strong>Polyglutamine expansion of huntingtin impairs its nuclear export.</strong> Nature Genet. 37: 198-204, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654337</a>] [<a href="https://doi.org/10.1038/ng1503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654337">Cornett et al. (2005)</a> studied the mechanism by which mutant HTT accumulates in the nucleus; wildtype HTT is normally found in the cytoplasm. They reported that N-terminal HTT shuttles between the cytoplasm and nucleus and that small N-terminal HTT fragments interact with the nuclear pore protein translocated promoter region (TPR; <a href="/entry/189940">189940</a>), which is involved in nuclear export. PolyQ expansion and aggregation decrease this interaction and increase the nuclear accumulation of HTT. Reducing the expression of TPR by RNA interference or deletion of 10 amino acids of N-terminal HTT, which are essential for the interaction of HTT with TPR, increased the nuclear accumulation of HTT. <a href="#14" class="mim-tip-reference" title="Cornett, J., Cao, F., Wang, C.-E., Ross, C. A., Bates, G. P., Li, S.-H., Li, X.-J. <strong>Polyglutamine expansion of huntingtin impairs its nuclear export.</strong> Nature Genet. 37: 198-204, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15654337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15654337</a>] [<a href="https://doi.org/10.1038/ng1503" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15654337">Cornett et al. (2005)</a> concluded that TPR has a role in the nuclear export of N-terminal HTT and that polyQ expansion reduces this nuclear export to cause the nuclear accumulation of HTT. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15654337" 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 yeast 2-hybrid analysis and coimmunoprecipitation analysis of cotransfected COS-1 cells, <a href="#33" class="mim-tip-reference" title="Horn, S. C., Lalowski, M., Goehler, H., Droge, A., Wanker, E. E., Stelzl, U. <strong>Huntingtin interacts with the receptor sorting family protein GASP2.</strong> J. Neural Transm. 113: 1081-1090, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16835690/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16835690</a>] [<a href="https://doi.org/10.1007/s00702-006-0514-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16835690">Horn et al. (2006)</a> found that the C-terminal conserved region of GASP2 (GPRASP2; <a href="/entry/300969">300969</a>) interacted with the N terminus of HTT. An expanded polyQ repeat in HTT increased binding affinity for GASP2. Confocal immunofluorescence microscopy showed partial colocalization of GASP2 and HTT in cytoplasm and cell membranes of undifferentiated SH-SY5Y human neuroblastoma cells, as well as colocalization of GASP2 and HTT in neurite-like extensions following induction of differentiation in SH-SY5Y cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16835690" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid analysis of a human brain cDNA library and affinity chromatography assays with mouse brain cytosol, <a href="#10" class="mim-tip-reference" title="Caviston, J. P., Ross, J. L., Antony, S. M., Tokito, M., Holzbaur, E. L. F. <strong>Huntingtin facilitates dynein/dynactin-mediated vesicle transport.</strong> Proc. Nat. Acad. Sci. 104: 10045-10050, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17548833/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17548833</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17548833[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.0610628104" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17548833">Caviston et al. (2007)</a> demonstrated that Htt and dynein intermediate chain (see DYNC1I1; <a href="/entry/603772">603772</a>) interacted directly. HTT RNA interference in HeLa cells resulted in Golgi disruption similar to the effects of compromised dynein/dynactin function. In vitro studies revealed that Htt and dynein were both present on vesicles purified from mouse brain. Antibodies to Htt inhibited vesicular transport along microtubules, suggesting that Htt facilitates dynein-mediated vesicle motility. In vivo inhibition of dynein function resulted in a significant redistribution of Htt to the cell periphery, suggesting that dynein transports Htt-associated vesicles toward the cell center. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17548833" 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>Argonaute proteins, such as AGO1 (EIF2C1; <a href="/entry/606228">606228</a>) and AGO2 (EIF2C2; <a href="/entry/606229">606229</a>), are components of a ribonucleoprotein complex that regulates mRNA translation via small interfering RNA. <a href="#68" class="mim-tip-reference" title="Savas, J. N., Makusky, A., Ottosen, S., Baillat, D., Then, F., Krainc, D., Shiekhattar, R., Markley, S. P., Tanese, N. <strong>Huntington's disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies.</strong> Proc. Nat. Acad. Sci. 105: 10820-10825, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18669659/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18669659</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18669659[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.0800658105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18669659">Savas et al. (2008)</a> found that an N-terminal fragment of Htt with 25 or 97 glutamines immunoprecipitated AGO1 and AGO2 from transfected HeLa cells. AGO2 also immunoprecipitated endogenous HTT from HeLa cells. A portion of endogenous HTT colocalized with AGO2 in P bodies in human and mouse cell lines and in primary rat hippocampal neurons, but not all HTT foci colocalized with AGO2 and a P-body marker. Small interfering RNA, reporter gene assays, and FRAP analysis suggested that HTT may have a role in gene silencing through the RNA interference pathway, and that mutant HTT may reduce incorporation of AGO2 into P bodies and P body-associated gene silencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18669659" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid and immunoprecipitation analyses, <a href="#70" class="mim-tip-reference" title="Shimojo, M. <strong>Huntingtin regulates RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) nuclear trafficking indirectly through a complex with REST/NRSF-interacting LIM domain protein (RILP) and dynactin p150-Glued.</strong> J. Biol. Chem. 283: 34880-34886, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18922795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18922795</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18922795[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.M804183200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18922795">Shimojo (2008)</a> showed that human RILP (PRICKLE1; <a href="/entry/608500">608500</a>) and huntingtin interacted directly with dynactin-1 to form a triplex. REST bound to the triplex through direct interaction with RILP, forming a quaternary complex involved in nuclear translocation of REST in non-neuronal cells. In neuronal cells, the complex also contained HAP1, which affected interaction of disease-causing mutant huntingtin, but not wildtype huntingtin, with dynactin-1 and RILP. Overexpression and knockout analyses demonstrated that the presence of HAP1 in the complex prevented nuclear translocation of REST and thereby regulated REST activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18922795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Futter, M., Diekmann, H., Schoenmakers, E., Sadiq, O., Chatterjee, K., Rubinsztein, D. C. <strong>Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors.</strong> J. Med. Genet. 46: 438-446, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19451134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19451134</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19451134[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/10.1136/jmg.2009.066399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19451134">Futter et al. (2009)</a> found that wildtype huntingtin could bind to a number of nuclear receptors, including LXR-alpha (NR1H3; <a href="/entry/602423">602423</a>), PPARG (<a href="/entry/601487">601487</a>), VDR (<a href="/entry/601769">601769</a>), and THRA1 (<a href="/entry/190120">190120</a>). Overexpression of huntingtin activated, whereas knockout of huntingtin decreased, LXR-mediated transcription of a reporter gene. Loss of huntingtin also decreased expression of the LXR target gene, ABCA1 (<a href="/entry/600046">600046</a>). In vivo, huntingtin-deficient zebrafish had a severe phenotype with reduction of cartilage in the jaw and reduced expression of LXR-regulated genes. An LXR agonist was able to partially rescue the phenotype and the expression of LXR target genes in huntingtin-deficient zebrafish during early development. The data suggested a novel function for wildtype huntingtin as a cofactor of LXR. However, this activity was lost by mutant polyQ huntingtin, which only interacted weakly with LXR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19451134" 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="#71" class="mim-tip-reference" title="Smith, R., Bacos, K., Fedele, V., Soulet, D., Walz, H. A., Obermuller, S., Lindqvist, A., Bjorkqvist, M., Klein, P., Onnerfjord, P., Brundin, P., Mulder, H., Li, J.-Y. <strong>Mutant huntingtin interacts with beta-tubulin and disrupts vesicular transport and insulin secretion.</strong> Hum. Molec. Genet. 18: 3942-3954, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19628478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19628478</a>] [<a href="https://doi.org/10.1093/hmg/ddp336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19628478">Smith et al. (2009)</a> showed that mutant huntingtin disrupted intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin (TUBB; <a href="/entry/191130">191130</a>). Mutant huntingtin impaired glucose-stimulated insulin secretion in insulin-producing beta cells, without altering stored levels of insulin. Mutant huntingtin also retarded post-Golgi transport, and the speed of insulin vesicle trafficking was reduced. There was an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. <a href="#71" class="mim-tip-reference" title="Smith, R., Bacos, K., Fedele, V., Soulet, D., Walz, H. A., Obermuller, S., Lindqvist, A., Bjorkqvist, M., Klein, P., Onnerfjord, P., Brundin, P., Mulder, H., Li, J.-Y. <strong>Mutant huntingtin interacts with beta-tubulin and disrupts vesicular transport and insulin secretion.</strong> Hum. Molec. Genet. 18: 3942-3954, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19628478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19628478</a>] [<a href="https://doi.org/10.1093/hmg/ddp336" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19628478">Smith et al. (2009)</a> proposed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19628478" 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="#69" class="mim-tip-reference" title="Seong, I. S., Woda, J. M., Song, J.-J., Lloret, A., Abeyrathne, P. D., Woo, C. J., Gregory, G., Lee, J.-M., Wheeler, V. C., Walz, T., Kingston, R. E., Gusella, J. F., Conlon, R. A., MacDonald, M. E. <strong>Huntingtin facilitates polycomb repressive complex 2.</strong> Hum. Molec. Genet. 19: 573-583, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19933700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19933700</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19933700[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/ddp524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19933700">Seong et al. (2010)</a> investigated huntingtin's domain structure and potential intersection with epigenetic silencer polycomb repressive complex-2 (PRC2, see EZH1; <a href="/entry/601674">601674</a>), suggested by shared embryonic deficiency phenotypes. Analysis of a set of full-length recombinant huntingtins, with different polyglutamine regions, demonstrated dramatic conformational flexibility, with an accessible hinge separating 2 large alpha-helical domains. Mouse embryos lacking huntingtin exhibited impaired PRC2 regulation of Hox gene expression, trophoblast giant cell differentiation, paternal X-chromosome inactivation, and histone H3K27 trimethylation, while full-length endogenous nuclear huntingtin in wildtype embryoid bodies was associated with PRC2 subunits and was detected with trimethylated histone H3K27 at Hoxb9 (<a href="/entry/142964">142964</a>). Supporting a direct stimulatory role, full-length recombinant huntingtin significantly increased the histone H3K27 trimethylase activity of reconstituted PRC2 in vitro, and structure-function analysis demonstrated that the polyglutamine region augmented full-length huntingtin PRC2 stimulation, both in Hdh(Q111) embryoid bodies and in vitro, with reconstituted PRC2. <a href="#69" class="mim-tip-reference" title="Seong, I. S., Woda, J. M., Song, J.-J., Lloret, A., Abeyrathne, P. D., Woo, C. J., Gregory, G., Lee, J.-M., Wheeler, V. C., Walz, T., Kingston, R. E., Gusella, J. F., Conlon, R. A., MacDonald, M. E. <strong>Huntingtin facilitates polycomb repressive complex 2.</strong> Hum. Molec. Genet. 19: 573-583, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19933700/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19933700</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19933700[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/ddp524" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19933700">Seong et al. (2010)</a> implicated a role for the multisubunit PRC2 complex in neurodegenerative disorders such as Huntington disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19933700" 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="#73" class="mim-tip-reference" title="Song, W., Chen, J., Petrilli, A., Liot, G., Klinglmayr, E., Zhou, Y., Poquiz, P., Tjong, J., Pouladi, M. A., Hayden, M. R., Masliah, E., Ellisman, M., Rouiller, I., Schwarzenbacher, R., Bossy, B., Perkins, G., Bossy-Wetzel, E. <strong>Mutant huntingtin binds the mitochondrial fission GTPase dynamin-related protein-1 and increases its enzymatic activity.</strong> Nature Med. 17: 377-382, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21336284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21336284</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21336284[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/nm.2313" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21336284">Song et al. (2011)</a> found fragmented mitochondria in fibroblasts from a patient with HD and in rat cortical neurons expressing human HTT with a polyQ expansion. Neurons expressing mutant HTT also showed arrest in mitochondrial movement and ultrastructural changes in mitochondrial cristae. Mitochondrial changes were observed in a mouse model of HD prior to emergence of neurologic deficits, neuronal cell death, and HTT aggregate formation. Immunoprecipitation of normal and HD human or mouse brain indicated that mutant, but not normal, huntingtin interacted with Drp1 (DNM1; <a href="/entry/603850">603850</a>), a protein involved in mitochondria and peroxisome fission. In vitro assays with liposomes that mimicked the mitochondrial outer membrane revealed that mutant huntingtin stimulated Drp1 GTPase activity. Expression of a dominant-negative Drp1 mutant rescued mutant huntingtin-mediated mitochondrial fragmentation, defects in mitochondrial transport, and neuronal cell death. Electron microscopy showed that the normal ring- and spiral-like organization of DRP1 oligomers had an additional layer of density with the addition of mutant, but not normal, huntingtin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21336284" 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="#67" class="mim-tip-reference" title="Sassone, F., Margulets, V., Maraschi, A., Rodighiero, S., Passafaro, M., Silani, V., Ciammola, A., Kirshenbaum, L. A., Sassone, J. <strong>Bcl-2/adenovirus E1B 19-kDa interacting protein (BNip3) has a key role in the mitochondrial dysfunction induced by mutant huntingtin.</strong> Hum. Molec. Genet. 24: 6530-6539, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26358776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26358776</a>] [<a href="https://doi.org/10.1093/hmg/ddv362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26358776">Sassone et al. (2015)</a> noted that mutant HTT causes mitochondrial depolarization and fragmentation and promotes activation of proapoptotic proteins, including BNIP3 (<a href="/entry/603293">603293</a>), BAX (<a href="/entry/600040">600040</a>), and BAK (BAK1; <a href="/entry/600516">600516</a>). They found that mouse embryonic fibroblasts lacking Bnip3, but not those lacking both Bax and Bak, were resistant to mitochondrial depolarization, fragmentation, and cell death induced by expression of mutant human HTT. Expression of a dominant-negative Bnip3 mutant lacking the transmembrane domain required for mitochondrial localization and function partially rescued mitochondrial pathology and cell death in a mouse striatal neuron HD model. <a href="#67" class="mim-tip-reference" title="Sassone, F., Margulets, V., Maraschi, A., Rodighiero, S., Passafaro, M., Silani, V., Ciammola, A., Kirshenbaum, L. A., Sassone, J. <strong>Bcl-2/adenovirus E1B 19-kDa interacting protein (BNip3) has a key role in the mitochondrial dysfunction induced by mutant huntingtin.</strong> Hum. Molec. Genet. 24: 6530-6539, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26358776/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26358776</a>] [<a href="https://doi.org/10.1093/hmg/ddv362" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26358776">Sassone et al. (2015)</a> concluded that mitochondrial dysfunction induced by mutant HTT depends on BNIP3, but not BAX or BAK. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26358776" 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>Neurodegeneration in HD is thought to be due to proteolytic release of toxic peptide fragments from mutant HTT. By transfecting small interfering RNAs directed against 514 human proteases into polyQ HTT-expressing HEK293 cells, <a href="#56" class="mim-tip-reference" title="Miller, J. P., Holcomb, J., Al-Ramahi, I., de Haro, M., Gafni, J., Zhang, N., Kim, E., Sanhueza, M., Torcassi, C., Kwak, S., Botas, J., Hughes, R. E., Ellerby, L. M. <strong>Matrix metalloproteinases are modifiers of huntingtin proteolysis and toxicity in Huntington's disease.</strong> Neuron 67: 199-212, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20670829/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20670829</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20670829[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/10.1016/j.neuron.2010.06.021" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20670829">Miller et al. (2010)</a> identified 11 proteases, including MMP10 (<a href="/entry/185260">185260</a>), MMP14 (<a href="/entry/600754">600754</a>), and MMP23B (<a href="/entry/603321">603321</a>), as putative polyQ HTT-processing proteases. Further characterization revealed that MMP10 was the only metalloprotease in this group that directly processed polyQ HTT; MMP14 and MMP23B appeared to cause polyQ HTT degradation indirectly. MMP10 cleaved polyQ HTT at a conserved site near the N terminus with the consensus sequence (S/T)xxGG(I/L). Both Mmp10 and Mmp14 were upregulated in mouse striatal cells expressing polyQ HTT, and knockdown of either Mmp10 or Mmp14 reduced cell death and caspase activation. Htt and Mmp10 colocalized in cells undergoing apoptosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20670829" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#24" class="mim-tip-reference" title="Godin, J. D., Colombo, K., Molina-Calavita, M., Keryer, G., Zala, D., Charrin, B. C., Dietrich, P., Volvert, M. L., Guillemot, F., Dragatsis, I., Bellaiche, Y., Sandou, F., Nguyen, L., Humbert, S. <strong>Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis.</strong> Neuron 67: 392-406, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20696378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20696378</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.06.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20696378">Godin et al. (2010)</a> noted that HTT expression is associated with the centrosomal region and microtubules of dividing cells. They found that HTT localized to the spindle poles during mitosis from prophase to anaphase in both HeLa cells and dividing mouse cortical neurons. Knockdown of HTT expression in either cell model resulted in a spindle orientation defect. The defect could be reversed in mouse cortical neurons by expression of a 1,301-amino acid N-terminal fragment of mouse Htt or a 620-amino acid N-terminal fragment of Drosophila Htt. Depletion of Htt in mouse cells caused partial mislocalization of p150(Glued), dispersal of dynein and Numa (NUMA1; <a href="/entry/164009">164009</a>), and asynchronous cell division. In day-14.5 mouse embryos, asynchronous division due to Htt depletion led to premature neuronal differentiation at the expense of proliferation and maintenance of progenitors in the neocortex. <a href="#24" class="mim-tip-reference" title="Godin, J. D., Colombo, K., Molina-Calavita, M., Keryer, G., Zala, D., Charrin, B. C., Dietrich, P., Volvert, M. L., Guillemot, F., Dragatsis, I., Bellaiche, Y., Sandou, F., Nguyen, L., Humbert, S. <strong>Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis.</strong> Neuron 67: 392-406, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20696378/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20696378</a>] [<a href="https://doi.org/10.1016/j.neuron.2010.06.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20696378">Godin et al. (2010)</a> concluded that HTT functions as a scaffold protein for the dynein/dynactin complex in dividing cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20696378" 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 mouse and cellular models of HD, <a href="#54" class="mim-tip-reference" title="McFarland, K. N., Huizenga, M. N., Darnell, S. B., Sangrey, G. R., Berezovska, O., Cha, J.-H. J., Outerio, T. F., Sadri-Vakili, G. <strong>MeCP2: a novel huntingtin interactor.</strong> Hum. Molec. Genet. 23: 1036-1044, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24105466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24105466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24105466[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/ddt499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24105466">McFarland et al. (2014)</a> showed that mutant Htt protein interacted directly with Mecp2 (<a href="/entry/300005">300005</a>). Htt-Mecp2 interactions were enhanced in the presence of the expanded polyglutamine tract and were stronger in nucleus compared with cytoplasm. Binding of Mecp2 to the promoter of Bdnf increased in the presence of mutant Htt. Decreasing Mecp2 expression through small interfering RNA treatment in cells expressing mutant Htt increased Bdnf levels, suggesting that MECP2 downregulates BDNF expression in HD. <a href="#54" class="mim-tip-reference" title="McFarland, K. N., Huizenga, M. N., Darnell, S. B., Sangrey, G. R., Berezovska, O., Cha, J.-H. J., Outerio, T. F., Sadri-Vakili, G. <strong>MeCP2: a novel huntingtin interactor.</strong> Hum. Molec. Genet. 23: 1036-1044, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24105466/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24105466</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24105466[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/ddt499" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24105466">McFarland et al. (2014)</a> proposed that aberrant interactions between HTT and MECP2 contribute to transcriptional dysregulation in HD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24105466" 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="#78" class="mim-tip-reference" title="Woerner, A. C., Frottin, F., Hornburg, D., Feng, L. R., Meissner, F., Patra, M., Tatzelt, J., Mann, M., Winklhofer, K. F., Hartl, F. U., Hipp, M. S. <strong>Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA.</strong> Science 351: 173-176, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26634439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26634439</a>] [<a href="https://doi.org/10.1126/science.aad2033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26634439">Woerner et al. (2016)</a> analyzed the compartment specificity of aggregate toxicity using artificial beta-sheet proteins, as well as fragments of mutant huntingtin and TAR DNA binding protein-43 (TDP43; <a href="/entry/605078">605078</a>). Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, <a href="#78" class="mim-tip-reference" title="Woerner, A. C., Frottin, F., Hornburg, D., Feng, L. R., Meissner, F., Patra, M., Tatzelt, J., Mann, M., Winklhofer, K. F., Hartl, F. U., Hipp, M. S. <strong>Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA.</strong> Science 351: 173-176, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26634439/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26634439</a>] [<a href="https://doi.org/10.1126/science.aad2033" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26634439">Woerner et al. (2016)</a> concluded that impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26634439" 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>Through biochemical and live cell imaging studies, <a href="#53" class="mim-tip-reference" title="Marcora, E., Kennedy, M. B. <strong>The Huntington's disease mutation impairs Huntingtin's role in the transport of NF-kappa-B from the synapse to the nucleus.</strong> Hum. Molec. Genet. 19: 4373-4384, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20739295/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20739295</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20739295[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/ddq358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20739295">Marcora and Kennedy (2010)</a> showed that wildtype Htt stimulated the transport of NFKB (see NFKB1, <a href="/entry/164011">164011</a>) out of dendritic spines (where NFKB is activated by excitatory synaptic input) and supported a high level of active NFKB in neuronal nuclei (where NFKB stimulates the transcription of target genes). This novel function of Htt was impaired by polyQ expansion; the authors suggested that this impairment may contribute to the etiology of HD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20739295" 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 translational profiling of corticospinal tract motor neurons in mice, <a href="#61" class="mim-tip-reference" title="Poplawski, G. H. D., Kawaguchi, R., Van Niekerk, E., Lu, P., Mehta, N., Canete, P., Lie, R., Dragatsis, I., Meves, J. M., Zheng, B., Coppola, G., Tuszynski, M. H. <strong>Injured adult neurons regress to an embryonic transcriptional growth state.</strong> Nature 581: 77-82, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32376949/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32376949</a>] [<a href="https://doi.org/10.1038/s41586-020-2200-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32376949">Poplawski et al. (2020)</a> identified their 'regenerative transcriptome' after spinal cord injury and neural progenitor cell grafting. Both injury alone and injury combined with neural progenitor cell grafts elicited virtually identical early transcriptomic responses in host neurons. However, in mice with injury alone, this regenerative transcriptome was downregulated after 2 weeks, whereas in neural progenitor stem cell-grafted mice, this transcriptome was sustained. The regenerative transcriptome appeared to represent a reversion to an embryonic transcriptional state of the corticospinal tract neuron. The Htt gene was a central hub in the regeneration transcriptome, and deletion of Htt significantly attenuated regeneration. The authors concluded that Htt has a key role in neural plasticity after injury. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32376949" 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>Huntington Disease</em></strong></p><p>
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The <a href="#34" class="mim-tip-reference" title="Huntington's Disease Collaborative Research Group. <strong>A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes.</strong> Cell 72: 971-983, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8458085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8458085</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90585-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8458085">Huntington's Disease Collaborative Research Group (1993)</a> identified an expanded (CAG)n repeat on 1 allele of the HTT gene (<a href="#0001">613004.0001</a>) in affected members from all of 75 families with Huntington disease (HD; <a href="/entry/143100">143100</a>) examined. The families came from a variety of ethnic backgrounds and demonstrated a variety of 4p16.3 haplotypes. The findings indicated that the HD mutation involves an unstable DNA segment similar to those previously observed in several disorders, including the fragile X syndrome (<a href="/entry/300624">300624</a>), Kennedy syndrome (<a href="/entry/313200">313200</a>), and myotonic dystrophy. The fact that the phenotype of HD is completely dominant suggested that the disorder results from a gain-of-function mutation in which either the mRNA product or the protein product of the disease allele has some new property or is expressed inappropriately (<a href="#57" class="mim-tip-reference" title="Myers, R. H., Leavitt, J., Farrer, L. A., Jagadeesh, J., McFarlane, H., Mastromauro, C. A., Mark, R. J., Gusella, J. F. <strong>Homozygote for Huntington disease.</strong> Am. J. Hum. Genet. 45: 615-618, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2535231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2535231</a>]" pmid="2535231">Myers et al., 1989</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2535231+8458085" 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="Duyao, M., Ambrose, C., Myers, R., Novelletto, A., Persichetti, F., Frontali, M., Folstein, S., Ross, C., Franz, M., Abbott, M., Gray, J., Conneally, P., and 30 others. <strong>Trinucleotide repeat length instability and age of onset in Huntington's disease.</strong> Nature Genet. 4: 387-392, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401587</a>] [<a href="https://doi.org/10.1038/ng0893-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401587">Duyao et al. (1993)</a>, <a href="#72" class="mim-tip-reference" title="Snell, R. G., MacMillan, J. C., Cheadle, J. P., Fenton, I., Lazarou, L. P., Davies, P., MacDonald, M. E., Gusella, J. F., Harper, P. S., Shaw, D. J. <strong>Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease.</strong> Nature Genet. 4: 393-397, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401588</a>] [<a href="https://doi.org/10.1038/ng0893-393" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401588">Snell et al. (1993)</a>, and <a href="#3" class="mim-tip-reference" title="Andrew, S. E., Goldberg, Y. P., Kremer, B., Telenius, H., Theilmann, J., Adam, S., Starr, E., Squitieri, F., Lin, B., Kalchman, M. A., Graham, R. K., Hayden, M. R. <strong>The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease.</strong> Nature Genet. 4: 398-403, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401589</a>] [<a href="https://doi.org/10.1038/ng0893-398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401589">Andrew et al. (1993)</a> analyzed the number of CAG repeats in a total of about 1,200 HTT genes and in over 2,000 normal controls. <a href="#63" class="mim-tip-reference" title="Read, A. P. <strong>Huntington's disease: testing the test.</strong> Nature Genet. 4: 329-330, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401575/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401575</a>] [<a href="https://doi.org/10.1038/ng0893-329" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401575">Read (1993)</a> summarized and collated the results. In all 3 studies, the normal range of repeat numbers was 9-11 at the low and 34-37 at the high end, with a mean ranging from 18.29 to 19.71. <a href="#18" class="mim-tip-reference" title="Duyao, M., Ambrose, C., Myers, R., Novelletto, A., Persichetti, F., Frontali, M., Folstein, S., Ross, C., Franz, M., Abbott, M., Gray, J., Conneally, P., and 30 others. <strong>Trinucleotide repeat length instability and age of onset in Huntington's disease.</strong> Nature Genet. 4: 387-392, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401587</a>] [<a href="https://doi.org/10.1038/ng0893-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401587">Duyao et al. (1993)</a> found a range of 37-86 in HD patients, with a mean of 46.42. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8401588+8401575+8401587+8401589" 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="#66" class="mim-tip-reference" title="Rubinsztein, D. C., Leggo, J., Coles, R., Almqvist, E., Biancalana, V., Cassiman, J.-J., Chotai, K., Connarty, M., Craufurd, D., Curtis, A., Curtis, D., Davidson, M. J., and 25 others. <strong>Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats.</strong> Am. J. Hum. Genet. 59: 16-22, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8659522/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8659522</a>]" pmid="8659522">Rubinsztein et al. (1996)</a> studied a large cohort of individuals who carried between 30 and 40 CAG repeats in the HTT gene. They used a PCR method that allowed the examination of CAG repeats only, thereby excluding the CCG repeats, which represent a polymorphism, as a confounding factor. No individual with 35 or fewer CAG repeats had clinical manifestations of HD. Most individuals with 36 to 39 CAG repeats were clinically affected, but 10 persons (aged 67-95 years) had no apparent symptoms of HD. The authors concluded that the HD mutation is not fully penetrant in individuals with a borderline number of CAG repeats. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8659522" 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="Gusella, J. F., McNeil, S., Persichetti, F., Srinidhi, J., Novelletto, A., Bird, E., Faber, P., Vonsattel, J.-P., Myers, R. H., MacDonald, M. E. <strong>Huntington's disease.</strong> Cold Spring Harbor Symp. Quant. Biol. 61: 615-626, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9246488/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9246488</a>]" pmid="9246488">Gusella et al. (1996)</a> gave a comprehensive review of the molecular genetic aspects of Huntington disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9246488" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a study of 4,068 patients with HD, <a href="#44" class="mim-tip-reference" title="Lee, J. M., Ramos, E. M., Lee, J. H., Gillis, T., Mysore, J. S., Hayden, M. R., Warby, S. C., Morrison, P., Nance, M., Ross, C. A., Margolis, R. L., Squitieri, F., and 30 others. <strong>CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion.</strong> Neurology 78: 690-695, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323755</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318249f683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323755">Lee et al. (2012)</a> found that CAG repeat length in the HTT gene in the expanded allele determined age of onset of motor symptoms in a dominant fashion, and that the unexpanded, wildtype allele CAG length did not have an effect. Furthermore, in 10 patients with 2 expanded CAG alleles, onset of motor symptoms was consistent with what would be expected for the longer repeat allele. <a href="#4" class="mim-tip-reference" title="Aziz, N. A., Roos, R. A., Gusella, J. F., Lee, J. M., Macdonald, M. E. <strong>CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. (Letter)</strong> Neurology 79: 952, 2012. Note: Author Reply 952-3, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927682</a>] [<a href="https://doi.org/10.1212/WNL.0b013e3182697986" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22927682">Aziz et al. (2012)</a> noted that the following should be considered in assessing the results of <a href="#44" class="mim-tip-reference" title="Lee, J. M., Ramos, E. M., Lee, J. H., Gillis, T., Mysore, J. S., Hayden, M. R., Warby, S. C., Morrison, P., Nance, M., Ross, C. A., Margolis, R. L., Squitieri, F., and 30 others. <strong>CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion.</strong> Neurology 78: 690-695, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22323755/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22323755</a>] [<a href="https://doi.org/10.1212/WNL.0b013e318249f683" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22323755">Lee et al. (2012)</a>: (1) behavioral disturbances often precede motor onset, and (2) age of motor onset may not correlate to rate of disease progression. Based on an analysis of GWAS data evaluating genetic modifiers of age of onset of HD, the <a href="#23" class="mim-tip-reference" title="Genetic Modifiers of Huntington's Disease (GeM-HD) Consortium. <strong>CAG repeat not polyglutamine length determines timing of Huntington's disease onset.</strong> Cell 178: 887-900.e14, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31398342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31398342</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31398342[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/10.1016/j.cell.2019.06.036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31398342">Genetic Modifiers of Huntington's Disease (GeM-HD) Consortium (2019)</a> found that timing of appearance of HD symptoms was dependent on the length of the CAG repeat rather than on the length of the polyglutamine tract in HTT. Specifically, the CAA-CAG sequence at the distal end of the CAG tract in most HTT alleles, although it encodes for 2 glutamines, does not contribute to earlier onset of disease. The Consortium further concluded that HD disease presentation is also associated with the degree to which genetic modifiers influence the CAG expansion rate and threshold by which the CAG length causes toxicity in specific cells that are important for HD disease pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22927682+31398342+22323755" 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="#60" class="mim-tip-reference" title="Neueder, A., Kojer, K., Gu, Z., Wang, Y., Hering, T., Tabrizi, S., Taanman, J. W., Orth, M. <strong>Huntington's disease affects mitochondrial network dynamics predisposing to pathogenic mitochondrial DNA mutations.</strong> Brain 147: 2009-2022, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38195181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38195181</a>] [<a href="https://doi.org/10.1093/brain/awae007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38195181">Neueder et al. (2024)</a> analyzed mitochondrial DNA (mtDNA) in skeletal muscle from patients with HD and controls and identified increased accumulation of mtDNA mutations in patients. Proteomics analysis of skeletal muscle tissue from the patients demonstrated abnormalities in mtDNA maintenance accompanied by increased biogenesis but decreased complex I and IV activity. <a href="#60" class="mim-tip-reference" title="Neueder, A., Kojer, K., Gu, Z., Wang, Y., Hering, T., Tabrizi, S., Taanman, J. W., Orth, M. <strong>Huntington's disease affects mitochondrial network dynamics predisposing to pathogenic mitochondrial DNA mutations.</strong> Brain 147: 2009-2022, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38195181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38195181</a>] [<a href="https://doi.org/10.1093/brain/awae007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38195181">Neueder et al. (2024)</a> concluded that mutant HTT leads to mtDNA instability and compensatory upregulation of mitochondrial mass. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38195181" 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>Mechanism of HTT Repeat Expansion in Huntington Disease</em></strong></p><p>
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<a href="#86" class="mim-tip-reference" title="Zuhlke, C., Riess, O., Bockel, B., Lange, H., Thies, U. <strong>Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington disease gene.</strong> Hum. Molec. Genet. 2: 2063-2067, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8111374/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8111374</a>] [<a href="https://doi.org/10.1093/hmg/2.12.2063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8111374">Zuhlke et al. (1993)</a> studied the length variation of the repeat in 513 non-HD chromosomes from normal individuals and HD patients; the group comprised 23 alleles with 11 to 33 repeats. In an analysis of the inheritance of the (CAG)n stretch, they found meiotic instability for HD alleles, (CAG)40 to (CAG)75, with a mutation frequency of approximately 70%; following the HD allele in 38 pedigrees during 54 meioses, they found a ratio of stable to altered copy number of 15:39. On the other hand, in 431 meioses of normal alleles, only 2 expansions were identified. They found that the risk of expansion during spermatogenesis was enhanced compared to oogenesis, explaining juvenile onset by transmission from affected fathers. No mosaicism or differences in repeat lengths were observed in the DNA from different tissues, including brain and lymphocytes of 2 HD patients, indicating mitotic stability of the mutation. Thus, the determination of the repeat number in the DNA of blood lymphocytes is probably representative of all tissues in a patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8111374" 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="#75" class="mim-tip-reference" title="Telenius, H., Kremer, B., Goldberg, Y. P., Theilmann, J., Andrew, S. E., Zeisler, J., Adam, S., Greenberg, C., Ives, E. J., Clarke, L. A., Hayden, M. R. <strong>Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm.</strong> Nature Genet. 6: 409-414, 1994. Note: Erratum: Nature Genet. 7: 113 only, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8054984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8054984</a>] [<a href="https://doi.org/10.1038/ng0494-409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8054984">Telenius et al. (1994)</a> found somatic mosaicism for the CAG repeat in different tissues from 12 HD patients. Mosaicism for the highest numbers of CAG repeats was found in the brain, particularly in the basal ganglia and cortex, with lesser changes in the cerebellum. Sperm samples from 4 males also showed high levels of somatic mosaicism. Blood and other tissues showed lower levels of mosaicism. <a href="#75" class="mim-tip-reference" title="Telenius, H., Kremer, B., Goldberg, Y. P., Theilmann, J., Andrew, S. E., Zeisler, J., Adam, S., Greenberg, C., Ives, E. J., Clarke, L. A., Hayden, M. R. <strong>Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm.</strong> Nature Genet. 6: 409-414, 1994. Note: Erratum: Nature Genet. 7: 113 only, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8054984/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8054984</a>] [<a href="https://doi.org/10.1038/ng0494-409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8054984">Telenius et al. (1994)</a> suggested that expanded HTT gene CAG repeats are associated with tissue-specific mitotic and meiotic instability. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8054984" 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="#51" class="mim-tip-reference" title="MacDonald, M. E., Barnes, G., Srinidhi, J., Duyao, M. P., Ambrose, C. M., Myers, R. H., Gray, J., Conneally, P. M., Young, A., Penney, J., Shoulson, I., Hollingsworth, Z., Koroshetz, W., Bird, E., Vonsattel, J. P., Bonilla, E., Moscowitz, C., Penchaszadeh, G., Brzustowicz, L., Alvir, J., Bickham Conde, J., Cha, J.-H., Dure, L., Gomez, F., Ramos-Arroyo, M., Sanchez-Ramos, J., Snodgrass, S. R., de Young, M., Wexler, N. S., MacFarlane, H., Anderson, M. A., Jenkins, B., Gusella, J. F. <strong>Gametic but not somatic instability of CAG repeat length in Huntington's disease.</strong> J. Med. Genet. 30: 982-986, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8133508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8133508</a>] [<a href="https://doi.org/10.1136/jmg.30.12.982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8133508">MacDonald et al. (1993)</a> found that unlike the similar CCG repeat in the fragile X syndrome, the expanded HD repeat shows no evidence of somatic instability in a comparison of blood, lymphoblast, and brain DNA from the same persons. Furthermore, 4 pairs of monozygotic HD twins displayed identical CAG repeat lengths, suggesting that repeat size is determined in gametogenesis. However, in contrast to the fragile X syndrome and with HD somatic tissue, mosaicism was readily detected as a diffuse spread of repeat lengths in DNA from HD sperm samples. Thus, the developmental timing of repeat instability appears to differ between HD and fragile X syndrome, indicating perhaps that the fundamental mechanisms leading to repeat expansion are distinct. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8133508" 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="#47" class="mim-tip-reference" title="Leeflang, E. P., Zhang, L., Tavare, S., Hubert, R., Srinidhi, J., MacDonald, M. E., Myers, R. H., de Young, M., Wexler, N. S., Gusella, J. F., Arnheim, N. <strong>Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: quantification of the mutation frequency spectrum.</strong> Hum. Molec. Genet. 4: 1519-1526, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541834</a>] [<a href="https://doi.org/10.1093/hmg/4.9.1519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8541834">Leeflang et al. (1995)</a> amplified the CAG triplet repeat region of the HD gene in 923 single sperm from 3 affected and 2 normal individuals. Average-sized alleles (15-18 repeats) showed only 3 contraction mutations among 475 sperm (0.6%). A 30-repeat normal allele showed an 11% mutation frequency. The mutation frequency of a 36-repeat intermediate allele was 53% with 8% of all gametes having expansions that brought the allele size into the HD disease range (38 repeats or more). Disease alleles (38-51 repeats) showed a very high mutation frequency (92-99%). As repeat number increased, the authors found a marked elevation in the frequency of expansions, in the mean number of repeats added per expansion, and in the size of the largest observed expansion. Contraction frequencies also appeared to increase with allele size but decreased as repeat number exceeded 36. Since the sperm typing data were of a discrete nature rather than consisting of smears of PCR products from pooled sperm, <a href="#47" class="mim-tip-reference" title="Leeflang, E. P., Zhang, L., Tavare, S., Hubert, R., Srinidhi, J., MacDonald, M. E., Myers, R. H., de Young, M., Wexler, N. S., Gusella, J. F., Arnheim, N. <strong>Single sperm analysis of the trinucleotide repeats in the Huntington's disease gene: quantification of the mutation frequency spectrum.</strong> Hum. Molec. Genet. 4: 1519-1526, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8541834/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8541834</a>] [<a href="https://doi.org/10.1093/hmg/4.9.1519" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8541834">Leeflang et al. (1995)</a> could compare the observed mutation frequency spectra to the distribution calculated using discrete stochastic models based on current molecular ideas of the expansion process. An excellent fit was found when the model specified that a random number of repeats are added during the progression of the DNA polymerase through the repeated region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8541834" 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>All mutations for Huntington disease arise from so-called intermediate alleles (IAs) containing between 29 and 35 CAG repeats. The CAG repeats expand on transmission through the paternal germline to 36 or more repeats. Intermediate alleles are present on approximately 1% of normal chromosomes of Caucasian descent. Affected individuals have an expanded allele of between 36 to 121 CAGs, but incomplete penetrance has been found for repeat lengths of 36 to 40 CAGs. Using single sperm analysis, <a href="#12" class="mim-tip-reference" title="Chong, S. S., Almqvist, E., Telenius, H., LaTray, L., Nichol, K., Bourdelat-Parks, B., Goldberg, Y. P., Haddad, B. R., Richards, F., Sillence, D., Greenberg, C. R., Ives, E., Van den Engh, G., Hughes, M. R., Hayden, M. R. <strong>Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses.</strong> Hum. Molec. Genet. 6: 301-309, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9063751/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9063751</a>] [<a href="https://doi.org/10.1093/hmg/6.2.301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9063751">Chong et al. (1997)</a> assessed CAG mutation frequencies of 4 IAs in families with sporadic HD and IAs ascertained from the general population by analyzing 1161 single sperm from 3 persons. They showed that the intermediate alleles of the former group were more unstable than those in the general population with identical size and sequence. Furthermore, comparison of different sized IAs and IAs with different sequences between the CAG and the adjacent CCG tracts indicated that DNA sequence is a major influence on CAG stability. These studies provided estimates of the likelihood of expansion to 36 or more CAG repeats for individuals in the 2 groups. For an IA with (CAG)35 in the family with sporadic HD, the likelihood for sibs to inherit a recurrent mutation equal to or more than (CAG)36 was approximately 10%. For intermediate alleles of a similar size in the general population, the risk of inheriting an expanded allele of 36 or more CAGs through the paternal germline was approximately 6%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9063751" 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 typing greater than 3,500 sperm, <a href="#46" class="mim-tip-reference" title="Leeflang, E. P., Tavare, S., Marjoram, P., Neal, C. O. S., Srinidhi, J., MacFarlane, H., MacDonald, M. E., Gusella, J. F., de Young, M., Wexler, N. S., Arnheim, N. <strong>Analysis of germline mutation spectra at the Huntington's disease locus supports a mitotic mutation mechanism.</strong> Hum. Molec. Genet. 8: 173-183, 1999. Note: Erratum: Hum. Molec. Genet. 8: 717 only, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9931325/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9931325</a>] [<a href="https://doi.org/10.1093/hmg/8.2.173" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9931325">Leeflang et al. (1999)</a> determined the size distribution of HD germline mutations produced by 26 men in the Venezuelan cohort with CAG/CTG repeat numbers ranging from 37 to 62. Both the mutation frequency and mean change in allele size increased with increasing somatic repeat number. The mutation frequencies averaged 82%, and for individuals with at least 50 repeats, 98%. The extraordinarily high mutation frequency levels are most consistent with a process that occurs throughout germline mitotic divisions, rather than resulting from a single meiotic event. A statistical model based on incomplete processing of Okazaki fragments during DNA replication was found to provide an excellent fit to the data, but variation in parameter values among individuals suggests that the molecular mechanism might be more complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9931325" 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>Large intergenerational repeat expansions of the CAG trinucleotide repeat in the HD gene are well documented for the male germline. <a href="#43" class="mim-tip-reference" title="Laccone, F., Christian, W. <strong>A recurrent expansion of a maternal allele with 36 CAG repeats causes Huntington disease in two sisters.</strong> Am. J. Hum. Genet. 66: 1145-1148, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712225</a>] [<a href="https://doi.org/10.1086/302810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712225">Laccone and Christian (2000)</a> described a recurrent large expansion of a maternal allele with 36 CAG repeats (to 66 and 57 repeats, respectively, in 2 daughters) associated with onset of Huntington disease in the second and third decade in a family without history of HD. The findings gave evidence of gonadal mosaicism in the unaffected mother. <a href="#43" class="mim-tip-reference" title="Laccone, F., Christian, W. <strong>A recurrent expansion of a maternal allele with 36 CAG repeats causes Huntington disease in two sisters.</strong> Am. J. Hum. Genet. 66: 1145-1148, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10712225/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10712225</a>] [<a href="https://doi.org/10.1086/302810" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10712225">Laccone and Christian (2000)</a> hypothesized that large expansions also occur in the female germline and that a negative selection of oocytes with long repeats may explain the different instability behavior of the male and female germlines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10712225" 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="#42" class="mim-tip-reference" title="Kovtun, I. V., Therneau, T. M., McMurray, C. T. <strong>Gender of the embryo contributes to CAG instability in transgenic mice containing a Huntington's disease gene.</strong> Hum. Molec. Genet. 9: 2767-2775, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11063736/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11063736</a>] [<a href="https://doi.org/10.1093/hmg/9.18.2767" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11063736">Kovtun et al. (2000)</a> followed the fate of the CAG trinucleotide repeat, during transmission, in a transgene containing the exon 1 portion of the human Huntington disease gene. Similar to humans, the mouse transmits expansions predominantly through the male germline. However, the CAG repeat size of the mutant human HD gene is different in male and female progeny from identical fathers. Males predominantly expanded the repeat, whereas females predominantly contracted the repeat. In contrast to the classic definition of imprinting, CAG expansion is influenced by the gender of the embryo. The authors hypothesized that there may be X- or Y-encoded factors that influence repair or replication of DNA in the embryo, and that gender dependence in the embryo may explain why expansion in HD from premutation to disease primarily occurs through the paternal line. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11063736" 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="#82" class="mim-tip-reference" title="Yoon, S.-R., Dubeau, L., de Young, M., Wexler, N. S., Arnheim, N. <strong>Huntington disease expansion mutations in humans can occur before meiosis is completed.</strong> Proc. Nat. Acad. Sci. 100: 8834-8838, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12857955/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12857955</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12857955[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.1331390100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12857955">Yoon et al. (2003)</a> performed single-molecule DNA analysis of testicular germ cells isolated by laser capture microdissection from 2 HD patients, showing that trinucleotide repeat expansion mutations were present before the end of the first present meiotic division, and some mutations were present even before meiosis began. Most of the larger Huntington disease mutations were found in the postmeiotic cell population, suggesting that expansions may continue to occur during meiosis and/or after meiosis is complete. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12857955" 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="#40" class="mim-tip-reference" title="Kennedy, L., Evans, E., Chen, C.-M., Craven, L., Detloff, P. J., Ennis, M., Shelbourne, P. F. <strong>Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis.</strong> Hum. Molec. Genet. 12: 3359-3367, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570710</a>] [<a href="https://doi.org/10.1093/hmg/ddg352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570710">Kennedy et al. (2003)</a> showed dramatic mutation length increases (gains of 16 to 1,000 CAG repeats) in human striatal cells early in the disease course, most likely before the onset of pathologic cell loss. Studies of knockin HD mice indicated that the size of the initial CAG repeat mutation may influence both onset and tissue-specific patterns of age-dependent, expansion-biased mutation length variability. Given that CAG repeat length strongly correlates with clinical severity, <a href="#40" class="mim-tip-reference" title="Kennedy, L., Evans, E., Chen, C.-M., Craven, L., Detloff, P. J., Ennis, M., Shelbourne, P. F. <strong>Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis.</strong> Hum. Molec. Genet. 12: 3359-3367, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570710</a>] [<a href="https://doi.org/10.1093/hmg/ddg352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570710">Kennedy et al. (2003)</a> suggested that somatic increases of mutation length may play a major role in the progressive nature and cell-selective aspects of both adult-onset and juvenile-onset HD pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14570710" 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="Cannella, M., Maglione, V., Martino, T., Simonelli, M., Ragona, G., Squitieri, F. <strong>New Huntington disease mutation arising from a paternal CAG(34) allele showing somatic length variation in serially passaged lymphoblasts.</strong> Am. J. Med. Genet. 133B: 127-130, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15546151/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15546151</a>] [<a href="https://doi.org/10.1002/ajmg.b.30125" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15546151">Cannella et al. (2005)</a> reported a triplet size increase in an intermediate-sized allele (34 CAG) of the huntingtin gene carried by a lymphoblast cell culture after 30 passages. This finding demonstrated that the huntingtin gene shows somatic as well as germline instability and has a propensity for somatic CAG variation in human cells even with repeat numbers under the expanded edge (i.e., intermediate alleles being defined as containing between 29 and 35 CAG repeats). Factors potentially cis acting with this particular mutation included a CCG polymorphic stretch, deletion of the glutamic acid residue at position 2642, and the 4-codon segment between CAG and CCG polymorphisms. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15546151" 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="#41" class="mim-tip-reference" title="Kovtun, I. V., Liu, Y., Bjoras, M., Klungland, A., Wilson, S. H., McMurray, C. T. <strong>OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells.</strong> Nature 447: 447-452, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17450122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17450122</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17450122[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/nature05778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17450122">Kovtun et al. (2007)</a> demonstrated that the age-dependent somatic CAG expansion associated with Huntington disease (<a href="#40" class="mim-tip-reference" title="Kennedy, L., Evans, E., Chen, C.-M., Craven, L., Detloff, P. J., Ennis, M., Shelbourne, P. F. <strong>Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis.</strong> Hum. Molec. Genet. 12: 3359-3367, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14570710/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14570710</a>] [<a href="https://doi.org/10.1093/hmg/ddg352" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14570710">Kennedy et al., 2003</a>) occurs in the process of removing oxidized base lesions, and is remarkably dependent on the single-base excision repair enzyme 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1; <a href="/entry/601982">601982</a>). Both in vivo and in vitro results supported a 'toxic oxidation' model in which OGG1 initiates an escalating oxidation-excision cycle that leads to progressive age-dependent expansion. <a href="#41" class="mim-tip-reference" title="Kovtun, I. V., Liu, Y., Bjoras, M., Klungland, A., Wilson, S. H., McMurray, C. T. <strong>OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells.</strong> Nature 447: 447-452, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17450122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17450122</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17450122[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/nature05778" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17450122">Kovtun et al. (2007)</a> concluded that age-dependent CAG expansion provides a direct molecular link between oxidative damage and toxicity in postmitotic neurons through a DNA damage response, and error-prone repair of single-strand breaks. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=17450122+14570710" 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="#79" class="mim-tip-reference" title="Wright, G. E. B., Collins, J. A., Kay, C., McDonald, C., Dolzhenko, E., Xia, Q., Becanovic, K., Drogemoller, B. I., Semaka, A., Nguyen, C. M., Trost, B., Richards, F., Bijlsma, E. K., Squitieri, F., Ross, C. J. D., Scherer, S. W., Eberle, M. A., Yuen, R. K. C., Hayden, M. R. <strong>Length of uninterrupted CAG, independent of polyglutamine size, results in increased somatic instability, hastening onset of Huntington disease.</strong> Am. J. Hum. Genet. 104: 1116-1126, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31104771/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31104771</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31104771[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/10.1016/j.ajhg.2019.04.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31104771">Wright et al. (2019)</a> assessed the effect of a sequence variant downstream of the CAG repeat in the HTT gene, a change from (CAG)n-CAA-CAG to (CAG)n-CAG-CAG, in 16 patients with HD from 6 families. The variant resulted in complete loss of interrupting (LOI) adenine nucleotides in this region. The LOI was associated with increased somatic CAG tract instability and increased repeat size as assessed in patient blood and sperm. Patients who were carriers of the LOI variant had an average of disease onset 25 years earlier than predicted by models. This effect was particularly seen in patients who were carriers of reduced penetrance alleles of 36 to 39 CAG repeat lengths in the HTT gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31104771" 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>Lopes-Maciel-Rodan Syndrome</em></strong></p><p>
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In an 18-year-old girl with Lopes-Maciel-Rodan syndrome (LOMARS; <a href="/entry/617435">617435</a>), <a href="#50" class="mim-tip-reference" title="Lopes, F., Barbosa, M., Ameur, A., Soares, G., de Sa, J., Dias, A. I., Oliveira, G., Cabral, P., Temudo, T., Calado, E., Cruz, I. F., Vieira, J. P., Oliveira, R., Esteves, S., Sauer, S., Jonasson, I., Syvanen, A.-C., Gyllensten, U., Pinto, D., Maciel, P. <strong>Identification of novel genetic causes of Rett syndrome-like phenotypes.</strong> J. Med. Genet. 53: 190-199, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26740508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26740508</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26740508">Lopes et al. (2016)</a> identified compound heterozygous missense mutations in the HTT gene (P703L, <a href="#0002">613004.0002</a> and T1260M, <a href="#0003">613004.0003</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but <a href="#50" class="mim-tip-reference" title="Lopes, F., Barbosa, M., Ameur, A., Soares, G., de Sa, J., Dias, A. I., Oliveira, G., Cabral, P., Temudo, T., Calado, E., Cruz, I. F., Vieira, J. P., Oliveira, R., Esteves, S., Sauer, S., Jonasson, I., Syvanen, A.-C., Gyllensten, U., Pinto, D., Maciel, P. <strong>Identification of novel genetic causes of Rett syndrome-like phenotypes.</strong> J. Med. Genet. 53: 190-199, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26740508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26740508</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26740508">Lopes et al. (2016)</a> noted that the HTT gene interacts with MECP2 (<a href="/entry/300005">300005</a>), which is mutant in Rett syndrome (RTT; <a href="/entry/312750">312750</a>). The patient filled diagnostic criteria for RTT, suggesting a common molecular pathogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26740508" 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 3 sibs, born of parents of Ecuadorian descent, with LOMARS, <a href="#64" class="mim-tip-reference" title="Rodan, L. H., Cohen, J., Fatemi, A., Gillis, T., Lucente, D., Gusella, J., Picker, J. D. <strong>A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene.</strong> Europ. J. Hum. Genet. 24: 1826-1827, 2016. Note: Erratum: Europ. J. Hum. Genet. 24: 1838 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27329733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27329733</a>] [<a href="https://doi.org/10.1038/ejhg.2016.74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27329733">Rodan et al. (2016)</a> identified compound heterozygous mutations in the HTT gene (<a href="#0004">613004.0004</a> and <a href="#0005">613004.0005</a>). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27329733" 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="#37" class="mim-tip-reference" title="Jung, R., Lee, Y., Barker, D., Correia, K., Shin, B., Loupe, J., Collins, R. L., Lucente, D., Ruliera, J., Gillis, T., Mysore, J. S., Rodan, L., Picker, J., Lee, J. M., Howland, D., Lee, R., Kwak, S., MacDonald, M. E., Gusella, J. F., Seong, I. S. <strong>Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs.</strong> Hum. Molec. Genet. 30: 135-148, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33432339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33432339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33432339[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/ddaa283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33432339">Jung et al. (2021)</a> performed functional studies in fibroblasts from the parents and 1 affected sib and in lymphoblastoid cell lines from another affected sib from the family described by <a href="#64" class="mim-tip-reference" title="Rodan, L. H., Cohen, J., Fatemi, A., Gillis, T., Lucente, D., Gusella, J., Picker, J. D. <strong>A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene.</strong> Europ. J. Hum. Genet. 24: 1826-1827, 2016. Note: Erratum: Europ. J. Hum. Genet. 24: 1838 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27329733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27329733</a>] [<a href="https://doi.org/10.1038/ejhg.2016.74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27329733">Rodan et al. (2016)</a> with LOMARS. The 2 affected sibs inherited F2719L (<a href="#0005">613004.0005</a>) from the mother and c.4469+1G-A (<a href="#0004">613004.0004</a>) from the father. There was reduced HTT mRNA in the cells from the father and the affected sibs, and RT-PCR studies demonstrated that the c.4469+1G-A mutation resulted in skipping of exon 34, with a subsequent frameshift and premature termination. Studies in the maternal cells showed that the F2719L mutation resulted in reduced protein stability. <a href="#37" class="mim-tip-reference" title="Jung, R., Lee, Y., Barker, D., Correia, K., Shin, B., Loupe, J., Collins, R. L., Lucente, D., Ruliera, J., Gillis, T., Mysore, J. S., Rodan, L., Picker, J., Lee, J. M., Howland, D., Lee, R., Kwak, S., MacDonald, M. E., Gusella, J. F., Seong, I. S. <strong>Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs.</strong> Hum. Molec. Genet. 30: 135-148, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33432339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33432339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33432339[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/ddaa283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33432339">Jung et al. (2021)</a> concluded that LOMARS is due to biallelic hypomorphic loss-of-function mutations in HTT, and that heterozygosity for a loss-of-function mutation in HTT is not disease causing. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27329733+33432339" 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="#58" class="mim-tip-reference" title="Nasir, J., Floresco, S. B., O'Kusky, J. R., Diewert, V. M., Richman, J. M., Zeisler, J., Borowski, A., Marth, J. D., Phillips, A. G., Hayden, M. R. <strong>Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes.</strong> Cell 81: 811-823, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7774020/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7774020</a>] [<a href="https://doi.org/10.1016/0092-8674(95)90542-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7774020">Nasir et al. (1995)</a> created a targeted disruption in exon 5 of Hdh, the murine homolog of the HTT gene, using homologous recombination. They found that homozygotes died before embryonic day 8.5 and initiated gastrulation, but did not proceed to the formation of somites or to organogenesis. Mice heterozygous for the mutation displayed increased motor activity and cognitive deficits. Neuropathologic assessment of 2 heterozygous mice showed a significant neuronal loss in the subthalamic nucleus. These studies showed that the HD gene is essential for postimplantation development and that it may play an important role in normal functioning of the basal ganglia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7774020" 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 distinguish between 'loss-of-function' and 'gain-of-function' models of HD, <a href="#19" class="mim-tip-reference" title="Duyao, M. P., Auerbach, A. B., Ryan, A., Persichetti, F., Barnes, G. T., McNeil, S. M., Ge, P., Vonsattel, J.-P., Gusella, J. F., Joyner, A. L., MacDonald, M. E. <strong>Inactivation of the mouse Huntington's disease gene homolog Hdh.</strong> Science 269: 407-410, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7618107/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7618107</a>] [<a href="https://doi.org/10.1126/science.7618107" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7618107">Duyao et al. (1995)</a> inactivated the mouse Hdh by gene targeting. Mice heterozygous for Hdh inactivation were phenotypically normal, whereas homozygosity resulted in embryonic death. Homozygotes displayed abnormal gastrulation at embryonic day 7.5 and were resorbing by day 8.5. The authors concluded that huntingtin is critical early in embryonic development, before the emergence of the nervous system. That Hdh inactivation did not mimic adult HD neuropathology suggested to the authors that the human disease involves a gain of function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7618107" 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="#83" class="mim-tip-reference" title="Zeitlin, S., Liu, J.-P., Chapman, D. L., Papaioannou, V. E., Efstratiadis, A. <strong>Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue.</strong> Nature Genet. 11: 155-163, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550343</a>] [<a href="https://doi.org/10.1038/ng1095-155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550343">Zeitlin et al. (1995)</a> also used targeted gene disruption of Hdh and found that mice nullizygous for the Hdh gene showed developmental retardation and disorganization as embryos and died between days 8.5 and 10.5 of gestation. Based on the observation that the level of the regionalized apoptotic cell death in the embryonic ectoderm, a layer expressing the Hdh gene, was much higher than normal in the null mutants, <a href="#83" class="mim-tip-reference" title="Zeitlin, S., Liu, J.-P., Chapman, D. L., Papaioannou, V. E., Efstratiadis, A. <strong>Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue.</strong> Nature Genet. 11: 155-163, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7550343/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7550343</a>] [<a href="https://doi.org/10.1038/ng1095-155" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7550343">Zeitlin et al. (1995)</a> proposed that huntingtin is involved in processes counterbalancing the operation of an apoptotic pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7550343" 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="#31" class="mim-tip-reference" title="Hodgson, J. G., Smith, D. J., McCutcheon, K., Koide, H. B., Nishiyama, K., Dinulos, M. B., Stevens, M. E., Bissada, N., Nasir, J., Kanazawa, I., Disteche, C. M., Rubin, E. M., Hayden, M. R. <strong>Human huntingtin derived from YAC transgenes compensates for loss of murine huntingtin by rescue of the embryonic lethal phenotype.</strong> Hum. Molec. Genet. 5: 1875-1885, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8968738/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8968738</a>] [<a href="https://doi.org/10.1093/hmg/5.12.1875" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8968738">Hodgson et al. (1996)</a> reported results of their studies designed to rescue the embryonic lethality phenotype that results from targeted disruption of the murine HD gene. They generated viable offspring that were homozygous for the disrupted murine HD gene and that expressed human huntingtin derived from a YAC transgene. These results indicated that the YAC transgene was expressed prior to 7.5 days' gestation and that the human huntingtin protein was functional in a murine background. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8968738" 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="#52" class="mim-tip-reference" title="MacDonald, M. E., Duyao, M., Calzonetti, T., Auerbach, A., Ryan, A., Barnes, G., White, J. K., Auerbach, W., Vonsattel, J.-P., Gusella, J. F., Joyner, A. L. <strong>Targeted inactivation of the mouse Huntington's disease gene homolog Hdh.</strong> Cold Spring Harbor Symp. Quant. Biol. 61: 627-638, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9246489/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9246489</a>]" pmid="9246489">MacDonald et al. (1996)</a> reviewed the work with targeted inactivation of the mouse Hdh gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9246489" 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>It is known that huntingtin plays a fundamental role in development, since gene targeted Hd -/- mouse embryos died shortly after gastrulation. <a href="#55" class="mim-tip-reference" title="Metzler, M., Helgason, C. D., Dragatsis, I., Zhang, T., Gan, L., Pineault, N., Zeitlin, S. O., Humphries, R. K., Hayden, M. R. <strong>Huntingtin is required for normal hematopoiesis.</strong> Hum. Molec. Genet. 9: 387-394, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10655548/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10655548</a>] [<a href="https://doi.org/10.1093/hmg/9.3.387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10655548">Metzler et al. (2000)</a> analyzed expression of huntingtin in a variety of hematopoietic cell types, and in vitro hematopoiesis was assessed using an Hd +/- and several Hd -/- embryonic stem (ES) cell lines. Although wildtype and the 2 mutant cell lines formed primary embryoid bodies (EBs) with similar efficiency, the number of hematopoietic progenitors detected at various stages of the in vitro differentiation were reduced in both of the heterozygous and the homozygous ES cell lines examined. Expression analyses of hematopoietic markers within the EBs revealed that primitive and definitive hematopoiesis occurs in the absence of huntingtin. However, further analysis using a suspension culture in the presence of hematopoietic cytokines demonstrated a highly significant gene dosage-dependent decrease in proliferation and/or survival of Hd +/- and Hd -/- cells. Enrichment for the CD34+ (<a href="/entry/142230">142230</a>) cells within the EB confirmed that the impairment is intrinsic to the hematopoietic cells. These observations suggested that huntingtin expression is required for the generation and expansion of hematopoietic cells and provides an alternative system in which to assess the function of huntingtin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10655548" 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="#13" class="mim-tip-reference" title="Clabough, E. B. D., Zeitlin, S. O. <strong>Deletion of the triplet repeat encoding polyglutamine within the mouse Huntington's disease gene results in subtle behavioral/motor phenotypes in vivo and elevated levels of ATP with cellular senescence in vitro.</strong> Hum. Molec. Genet. 15: 607-623, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16403806/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16403806</a>] [<a href="https://doi.org/10.1093/hmg/ddi477" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16403806">Clabough and Zeitlin (2006)</a> found that mice with targeted deletion of the short CAG triplet repeat (7Q) in the Htt gene showed no gross phenotypic differences compared to control littermates. However, adult mice showed mild learning and memory deficits and slightly better motor coordination compared to wildtype mice. Fibroblast cultures derived from the 7Q-deletion mice had increased levels of ATP and senesced earlier compared to wildtype fibroblasts. The findings indicated that the polyQ stretch is not required for an essential function of HTT, but may be required for modulating longevity in culture or modulating a function involved in regulating energy homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16403806" 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 determine whether caspase cleavage of HTT is a key event in the neuronal dysfunction and selective neurodegeneration in HD, <a href="#25" class="mim-tip-reference" title="Graham, R. K., Deng, Y., Slow, E. J., Haigh, B., Bissada, N., Lu, G., Pearson, J., Shehadeh, J., Bertram, L., Murphy, Z., Warby, S. C., Doty, C. N., Roy, S., Wellington, C. L., Leavitt, B. R., Raymond, L. A., Nicholson, D. W., Hayden, M. R. <strong>Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin.</strong> Cell 125: 1179-1191, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16777606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16777606</a>] [<a href="https://doi.org/10.1016/j.cell.2006.04.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16777606">Graham et al. (2006)</a> generated YAC mice expressing caspase-3 (CASP3; <a href="/entry/600636">600636</a>)- and caspase-6 (CASP6; <a href="/entry/601532">601532</a>)-resistant mutant human HTT. Mice expressing mutant HTT resistant to cleavage by caspase-6, but not by caspase-3, maintained normal neuronal function and did not develop neurodegeneration. Furthermore, caspase-6-resistant mutant HTT mice were protected against neurotoxicity induced by multiple stressors, including NMDA, quinolinic acid, and staurosporine. <a href="#25" class="mim-tip-reference" title="Graham, R. K., Deng, Y., Slow, E. J., Haigh, B., Bissada, N., Lu, G., Pearson, J., Shehadeh, J., Bertram, L., Murphy, Z., Warby, S. C., Doty, C. N., Roy, S., Wellington, C. L., Leavitt, B. R., Raymond, L. A., Nicholson, D. W., Hayden, M. R. <strong>Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin.</strong> Cell 125: 1179-1191, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16777606/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16777606</a>] [<a href="https://doi.org/10.1016/j.cell.2006.04.026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16777606">Graham et al. (2006)</a> concluded that proteolysis of HTT at the caspase-6 cleavage site is a crucial and rate-limiting step in the pathogenesis of HD. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16777606" 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="Dietrich, P., Shanmugasundaram, R., E, S., Dragatsis, I. <strong>Congenital hydrocephalus associated with abnormal subcommissural organ in mice lacking huntingtin in Wnt1 cell lineages.</strong> Hum. Molec. Genet. 18: 142-150, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18838463/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18838463</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18838463[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/ddn324" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18838463">Dietrich et al. (2009)</a> inactivated the mouse Hdh gene in Wnt1 (<a href="/entry/164820">164820</a>) cell lineages, which contribute to development of the midbrain, hindbrain, granular cells of the cerebellum, and dorsal midline-derived ependymal secretory structures, using the Cre-loxP system of recombination. Conditional inactivation of the Hdh gene in Wnt1 cell lineages resulted in congenital hydrocephalus, which was associated with increase in CSF production by the choroid plexus, and abnormal subcommissural organ. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18838463" 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 synthetic antisense morpholinos to inhibit the translation of huntingtin mRNA during early zebrafish development, <a href="#30" class="mim-tip-reference" title="Henshall, T. L., Tucker, B., Lumsden, A. L., Nornes, S., Lardelli, M. T., Richards, R. I. <strong>Selective neuronal requirement for huntingtin in the developing zebrafish.</strong> Hum. Molec. Genet. 18: 4830-4842, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19797250/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19797250</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19797250[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/ddp455" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19797250">Henshall et al. (2009)</a> determined the effects of huntingtin loss of function on the developing nervous system, observing distinct defects in morphology of neuromasts, olfactory placode, and branchial arches. There was impaired formation of the anterior-most region of the neural plate as indicated by reduced pre-placodal and telencephalic gene expression, with no effect on mid- or hindbrain formation. The authors suggested a specific 'rate-limiting' role for huntingtin in formation of the telencephalon and the pre-placodal region, and differing levels of requirement for huntingtin function in specific nerve cell types. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19797250" 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="#81" class="mim-tip-reference" title="Yamanaka, T., Tosaki, A., Miyazaki, H., Kurosawa, M., Furukawa, Y., Yamada, M., Nukini, N. <strong>Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction.</strong> Hum. Molec. Genet. 19: 2099-2112, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20185558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20185558</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20185558[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/ddq087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20185558">Yamanaka et al. (2010)</a> performed a comprehensive analysis of altered DNA binding of multiple transcription factors using brains from R6/2 HD mice, which express an N-terminal fragment of mutant huntingtin (Nhtt). The authors observed a reduction of DNA binding of Brn2 (<a href="/entry/600494">600494</a>), a POU domain transcription factor involved in differentiation and function of hypothalamic neurosecretory neurons. Brn2 lost its function through 2 pathways, sequestration by mutant Nhtt and reduced transcription, leading to reduced expression of hypothalamic neuropeptides. In contrast, Brn1 (<a href="/entry/602480">602480</a>) was not sequestered by mutant Nhtt but was upregulated in R6/2 brain, except in hypothalamus. <a href="#81" class="mim-tip-reference" title="Yamanaka, T., Tosaki, A., Miyazaki, H., Kurosawa, M., Furukawa, Y., Yamada, M., Nukini, N. <strong>Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction.</strong> Hum. Molec. Genet. 19: 2099-2112, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20185558/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20185558</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20185558[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/ddq087" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20185558">Yamanaka et al. (2010)</a> concluded that functional suppression of Brn2 together with a region-specific lack of compensation by Brn1 may mediate hypothalamic cell dysfunction by mutant Nhtt. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20185558" 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="#36" class="mim-tip-reference" title="Jiang, M., Wang, J., Fu, J., Du, L., Jeong, H., West, T., Xiang, L., Peng, Q., Hou, Z., Cai, H., Seredenina, T., Arbez, N., and 18 others. <strong>Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets.</strong> Nature Med. 18: 153-158, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22179319/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22179319</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22179319[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/nm.2558" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22179319">Jiang et al. (2012)</a> found that mutant Htt interacted with Sirt1 (<a href="/entry/604479">604479</a>) and interfered with Sirt1 deacetylase activity in a mouse model of HD. Overexpression of Sirt1 reversed neurodegeneration and molecular changes observed in HD mice. Independently, <a href="#35" class="mim-tip-reference" title="Jeong, H., Cohen, D. E., Cui, L., Supinski, A., Savas, J. N., Mazzulli, J. R., Yates, J. R., III, Bordone, L., Guarente, L., Krainc, D. <strong>Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway.</strong> Nature Med. 18: 159-165, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22179316/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22179316</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22179316[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/nm.2559" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22179316">Jeong et al. (2012)</a> presented similar findings, including interaction of Htt with Sirt1. They found that interaction between Torc1 (CRTC1; <a href="/entry/607536">607536</a>) and Creb (<a href="/entry/123810">123810</a>) had a crucial role in Sirt1-mediated reversal of mutant Htt effects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=22179319+22179316" 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>For a discussion of animal models of Huntington disease, see ANIMAL MODEL section in <a href="/entry/143100">143100</a>.</p>
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<a href="/allelicVariants/613004" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=613004[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 HUNTINGTON DISEASE</strong>
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HTT, (CAG)n REPEAT EXPANSION
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000030659" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030659" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030659</a>
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<p>Huntington disease (HD; <a href="/entry/143100">143100</a>) is caused by expansion of a polymorphic trinucleotide repeat (CAG)n, encoding glutamine, located in the N-terminal coding region of the HTT gene. In normal individuals, the range of repeat numbers is 9 to 36. In those with HD, the repeat number is above 37 (<a href="#18" class="mim-tip-reference" title="Duyao, M., Ambrose, C., Myers, R., Novelletto, A., Persichetti, F., Frontali, M., Folstein, S., Ross, C., Franz, M., Abbott, M., Gray, J., Conneally, P., and 30 others. <strong>Trinucleotide repeat length instability and age of onset in Huntington's disease.</strong> Nature Genet. 4: 387-392, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401587</a>] [<a href="https://doi.org/10.1038/ng0893-387" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401587">Duyao et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8401587" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The trinucleotide repeat expansion was identified in affected members of 75 families with HD by the <a href="#34" class="mim-tip-reference" title="Huntington's Disease Collaborative Research Group. <strong>A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes.</strong> Cell 72: 971-983, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8458085/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8458085</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90585-e" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8458085">Huntington's Disease Collaborative Research Group (1993)</a>. The families came from a variety of ethnic backgrounds and demonstrated a variety of 4p16.3 haplotypes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8458085" 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="Gellera, C., Meoni, C., Castellotti, B., Zappacosta, B., Girotti, F., Taroni, F., DiDonato, S. <strong>Errors in Huntington disease diagnostic test caused by trinucleotide deletion in the IT15 gene. (Letter)</strong> Am. J. Hum. Genet. 59: 475-477, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755937</a>]" pmid="8755937">Gellera et al. (1996)</a> noted that the unstable (CAG)n repeat lies immediately upstream from a moderately polymorphic polyproline-encoding (CCG)n repeat. They noted further that a number of reports in the literature indicated that in normal subjects the number of (CAG)n repeats ranges from 9 to 36, while in HD patients it ranges from 37 to 100. The downstream (CCG)n repeat may vary in size between 7 and 12 repeats in both affected and normal individuals. They reported the occurrence of a CAA trinucleotide deletion (nucleotides 433-435) in HD chromosomes in 2 families that, because of its position within the conventional antisense primer hd447, hampered HD mutation detection if only the (CAG)n tract were amplified. Therefore, <a href="#22" class="mim-tip-reference" title="Gellera, C., Meoni, C., Castellotti, B., Zappacosta, B., Girotti, F., Taroni, F., DiDonato, S. <strong>Errors in Huntington disease diagnostic test caused by trinucleotide deletion in the IT15 gene. (Letter)</strong> Am. J. Hum. Genet. 59: 475-477, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755937</a>]" pmid="8755937">Gellera et al. (1996)</a> stressed the importance of using a series of 3 diagnostic PCR reactions: one that amplified the (CAG)n tract alone, one that amplified the (CCG)n tract alone, and one that amplified the whole region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8755937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0002 LOPES-MACIEL-RODAN SYNDROME</strong>
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HTT, PRO703LEU
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs768047421 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs768047421;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs768047421?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs768047421" 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=rs768047421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000477706 OR RCV001851126 OR RCV004760523" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000477706, RCV001851126, RCV004760523" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000477706...</a>
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<p>In an 18-year-old girl (proband 2) with Lopes-Maciel-Rodan syndrome (LOMARS; <a href="/entry/617435">617435</a>), <a href="#50" class="mim-tip-reference" title="Lopes, F., Barbosa, M., Ameur, A., Soares, G., de Sa, J., Dias, A. I., Oliveira, G., Cabral, P., Temudo, T., Calado, E., Cruz, I. F., Vieira, J. P., Oliveira, R., Esteves, S., Sauer, S., Jonasson, I., Syvanen, A.-C., Gyllensten, U., Pinto, D., Maciel, P. <strong>Identification of novel genetic causes of Rett syndrome-like phenotypes.</strong> J. Med. Genet. 53: 190-199, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26740508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26740508</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26740508">Lopes et al. (2016)</a> identified compound heterozygous mutations in the HTT gene: a c.2108C-T transition (c.2108C-T, NM_002111), resulting in a pro703-to-leu (P703L) substitution, and a c.3779C-T transition, resulting in a thr1260-to-met (T1260M; <a href="#0003">613004.0003</a>) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The T1260M variant was present at a low frequency in the dbSNP database (0.0276/138). Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26740508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 LOPES-MACIEL-RODAN SYNDROME</strong>
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HTT, THR1260MET (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34315806;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs34315806</a>)
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs34315806 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs34315806;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs34315806?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs34315806" 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=rs34315806" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000477735 OR RCV001662450 OR RCV001777163" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000477735, RCV001662450, RCV001777163" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000477735...</a>
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<p>For discussion of the c.3779C-T transition (c.3779C-T, NM_002111) in the HTT gene, resulting in a thr1260-to-met (T1260M) substitution, that was found in compound heterozygous state in a patient with Lopes-Maciel-Rodan syndrome (LOMARS; <a href="/entry/617435">617435</a>) by <a href="#50" class="mim-tip-reference" title="Lopes, F., Barbosa, M., Ameur, A., Soares, G., de Sa, J., Dias, A. I., Oliveira, G., Cabral, P., Temudo, T., Calado, E., Cruz, I. F., Vieira, J. P., Oliveira, R., Esteves, S., Sauer, S., Jonasson, I., Syvanen, A.-C., Gyllensten, U., Pinto, D., Maciel, P. <strong>Identification of novel genetic causes of Rett syndrome-like phenotypes.</strong> J. Med. Genet. 53: 190-199, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26740508/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26740508</a>] [<a href="https://doi.org/10.1136/jmedgenet-2015-103568" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26740508">Lopes et al. (2016)</a>, see <a href="#0002">613004.0002</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26740508" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1060505027 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1060505027;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=rs1060505027" 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=rs1060505027" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000477676 OR RCV000490292" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000477676, RCV000490292" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000477676...</a>
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<p>In 3 sibs, born of parents of Ecuadorian descent, with Lopes-Maciel-Rodan syndrome (LOMARS; <a href="/entry/617435">617435</a>), <a href="#64" class="mim-tip-reference" title="Rodan, L. H., Cohen, J., Fatemi, A., Gillis, T., Lucente, D., Gusella, J., Picker, J. D. <strong>A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene.</strong> Europ. J. Hum. Genet. 24: 1826-1827, 2016. Note: Erratum: Europ. J. Hum. Genet. 24: 1838 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27329733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27329733</a>] [<a href="https://doi.org/10.1038/ejhg.2016.74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27329733">Rodan et al. (2016)</a> identified compound heterozygous mutations in the HTT gene: a paternally inherited c.4469+1G-A transition in intron 34, predicted to result in abnormal gene splicing, and a maternally inherited c.8156T-A transversion, resulting in a phe2719-to-leu (F2719L; <a href="#0005">613004.0005</a>) substitution at a conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the Exome Sequencing Project or ExAC databases or in about 6,000 control individuals. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27329733" 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="#37" class="mim-tip-reference" title="Jung, R., Lee, Y., Barker, D., Correia, K., Shin, B., Loupe, J., Collins, R. L., Lucente, D., Ruliera, J., Gillis, T., Mysore, J. S., Rodan, L., Picker, J., Lee, J. M., Howland, D., Lee, R., Kwak, S., MacDonald, M. E., Gusella, J. F., Seong, I. S. <strong>Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs.</strong> Hum. Molec. Genet. 30: 135-148, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33432339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33432339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33432339[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/ddaa283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33432339">Jung et al. (2021)</a> noted that the correct nucleotide change for the maternally inherited variant reported by <a href="#64" class="mim-tip-reference" title="Rodan, L. H., Cohen, J., Fatemi, A., Gillis, T., Lucente, D., Gusella, J., Picker, J. D. <strong>A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene.</strong> Europ. J. Hum. Genet. 24: 1826-1827, 2016. Note: Erratum: Europ. J. Hum. Genet. 24: 1838 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27329733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27329733</a>] [<a href="https://doi.org/10.1038/ejhg.2016.74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27329733">Rodan et al. (2016)</a> is c.8157T-A (c.8157T-A, NM_002111.8). They also noted that c.4469+1G-A (NM_002111.8) corresponds to c.4463+1G-A (GRCh38). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27329733+33432339" 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="#37" class="mim-tip-reference" title="Jung, R., Lee, Y., Barker, D., Correia, K., Shin, B., Loupe, J., Collins, R. L., Lucente, D., Ruliera, J., Gillis, T., Mysore, J. S., Rodan, L., Picker, J., Lee, J. M., Howland, D., Lee, R., Kwak, S., MacDonald, M. E., Gusella, J. F., Seong, I. S. <strong>Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs.</strong> Hum. Molec. Genet. 30: 135-148, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33432339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33432339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33432339[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/ddaa283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33432339">Jung et al. (2021)</a> performed functional studies in fibroblasts from the parents and 1 affected sib and in lymphoblastoid cell lines from another affected sib from the family described by <a href="#64" class="mim-tip-reference" title="Rodan, L. H., Cohen, J., Fatemi, A., Gillis, T., Lucente, D., Gusella, J., Picker, J. D. <strong>A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene.</strong> Europ. J. Hum. Genet. 24: 1826-1827, 2016. Note: Erratum: Europ. J. Hum. Genet. 24: 1838 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27329733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27329733</a>] [<a href="https://doi.org/10.1038/ejhg.2016.74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27329733">Rodan et al. (2016)</a> with LOMARS. There was reduced HTT mRNA in cells from the father and the affected sibs, and RT-PCR studies demonstrated that the c.4469+1G-A mutation resulted in skipping of exon 34, with a subsequent frameshift and premature termination. Studies in the maternal cells showed that the F2719L mutation resulted in reduced protein stability. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27329733+33432339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 LOPES-MACIEL-RODAN SYNDROME</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">rs1060505028 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1060505028;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=rs1060505028" 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=rs1060505028" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000477714" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000477714" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000477714</a>
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<p>For discussion of the phe2719-to-leu (F2719L) substitution in the HTT gene that was found in compound heterozygous state in 3 sibs with Lopes-Maciel-Rodan syndrome (LOMARS; <a href="/entry/617435">617435</a>) by <a href="#64" class="mim-tip-reference" title="Rodan, L. H., Cohen, J., Fatemi, A., Gillis, T., Lucente, D., Gusella, J., Picker, J. D. <strong>A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene.</strong> Europ. J. Hum. Genet. 24: 1826-1827, 2016. Note: Erratum: Europ. J. Hum. Genet. 24: 1838 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27329733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27329733</a>] [<a href="https://doi.org/10.1038/ejhg.2016.74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27329733">Rodan et al. (2016)</a>, see <a href="#0004">613004.0004</a>. <a href="#64" class="mim-tip-reference" title="Rodan, L. H., Cohen, J., Fatemi, A., Gillis, T., Lucente, D., Gusella, J., Picker, J. D. <strong>A novel neurodevelopmental disorder associated with compound heterozygous variants in the huntingtin gene.</strong> Europ. J. Hum. Genet. 24: 1826-1827, 2016. Note: Erratum: Europ. J. Hum. Genet. 24: 1838 only, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27329733/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27329733</a>] [<a href="https://doi.org/10.1038/ejhg.2016.74" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27329733">Rodan et al. (2016)</a> reported the nucleotide change for this variant as a c.8156T-A transversion, but <a href="#37" class="mim-tip-reference" title="Jung, R., Lee, Y., Barker, D., Correia, K., Shin, B., Loupe, J., Collins, R. L., Lucente, D., Ruliera, J., Gillis, T., Mysore, J. S., Rodan, L., Picker, J., Lee, J. M., Howland, D., Lee, R., Kwak, S., MacDonald, M. E., Gusella, J. F., Seong, I. S. <strong>Mutations causing Lopes-Maciel-Rodan syndrome are huntingtin hypomorphs.</strong> Hum. Molec. Genet. 30: 135-148, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33432339/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33432339</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33432339[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/ddaa283" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33432339">Jung et al. (2021)</a> noted that the correct nucleotide change for this variant is c.8157T-A (c.8157T-A, NM_002111.8). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=27329733+33432339" 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>REFERENCES</strong>
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<a id="Altherr1992" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1315306/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1315306</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1315306" 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/10.1016/0888-7543(92)90305-c" target="_blank">Full Text</a>]
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<a id="Ambrose1994" class="mim-anchor"></a>
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Ambrose, C. M., Duyao, M. P., Barnes, G., Bates, G. P., Lin, C. S., Srinidhi, J., Baxendale, S., Hummerich, H., Lehrach, H., Altherr, M., Wasmuth, J., Buckler, A., Church, D., Housman, D., Berks, M., Micklem, G., Durbin, R., Dodge, A., Read, A., Gusella, J., MacDonald, M. E.
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<strong>Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8197474/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8197474</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8197474" 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/BF02257483" target="_blank">Full Text</a>]
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<a id="Andrew1993" class="mim-anchor"></a>
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Andrew, S. E., Goldberg, Y. P., Kremer, B., Telenius, H., Theilmann, J., Adam, S., Starr, E., Squitieri, F., Lin, B., Kalchman, M. A., Graham, R. K., Hayden, M. R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401589/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401589</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8401589" 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/ng0893-398" target="_blank">Full Text</a>]
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Aziz, N. A., Roos, R. A., Gusella, J. F., Lee, J. M., Macdonald, M. E.
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<strong>CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. (Letter)</strong>
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Neurology 79: 952, 2012. Note: Author Reply 952-3, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22927682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22927682</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22927682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1212/WNL.0b013e3182697986" target="_blank">Full Text</a>]
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Barinaga, M.
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Science 271: 1233-1234, 1996.
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Barnes, G. T., Duyao, M. P., Ambrose, C. M., McNeil, S., Perischetti, F., Srinidhi, J., Gusella, J. F., MacDonald, M. E.
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<strong>Mouse Huntington's disease gene homolog (Hdh).</strong>
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[<a href="https://doi.org/10.1007/BF02290678" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8612237/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8612237</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8612237" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nm0396-347" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/ajmg.b.30125" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.cell.2004.06.018" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2010.06.027" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1059581" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/2.12.2063" target="_blank">Full Text</a>]
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Hilary J. Vernon - updated : 09/05/2024
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Hilary J. Vernon - updated : 08/30/2024<br>Hilary J. Vernon - updated : 12/01/2022<br>Ada Hamosh - updated : 11/04/2020<br>Bao Lige - updated : 09/23/2019<br>Ada Hamosh - updated : 05/25/2018<br>George E. Tiller - updated : 09/12/2017<br>Paul J. Converse - updated : 05/16/2017<br>Cassandra L. Kniffin - updated : 04/12/2017<br>Ada Hamosh - updated : 09/14/2016<br>Patricia A. Hartz - updated : 08/12/2016<br>Patricia A. Hartz - updated : 02/29/2016<br>George E. Tiller - updated : 8/16/2013<br>Patricia A. Hartz - updated : 4/6/2012<br>Patricia A. Hartz - updated : 11/15/2011<br>Patricia A. Hartz - updated : 8/22/2011<br>George E. Tiller - updated : 2/8/2011<br>George E. Tiller - updated : 11/1/2010<br>George E. Tiller - updated : 8/6/2010<br>Matthew B. Gross - updated : 4/28/2010<br>George E. Tiller - updated : 11/4/2009<br>Cassandra L. Kniffin - updated : 11/2/2009
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Creation Date:
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Cassandra L. Kniffin : 9/8/2009
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carol : 09/09/2024
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carol : 09/05/2024<br>carol : 09/05/2024<br>carol : 08/30/2024<br>carol : 12/01/2022<br>carol : 02/22/2022<br>mgross : 11/04/2020<br>alopez : 10/31/2019<br>mgross : 09/23/2019<br>mgross : 06/07/2018<br>mgross : 06/07/2018<br>alopez : 05/25/2018<br>carol : 01/24/2018<br>carol : 01/23/2018<br>alopez : 09/12/2017<br>carol : 07/19/2017<br>mgross : 05/16/2017<br>carol : 04/15/2017<br>carol : 04/14/2017<br>ckniffin : 04/12/2017<br>carol : 02/27/2017<br>alopez : 09/14/2016<br>mgross : 08/12/2016<br>mgross : 02/29/2016<br>tpirozzi : 8/19/2013<br>tpirozzi : 8/16/2013<br>tpirozzi : 8/16/2013<br>carol : 4/18/2013<br>mgross : 6/12/2012<br>mgross : 5/17/2012<br>terry : 4/6/2012<br>mgross : 2/1/2012<br>terry : 11/15/2011<br>mgross : 8/24/2011<br>terry : 8/22/2011<br>wwang : 3/11/2011<br>terry : 2/8/2011<br>alopez : 1/10/2011<br>alopez : 11/5/2010<br>terry : 11/1/2010<br>terry : 8/12/2010<br>wwang : 8/10/2010<br>terry : 8/6/2010<br>wwang : 5/5/2010<br>mgross : 4/28/2010<br>wwang : 11/4/2009<br>ckniffin : 11/2/2009<br>carol : 9/15/2009<br>ckniffin : 9/10/2009
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<strong>*</strong> 613004
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<h3>
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HUNTINGTIN; HTT
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IT15<br />
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HD GENE
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<strong><em>HGNC Approved Gene Symbol: HTT</em></strong>
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<strong>SNOMEDCT:</strong> 58756001;
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<strong>ICD10CM:</strong> G10;
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<strong>ICD9CM:</strong> 333.4;
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Cytogenetic location: 4p16.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 4:3,074,681-3,243,960 </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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4p16.3
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Huntington disease
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143100
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Autosomal dominant
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3
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Lopes-Maciel-Rodan syndrome
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617435
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Autosomal recessive
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The HTT gene encodes huntingtin, a ubiquitously expressed nuclear protein that binds to a number of transcription factors to regulate transcription. Abnormal expansion of a polyglutamine tract in the N terminus of huntingtin causes Huntington disease (143100), a devastating autosomal dominant neurodegenerative disease characterized by motor, psychiatric, and cognitive dysfunction (summary by Futter et al., 2009). </p>
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<strong>Cloning and Expression</strong>
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<p>By positional cloning and exon amplification of the Huntington disease (HD; 143100) locus on chromosome 4p16.3, the Huntington's Disease Collaborative Research Group (1993) identified a novel transcript, designated IT15 (important transcript 15), from human retinal and frontal cortex cDNA libraries. The corresponding gene was predicted to encode a 3,144-residue protein with a molecular mass of 348 kD. The protein was called 'huntingtin' (HTT) (Hoogeveen et al., 1993). Northern blot analysis detected a 10 to 11-kb transcript in a variety of human tissues. The reading frame was found to contain a polymorphic trinucleotide repeat varying from 11 to 34 CAG copies in normal individuals. This repeat was expanded to a range of 42 to over 66 copies (613004.0001) in 1 allele from patients with Huntington disease. </p><p>Lee et al. (2002) identified an upstream open reading frame (uORF) encoding a 21-amino acid peptide within the 5-prime UTR of the huntingtin gene. This upstream ORF negatively influenced expression from the huntingtin mRNA, perhaps by limiting ribosomal access to downstream initiation sites. </p><p>Barnes et al. (1994) found that mouse Htt (It15, Hdh) shares 86% and 91% sequence identity with human HTT DNA and protein, respectively. Despite the overall high level of conservation, the murine gene possesses an imperfect CAG repeat encoding only 7 consecutive glutamines, compared to the 13 to 36 residues that are normal in the human. Although no evidence for polymorphic variation of the CAG repeat was seen in mice, a nearby CCG repeat differed in length by 1 unit between several strains of laboratory mouse and Mus spretus. The absence of a long CAG repeat in the mouse was consistent with the lack of a spontaneous mouse model of HD. </p><p>Baxendale et al. (1995) cloned and sequenced the homolog of the HTT gene in the pufferfish, Fugu rubripes. </p>
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<h4>
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<strong>Gene Structure</strong>
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<span class="mim-text-font">
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<p>Ambrose et al. (1994) found that the HTT gene spans 180 kb and contains 67 exons ranging in size from 48 bp to 341 bp with an average of 138 bp. </p><p>Lin et al. (1995) presented a detailed comparison of the sequence of the putative promoter and the organization of the 5-prime genomic region encompassing the first 5 exons of the mouse Htt and human HTT genes. They found 2 dinucleotide (CT) and 1 trinucleotide intronic polymorphism in Htt and an intronic CA polymorphism in HTT. A comparison of 940-bp sequence 5-prime to the putative translation start site revealed a highly conserved region (78.8% nucleotide identity) between the Htt and the HTT gene from mouse nucleotide -56 to -206. </p><p>Baxendale et al. (1995) found that the Fugu HTT homolog spans only 23 kb of genomic DNA, compared to the 170-kb human gene, and yet all 67 exons are conserved. The first exon, the site of the disease-causing triplet repeat in the human, is highly conserved. However, the glutamine repeat in Fugu consists of only 4 residues. Baxendale et al. (1995) also showed that synteny may be conserved over longer stretches of the 2 genomes. The work described a detailed example of sequence comparison between human and Fugu and illustrated the power of the pufferfish genome as a model system in the analysis of human genes. </p>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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<span class="mim-text-font">
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<p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Guo et al. (2018) used cryoelectron microscopy to determine the structure of full-length human HTT in a complex with HTT-associated protein-40 (HAP40; 305423) to an overall resolution of 4 angstroms. HTT is largely alpha-helical and consists of 3 major domains. The amino- and carboxy-terminal domains contain multiple HEAT repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely alpha-helical and has a tetratricopeptide repeat-like organization. HAP40 binds in a cleft and contacts the 3 HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing the conformation of HTT. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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</div>
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<span class="mim-text-font">
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<p>The human HTT gene maps to chromosome 4p16.3 (Huntington's Disease Collaborative Research Group, 1993). </p><p><strong><em>Mouse Gene</em></strong></p><p>
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Using DNA markers near the Huntington disease gene on 4p, Cheng et al. (1989) defined a conserved linkage group on mouse chromosome 5. By linkage analyses using recombinant inbred strains, a standard outcross, and an interspecific backcross, they assigned homologs of 4 anonymous DNA segments and the QDPR gene (612676) to mouse chromosome 5 and determined their relationship to previously mapped markers on that autosome. The findings suggested that the murine counterpart of the HD gene may lie between Hx and Emv1. Hx stands for hemimelia-extra toes; the gene lies 6 cM distal to Emv1, an endogenous ecotropic provirus. </p><p>From studies of the comparative mapping of the 4p16.3 region in man and mouse, Altherr et al. (1992) concluded that the homolog of the HD gene should be located on mouse chromosome 5. Nasir et al. (1994) confirmed this conclusion by using an interspecific backcross to map the murine homolog of IT15 (Hdh) to an area of mouse chromosome 5 that is within the region of conserved synteny with human chromosome 4p16.3. Near the unstable CAG repeat encoding a stretch of polyglutamine that is involved in the pathogenesis of HD, there is a polyproline-encoding CCG repeat that shows more limited allelic variation. Barnes et al. (1994) used the mouse homolog, Hdh, to map the gene to mouse chromosome 5 in a region devoid of mutations causing any comparable phenotype. </p><p>Grosson et al. (1994) localized the mouse homologs of the HD gene and 17 other human chromosome 4 loci, including 6 previously unmapped genes, by use of an interspecific cross. All loci mapped in a continuous linkage group on mouse chromosome 5, distal to En2 (engrailed-2; 131310) and Il6 (interleukin-6; 147620), the human counterparts of which are located on chromosome 7. The relative order of the loci on human chromosome 4 and mouse chromosome 5 was maintained for the most part. Grosson et al. (1994) knew of no phenotypic correspondence between human and mouse mutations mapping to this region of syntenic conservation. The gene that is mutant in achondroplasia (100800), namely, fibroblast growth factor receptor-3 (FGFR3; 134934), was not among the genes mapped. </p><p>Lin et al. (1995) cloned the mouse Htt gene and showed that it maps to mouse chromosome 5 within a region of conserved synteny with human 4p16.3. </p>
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<span class="mim-font">
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<strong>Gene Function</strong>
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<span class="mim-text-font">
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<p>Hoogeveen et al. (1993) synthesized oligopeptides corresponding to the C-terminal end of the predicted HD gene product. Immunobiochemical studies with polyclonal antibodies directed against this synthetic peptide revealed the presence of a protein, called huntingtin by them, with a molecular mass of approximately 330 kD in lymphoblastoid cells from normal individuals and patients with Huntington disease. Immunocytochemical studies showed a cytoplasmic localization in various cell types, including neurons. In most of the neuronal cells, the protein was also present in the nucleus. No difference in molecular mass or intracellular localization was found between normal and mutant cells. </p><p>Dure et al. (1994) examined the in situ hybridization of riboprobes specific for the IT15 gene against normal human fetal and adult brains. In both types of specimen, the autoradiographic signal correlated strongly with cell number except in the germinal matrix and white matter where there is a significant proportion of glial cells. This suggested that IT15 expression is predominantly neuronal. However, there was no predominance of IT15 expression in the striatum of the fetal brain. </p><p>The wide expression of the HTT transcript does not correlate with the pattern of neuropathology in the disease. To study the huntingtin protein, Trottier et al. (1995) generated monoclonal antibodies against 4 different regions of the protein. On Western blots, these monoclonals detected the huntingtin protein of approximately 350 kD in various human cell lines and in neural and nonneural rodent tissues. A doublet protein was detected in cell lines from HD patients, corresponding to the mutant and normal huntingtin. Immunohistochemical studies in the human brain, using 2 of these antibodies, detected huntingtin in perikarya of some neurons, neuropils, and varicosities. Huntingtin was also visualized as punctate staining likely to represent nerve endings. </p><p>Gutekunst et al. (1995) used both polyclonal and monoclonal antifusion protein antibodies to identify native huntingtin in rat, monkey, and human. Western blots revealed a protein with the expected molecular weight that is present in the soluble fraction of rat and monkey brain tissues and lymphoblastoid cell lines from control cases. Immunocytochemistry indicated that huntingtin is located in neurons throughout the brain, with the highest levels evident in larger neurons. In the human striatum, huntingtin was enriched in a patch-like distribution, potentially corresponding to the first areas affected in HD. Subcellular localization of huntingtin was consistent with a cytosolic protein primarily found in somatodendritic regions. Huntingtin appears to be associated particularly with microtubules, although some is also associated with synaptic vesicles. On the basis of the localization of huntingtin in association with microtubules, Gutekunst et al. (1995) speculated that the mutation impairs the cytoskeletal anchoring or transport of mitochondria, vesicles, or other organelles or molecules. Lymphoblastoid cell lines from juvenile-onset heterozygote HD cases showed expression of both normal and mutant huntingtin; increasing repeat expansion leads to lower levels of the mutant protein. </p><p>Li et al. (1995) described a huntingtin-associated protein (HAP1; 600947), which is enriched in brain. The authors found that binding of HAP1 to huntingtin was enhanced by an expanded polyglutamine repeat. </p><p>De Rooij et al. (1996) used affinity-purified antibodies to analyze the subcellular location of huntingtin. In mouse embryonic fibroblasts, human skin fibroblasts, and mouse neuroblastoma cells, they detected huntingtin in the cytoplasm and the nucleus. </p><p>Burke et al. (1996) described the isolation of a protein present in brain homogenates that bound to a synthetic 60-glutamine peptide (such as that found in huntingtin). Eighteen amino acids of this protein were found to be identical to the N terminus of glyceraldehyde-3-phosphate dehydrogenase (GAPD, or GAPDH; 138400). GAPD was also found to bind to another protein with a polyglutamine tract, namely the DRPLA protein, atrophin-1 (607462). Burke et al. (1996) demonstrated that synthetic polyglutamine peptides, DRPLA protein, and huntingtin from unaffected individuals with normal-sized polyglutamine tracts bind to GAPD. GAPD had also been shown to bind to RNA, ATP, calcyclin (114110), actin (see 102610), tubulin (see 191130) and amyloid precursor protein (104760). On the basis of their findings, the authors postulated that disease characterized by the presence of an expanded CAG repeat, which share a common mode of heritability, may also share a common metabolic pathogenesis involving GAPD as a functional component. Both Roses (1996) and Barinaga (1996) reviewed these findings. </p><p>In human lymphoblastoid cells, Kahlem et al. (1998) showed that huntingtin is a substrate of transglutaminase (see, e.g., TGM1; 190195) in vitro and that the rate constant of the reaction increases with length of the polyglutamine over a range of an order of magnitude. As a result, huntingtin with expanded polyglutamine is preferentially incorporated into polymers. Both disappearance of huntingtin with expanded polyglutamine and its replacement by polymeric forms are prevented by inhibitors of transglutaminase. The effect of transglutaminase therefore duplicates the changes in the affected parts of the brain. In the presence of either tissue or brain transglutaminase, monomeric huntingtin bearing a polyglutamine expansion formed polymers much more rapidly than one with a short polyglutamine sequence. </p><p>Zuccato et al. (2001) demonstrated that wildtype huntingtin upregulates transcription of brain-derived neurotrophic factor (BDNF; 113505), a prosurvival factor produced by cortical neurons that is necessary for survival of striatal neurons in the brain. Zuccato et al. (2001) showed that this beneficial activity of huntingtin is lost when the protein becomes mutated, resulting in decreased production of cortical BDNF. This leads to insufficient neurotrophic support for striatal neurons, which then die. Zuccato et al. (2001) suggested that restoring wildtype huntingtin activity and increasing BDNF production may be therapeutic approaches for treating HD. </p><p>Kegel et al. (2002) demonstrated localization of huntingtin to subnuclear compartments, including speckles, promyelocytic leukemia protein bodies, and nucleoli, in normal and HD human fibroblasts and in mouse neurons. Western blot analysis showed that purified nuclei had low levels of full-length huntingtin compared with the cytoplasm, but contained high levels of N- and C-terminal huntingtin fragments, which tightly bound to the nuclear matrix. Full-length huntingtin coimmunoprecipitated with the transcriptional CTBP1 (602618) protein, and polyglutamine expansion in huntingtin reduced this interaction. Full-length wildtype and mutant huntingtin repressed transcription when targeted to DNA, but truncated N-terminal wildtype huntingtin did not, suggesting that proteolysis of huntingtin in the nucleus may normally occur in cells to terminate or modulate huntingtin function. However, truncated N-terminal mutant huntingtin retained the ability to repress transcription, suggesting an abnormal gain of function. Kegel et al. (2002) suggested that wildtype huntingtin may function in the nucleus in the assembly of nuclear matrix-bound protein complexes involved with transcriptional repression and RNA processing. Proteolysis of mutant huntingtin may disrupt nuclear functions by altering protein complex interactions and inappropriately repressing transcription in HD. </p><p>By live-cell time-lapse video microscopy, Xia et al. (2003) visualized polyglutamine-mediated aggregation and transient nuclear localization of huntingtin over time in a striatal cell line. A classic nuclear localization signal could not be detected in the huntingtin amino acid sequence, but a nuclear export signal (NES) in the carboxy terminus of huntingtin was discovered. Leptomycin B treatment of clonal striatal cells enhanced the nuclear localization of huntingtin, and a mutant NES huntingtin displayed increased nuclear localization, indicating that huntingtin can shuttle to and from the nucleus. The huntingtin NES is strictly conserved among all huntingtin proteins from diverse species. This export signal may be important in Huntington disease because this fragment of huntingtin is proteolytically cleaved during HD. </p><p>Zuccato et al. (2003) showed that the neuron-restrictive silencer element (NRSE) is the target of wildtype huntingtin activity on BDNF promoter II. Wildtype huntingtin inhibits the silencing activity of the NRSE, increasing transcription of BDNF. Zuccato et al. (2003) showed that this effect occurs through cytoplasmic sequestering of repressor element-1 transcription factor/neuron-restrictive silencer factor (REST/NRSF; 600571), the transcription factor that binds to NRSE. In contrast, aberrant accumulation of REST/NRSF in the nucleus is present in Huntington disease. Wildtype huntingtin coimmunoprecipitates with REST/NRSF, and less immunoprecipitated material is found in brain tissue with Huntington disease. Zuccato et al. (2003) also reported that wildtype huntingtin acts as a positive transcriptional regulator for other NRSE-containing genes involved in the maintenance of the neuronal phenotype. Consistently, loss of expression of NRSE-controlled neuronal genes was shown in cells, mice, and human brain with Huntington disease. Zuccato et al. (2003) concluded that wildtype huntingtin acts in the cytoplasm of neurons to regulate the availability of REST/NRSF to its nuclear NRSE-binding site and that this control is lost in the pathology of Huntington disease. The findings indicated a novel mechanism by which mutation of huntingtin causes loss of transcription of neuronal genes. </p><p>Gauthier et al. (2004) showed that huntingtin specifically enhances vesicular transport of BDNF along microtubules. They determined that huntingtin-mediated transport involves HAP1 and the p150(Glued) (DCTN1; 601143) subunit of dynactin, an essential component of molecular motors. BDNF transport was attenuated both in the disease context and by reducing the levels of wildtype huntingtin. The alteration of the huntingtin/HAP1/p150(Glued) complex correlated with reduced association of motor proteins with microtubules. The polyglutamine-huntingtin-induced transport deficit resulted in the loss of neurotrophic support and neuronal toxicity. Gauthier et al. (2004) concluded that a key role of huntingtin is to promote BDNF transport and suggested that loss of this function might contribute to pathogenesis. </p><p>By yeast 1-hybrid and DNase footprint analyses, Tanaka et al. (2004) identified 2 proteins, HDBP1 (SLC2A4RG; 609493) and HDBP2 (ZNF395; 609494), that bound a 7-bp consensus sequence (GCCGGCG) in the HTT promoter. Mutation of the 7-bp consensus sequence abolished HTT promoter function in a human neuronal cell line. </p><p>Using an antibody specific for HTT phosphorylated on ser421, Warby et al. (2005) demonstrated that HTT phosphorylation was present at significant levels under normal physiologic conditions in human and mouse brain. Htt phosphorylation showed a regional distribution with highest levels in the cerebellum, less in the cortex, and least in the striatum. In cell cultures and in YAC transgenic mice, endogenous phosphorylation of polyglutamine-expanded HTT was significantly reduced relative to wildtype HTT. The presence and pattern of significant HTT phosphorylation in the brain suggested to the authors that this dynamic posttranslational modification may be important for the regulation of HTT and may contribute to the selective neurodegeneration seen in HD. </p><p>Ralser et al. (2005) demonstrated that ataxin-2 (601517) interacted with endophilin-A1 (SH3GL2; 604465) and endophilin-A3 (SH3GL3; 603362). In a yeast model system, expression of ataxin-2 as well as both endophilin proteins was toxic for yeast lacking Sac6, which encodes fimbrin (PLS3; 300131), a protein involved in actin filament organization and endocytotic processes. Expression of huntingtin was also toxic in Sac6-null yeast. These effects could be suppressed by simultaneous expression of 1 of the 2 human fimbrin orthologs, L-plastin (LCP1; 153430) or T-plastin (PLS3). Ataxin-2 associated with L- and T-plastin, and overexpression of ataxin-2 led to accumulation of T-plastin in mammalian cells. Ralser et al. (2005) suggested an interplay between ataxin-2, endophilin proteins, and huntingtin in plastin-associated cellular pathways. </p><p>Cornett et al. (2005) studied the mechanism by which mutant HTT accumulates in the nucleus; wildtype HTT is normally found in the cytoplasm. They reported that N-terminal HTT shuttles between the cytoplasm and nucleus and that small N-terminal HTT fragments interact with the nuclear pore protein translocated promoter region (TPR; 189940), which is involved in nuclear export. PolyQ expansion and aggregation decrease this interaction and increase the nuclear accumulation of HTT. Reducing the expression of TPR by RNA interference or deletion of 10 amino acids of N-terminal HTT, which are essential for the interaction of HTT with TPR, increased the nuclear accumulation of HTT. Cornett et al. (2005) concluded that TPR has a role in the nuclear export of N-terminal HTT and that polyQ expansion reduces this nuclear export to cause the nuclear accumulation of HTT. </p><p>By yeast 2-hybrid analysis and coimmunoprecipitation analysis of cotransfected COS-1 cells, Horn et al. (2006) found that the C-terminal conserved region of GASP2 (GPRASP2; 300969) interacted with the N terminus of HTT. An expanded polyQ repeat in HTT increased binding affinity for GASP2. Confocal immunofluorescence microscopy showed partial colocalization of GASP2 and HTT in cytoplasm and cell membranes of undifferentiated SH-SY5Y human neuroblastoma cells, as well as colocalization of GASP2 and HTT in neurite-like extensions following induction of differentiation in SH-SY5Y cells. </p><p>Using yeast 2-hybrid analysis of a human brain cDNA library and affinity chromatography assays with mouse brain cytosol, Caviston et al. (2007) demonstrated that Htt and dynein intermediate chain (see DYNC1I1; 603772) interacted directly. HTT RNA interference in HeLa cells resulted in Golgi disruption similar to the effects of compromised dynein/dynactin function. In vitro studies revealed that Htt and dynein were both present on vesicles purified from mouse brain. Antibodies to Htt inhibited vesicular transport along microtubules, suggesting that Htt facilitates dynein-mediated vesicle motility. In vivo inhibition of dynein function resulted in a significant redistribution of Htt to the cell periphery, suggesting that dynein transports Htt-associated vesicles toward the cell center. </p><p>Argonaute proteins, such as AGO1 (EIF2C1; 606228) and AGO2 (EIF2C2; 606229), are components of a ribonucleoprotein complex that regulates mRNA translation via small interfering RNA. Savas et al. (2008) found that an N-terminal fragment of Htt with 25 or 97 glutamines immunoprecipitated AGO1 and AGO2 from transfected HeLa cells. AGO2 also immunoprecipitated endogenous HTT from HeLa cells. A portion of endogenous HTT colocalized with AGO2 in P bodies in human and mouse cell lines and in primary rat hippocampal neurons, but not all HTT foci colocalized with AGO2 and a P-body marker. Small interfering RNA, reporter gene assays, and FRAP analysis suggested that HTT may have a role in gene silencing through the RNA interference pathway, and that mutant HTT may reduce incorporation of AGO2 into P bodies and P body-associated gene silencing. </p><p>Using yeast 2-hybrid and immunoprecipitation analyses, Shimojo (2008) showed that human RILP (PRICKLE1; 608500) and huntingtin interacted directly with dynactin-1 to form a triplex. REST bound to the triplex through direct interaction with RILP, forming a quaternary complex involved in nuclear translocation of REST in non-neuronal cells. In neuronal cells, the complex also contained HAP1, which affected interaction of disease-causing mutant huntingtin, but not wildtype huntingtin, with dynactin-1 and RILP. Overexpression and knockout analyses demonstrated that the presence of HAP1 in the complex prevented nuclear translocation of REST and thereby regulated REST activity. </p><p>Futter et al. (2009) found that wildtype huntingtin could bind to a number of nuclear receptors, including LXR-alpha (NR1H3; 602423), PPARG (601487), VDR (601769), and THRA1 (190120). Overexpression of huntingtin activated, whereas knockout of huntingtin decreased, LXR-mediated transcription of a reporter gene. Loss of huntingtin also decreased expression of the LXR target gene, ABCA1 (600046). In vivo, huntingtin-deficient zebrafish had a severe phenotype with reduction of cartilage in the jaw and reduced expression of LXR-regulated genes. An LXR agonist was able to partially rescue the phenotype and the expression of LXR target genes in huntingtin-deficient zebrafish during early development. The data suggested a novel function for wildtype huntingtin as a cofactor of LXR. However, this activity was lost by mutant polyQ huntingtin, which only interacted weakly with LXR. </p><p>Smith et al. (2009) showed that mutant huntingtin disrupted intracellular transport and insulin secretion by direct interference with microtubular beta-tubulin (TUBB; 191130). Mutant huntingtin impaired glucose-stimulated insulin secretion in insulin-producing beta cells, without altering stored levels of insulin. Mutant huntingtin also retarded post-Golgi transport, and the speed of insulin vesicle trafficking was reduced. There was an enhanced and aberrant interaction between mutant huntingtin and beta-tubulin, implying the underlying mechanism of impaired intracellular transport. Smith et al. (2009) proposed a novel pathogenetic process by which mutant huntingtin may disrupt hormone exocytosis from beta cells and possibly impair vesicular transport in any cell that expresses the pathogenic protein. </p><p>Seong et al. (2010) investigated huntingtin's domain structure and potential intersection with epigenetic silencer polycomb repressive complex-2 (PRC2, see EZH1; 601674), suggested by shared embryonic deficiency phenotypes. Analysis of a set of full-length recombinant huntingtins, with different polyglutamine regions, demonstrated dramatic conformational flexibility, with an accessible hinge separating 2 large alpha-helical domains. Mouse embryos lacking huntingtin exhibited impaired PRC2 regulation of Hox gene expression, trophoblast giant cell differentiation, paternal X-chromosome inactivation, and histone H3K27 trimethylation, while full-length endogenous nuclear huntingtin in wildtype embryoid bodies was associated with PRC2 subunits and was detected with trimethylated histone H3K27 at Hoxb9 (142964). Supporting a direct stimulatory role, full-length recombinant huntingtin significantly increased the histone H3K27 trimethylase activity of reconstituted PRC2 in vitro, and structure-function analysis demonstrated that the polyglutamine region augmented full-length huntingtin PRC2 stimulation, both in Hdh(Q111) embryoid bodies and in vitro, with reconstituted PRC2. Seong et al. (2010) implicated a role for the multisubunit PRC2 complex in neurodegenerative disorders such as Huntington disease. </p><p>Song et al. (2011) found fragmented mitochondria in fibroblasts from a patient with HD and in rat cortical neurons expressing human HTT with a polyQ expansion. Neurons expressing mutant HTT also showed arrest in mitochondrial movement and ultrastructural changes in mitochondrial cristae. Mitochondrial changes were observed in a mouse model of HD prior to emergence of neurologic deficits, neuronal cell death, and HTT aggregate formation. Immunoprecipitation of normal and HD human or mouse brain indicated that mutant, but not normal, huntingtin interacted with Drp1 (DNM1; 603850), a protein involved in mitochondria and peroxisome fission. In vitro assays with liposomes that mimicked the mitochondrial outer membrane revealed that mutant huntingtin stimulated Drp1 GTPase activity. Expression of a dominant-negative Drp1 mutant rescued mutant huntingtin-mediated mitochondrial fragmentation, defects in mitochondrial transport, and neuronal cell death. Electron microscopy showed that the normal ring- and spiral-like organization of DRP1 oligomers had an additional layer of density with the addition of mutant, but not normal, huntingtin. </p><p>Sassone et al. (2015) noted that mutant HTT causes mitochondrial depolarization and fragmentation and promotes activation of proapoptotic proteins, including BNIP3 (603293), BAX (600040), and BAK (BAK1; 600516). They found that mouse embryonic fibroblasts lacking Bnip3, but not those lacking both Bax and Bak, were resistant to mitochondrial depolarization, fragmentation, and cell death induced by expression of mutant human HTT. Expression of a dominant-negative Bnip3 mutant lacking the transmembrane domain required for mitochondrial localization and function partially rescued mitochondrial pathology and cell death in a mouse striatal neuron HD model. Sassone et al. (2015) concluded that mitochondrial dysfunction induced by mutant HTT depends on BNIP3, but not BAX or BAK. </p><p>Neurodegeneration in HD is thought to be due to proteolytic release of toxic peptide fragments from mutant HTT. By transfecting small interfering RNAs directed against 514 human proteases into polyQ HTT-expressing HEK293 cells, Miller et al. (2010) identified 11 proteases, including MMP10 (185260), MMP14 (600754), and MMP23B (603321), as putative polyQ HTT-processing proteases. Further characterization revealed that MMP10 was the only metalloprotease in this group that directly processed polyQ HTT; MMP14 and MMP23B appeared to cause polyQ HTT degradation indirectly. MMP10 cleaved polyQ HTT at a conserved site near the N terminus with the consensus sequence (S/T)xxGG(I/L). Both Mmp10 and Mmp14 were upregulated in mouse striatal cells expressing polyQ HTT, and knockdown of either Mmp10 or Mmp14 reduced cell death and caspase activation. Htt and Mmp10 colocalized in cells undergoing apoptosis. </p><p>Godin et al. (2010) noted that HTT expression is associated with the centrosomal region and microtubules of dividing cells. They found that HTT localized to the spindle poles during mitosis from prophase to anaphase in both HeLa cells and dividing mouse cortical neurons. Knockdown of HTT expression in either cell model resulted in a spindle orientation defect. The defect could be reversed in mouse cortical neurons by expression of a 1,301-amino acid N-terminal fragment of mouse Htt or a 620-amino acid N-terminal fragment of Drosophila Htt. Depletion of Htt in mouse cells caused partial mislocalization of p150(Glued), dispersal of dynein and Numa (NUMA1; 164009), and asynchronous cell division. In day-14.5 mouse embryos, asynchronous division due to Htt depletion led to premature neuronal differentiation at the expense of proliferation and maintenance of progenitors in the neocortex. Godin et al. (2010) concluded that HTT functions as a scaffold protein for the dynein/dynactin complex in dividing cells. </p><p>Using mouse and cellular models of HD, McFarland et al. (2014) showed that mutant Htt protein interacted directly with Mecp2 (300005). Htt-Mecp2 interactions were enhanced in the presence of the expanded polyglutamine tract and were stronger in nucleus compared with cytoplasm. Binding of Mecp2 to the promoter of Bdnf increased in the presence of mutant Htt. Decreasing Mecp2 expression through small interfering RNA treatment in cells expressing mutant Htt increased Bdnf levels, suggesting that MECP2 downregulates BDNF expression in HD. McFarland et al. (2014) proposed that aberrant interactions between HTT and MECP2 contribute to transcriptional dysregulation in HD. </p><p>Woerner et al. (2016) analyzed the compartment specificity of aggregate toxicity using artificial beta-sheet proteins, as well as fragments of mutant huntingtin and TAR DNA binding protein-43 (TDP43; 605078). Aggregation in the cytoplasm interfered with nucleocytoplasmic protein and RNA transport. In contrast, the same proteins did not inhibit transport when forming inclusions in the nucleus at or around the nucleolus. Protein aggregation in the cytoplasm, but not the nucleus, caused the sequestration and mislocalization of proteins containing disordered and low-complexity sequences, including multiple factors of the nuclear import and export machinery. Thus, Woerner et al. (2016) concluded that impairment of nucleocytoplasmic transport may contribute to the cellular pathology of various aggregate deposition diseases. </p><p>Through biochemical and live cell imaging studies, Marcora and Kennedy (2010) showed that wildtype Htt stimulated the transport of NFKB (see NFKB1, 164011) out of dendritic spines (where NFKB is activated by excitatory synaptic input) and supported a high level of active NFKB in neuronal nuclei (where NFKB stimulates the transcription of target genes). This novel function of Htt was impaired by polyQ expansion; the authors suggested that this impairment may contribute to the etiology of HD. </p><p>By translational profiling of corticospinal tract motor neurons in mice, Poplawski et al. (2020) identified their 'regenerative transcriptome' after spinal cord injury and neural progenitor cell grafting. Both injury alone and injury combined with neural progenitor cell grafts elicited virtually identical early transcriptomic responses in host neurons. However, in mice with injury alone, this regenerative transcriptome was downregulated after 2 weeks, whereas in neural progenitor stem cell-grafted mice, this transcriptome was sustained. The regenerative transcriptome appeared to represent a reversion to an embryonic transcriptional state of the corticospinal tract neuron. The Htt gene was a central hub in the regeneration transcriptome, and deletion of Htt significantly attenuated regeneration. The authors concluded that Htt has a key role in neural plasticity after injury. </p>
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<strong>Molecular Genetics</strong>
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<p><strong><em>Huntington Disease</em></strong></p><p>
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The Huntington's Disease Collaborative Research Group (1993) identified an expanded (CAG)n repeat on 1 allele of the HTT gene (613004.0001) in affected members from all of 75 families with Huntington disease (HD; 143100) examined. The families came from a variety of ethnic backgrounds and demonstrated a variety of 4p16.3 haplotypes. The findings indicated that the HD mutation involves an unstable DNA segment similar to those previously observed in several disorders, including the fragile X syndrome (300624), Kennedy syndrome (313200), and myotonic dystrophy. The fact that the phenotype of HD is completely dominant suggested that the disorder results from a gain-of-function mutation in which either the mRNA product or the protein product of the disease allele has some new property or is expressed inappropriately (Myers et al., 1989). </p><p>Duyao et al. (1993), Snell et al. (1993), and Andrew et al. (1993) analyzed the number of CAG repeats in a total of about 1,200 HTT genes and in over 2,000 normal controls. Read (1993) summarized and collated the results. In all 3 studies, the normal range of repeat numbers was 9-11 at the low and 34-37 at the high end, with a mean ranging from 18.29 to 19.71. Duyao et al. (1993) found a range of 37-86 in HD patients, with a mean of 46.42. </p><p>Rubinsztein et al. (1996) studied a large cohort of individuals who carried between 30 and 40 CAG repeats in the HTT gene. They used a PCR method that allowed the examination of CAG repeats only, thereby excluding the CCG repeats, which represent a polymorphism, as a confounding factor. No individual with 35 or fewer CAG repeats had clinical manifestations of HD. Most individuals with 36 to 39 CAG repeats were clinically affected, but 10 persons (aged 67-95 years) had no apparent symptoms of HD. The authors concluded that the HD mutation is not fully penetrant in individuals with a borderline number of CAG repeats. </p><p>Gusella et al. (1996) gave a comprehensive review of the molecular genetic aspects of Huntington disease. </p><p>In a study of 4,068 patients with HD, Lee et al. (2012) found that CAG repeat length in the HTT gene in the expanded allele determined age of onset of motor symptoms in a dominant fashion, and that the unexpanded, wildtype allele CAG length did not have an effect. Furthermore, in 10 patients with 2 expanded CAG alleles, onset of motor symptoms was consistent with what would be expected for the longer repeat allele. Aziz et al. (2012) noted that the following should be considered in assessing the results of Lee et al. (2012): (1) behavioral disturbances often precede motor onset, and (2) age of motor onset may not correlate to rate of disease progression. Based on an analysis of GWAS data evaluating genetic modifiers of age of onset of HD, the Genetic Modifiers of Huntington's Disease (GeM-HD) Consortium (2019) found that timing of appearance of HD symptoms was dependent on the length of the CAG repeat rather than on the length of the polyglutamine tract in HTT. Specifically, the CAA-CAG sequence at the distal end of the CAG tract in most HTT alleles, although it encodes for 2 glutamines, does not contribute to earlier onset of disease. The Consortium further concluded that HD disease presentation is also associated with the degree to which genetic modifiers influence the CAG expansion rate and threshold by which the CAG length causes toxicity in specific cells that are important for HD disease pathogenesis. </p><p>Neueder et al. (2024) analyzed mitochondrial DNA (mtDNA) in skeletal muscle from patients with HD and controls and identified increased accumulation of mtDNA mutations in patients. Proteomics analysis of skeletal muscle tissue from the patients demonstrated abnormalities in mtDNA maintenance accompanied by increased biogenesis but decreased complex I and IV activity. Neueder et al. (2024) concluded that mutant HTT leads to mtDNA instability and compensatory upregulation of mitochondrial mass. </p><p><strong><em>Mechanism of HTT Repeat Expansion in Huntington Disease</em></strong></p><p>
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Zuhlke et al. (1993) studied the length variation of the repeat in 513 non-HD chromosomes from normal individuals and HD patients; the group comprised 23 alleles with 11 to 33 repeats. In an analysis of the inheritance of the (CAG)n stretch, they found meiotic instability for HD alleles, (CAG)40 to (CAG)75, with a mutation frequency of approximately 70%; following the HD allele in 38 pedigrees during 54 meioses, they found a ratio of stable to altered copy number of 15:39. On the other hand, in 431 meioses of normal alleles, only 2 expansions were identified. They found that the risk of expansion during spermatogenesis was enhanced compared to oogenesis, explaining juvenile onset by transmission from affected fathers. No mosaicism or differences in repeat lengths were observed in the DNA from different tissues, including brain and lymphocytes of 2 HD patients, indicating mitotic stability of the mutation. Thus, the determination of the repeat number in the DNA of blood lymphocytes is probably representative of all tissues in a patient. </p><p>Telenius et al. (1994) found somatic mosaicism for the CAG repeat in different tissues from 12 HD patients. Mosaicism for the highest numbers of CAG repeats was found in the brain, particularly in the basal ganglia and cortex, with lesser changes in the cerebellum. Sperm samples from 4 males also showed high levels of somatic mosaicism. Blood and other tissues showed lower levels of mosaicism. Telenius et al. (1994) suggested that expanded HTT gene CAG repeats are associated with tissue-specific mitotic and meiotic instability. </p><p>MacDonald et al. (1993) found that unlike the similar CCG repeat in the fragile X syndrome, the expanded HD repeat shows no evidence of somatic instability in a comparison of blood, lymphoblast, and brain DNA from the same persons. Furthermore, 4 pairs of monozygotic HD twins displayed identical CAG repeat lengths, suggesting that repeat size is determined in gametogenesis. However, in contrast to the fragile X syndrome and with HD somatic tissue, mosaicism was readily detected as a diffuse spread of repeat lengths in DNA from HD sperm samples. Thus, the developmental timing of repeat instability appears to differ between HD and fragile X syndrome, indicating perhaps that the fundamental mechanisms leading to repeat expansion are distinct. </p><p>Leeflang et al. (1995) amplified the CAG triplet repeat region of the HD gene in 923 single sperm from 3 affected and 2 normal individuals. Average-sized alleles (15-18 repeats) showed only 3 contraction mutations among 475 sperm (0.6%). A 30-repeat normal allele showed an 11% mutation frequency. The mutation frequency of a 36-repeat intermediate allele was 53% with 8% of all gametes having expansions that brought the allele size into the HD disease range (38 repeats or more). Disease alleles (38-51 repeats) showed a very high mutation frequency (92-99%). As repeat number increased, the authors found a marked elevation in the frequency of expansions, in the mean number of repeats added per expansion, and in the size of the largest observed expansion. Contraction frequencies also appeared to increase with allele size but decreased as repeat number exceeded 36. Since the sperm typing data were of a discrete nature rather than consisting of smears of PCR products from pooled sperm, Leeflang et al. (1995) could compare the observed mutation frequency spectra to the distribution calculated using discrete stochastic models based on current molecular ideas of the expansion process. An excellent fit was found when the model specified that a random number of repeats are added during the progression of the DNA polymerase through the repeated region. </p><p>All mutations for Huntington disease arise from so-called intermediate alleles (IAs) containing between 29 and 35 CAG repeats. The CAG repeats expand on transmission through the paternal germline to 36 or more repeats. Intermediate alleles are present on approximately 1% of normal chromosomes of Caucasian descent. Affected individuals have an expanded allele of between 36 to 121 CAGs, but incomplete penetrance has been found for repeat lengths of 36 to 40 CAGs. Using single sperm analysis, Chong et al. (1997) assessed CAG mutation frequencies of 4 IAs in families with sporadic HD and IAs ascertained from the general population by analyzing 1161 single sperm from 3 persons. They showed that the intermediate alleles of the former group were more unstable than those in the general population with identical size and sequence. Furthermore, comparison of different sized IAs and IAs with different sequences between the CAG and the adjacent CCG tracts indicated that DNA sequence is a major influence on CAG stability. These studies provided estimates of the likelihood of expansion to 36 or more CAG repeats for individuals in the 2 groups. For an IA with (CAG)35 in the family with sporadic HD, the likelihood for sibs to inherit a recurrent mutation equal to or more than (CAG)36 was approximately 10%. For intermediate alleles of a similar size in the general population, the risk of inheriting an expanded allele of 36 or more CAGs through the paternal germline was approximately 6%. </p><p>By typing greater than 3,500 sperm, Leeflang et al. (1999) determined the size distribution of HD germline mutations produced by 26 men in the Venezuelan cohort with CAG/CTG repeat numbers ranging from 37 to 62. Both the mutation frequency and mean change in allele size increased with increasing somatic repeat number. The mutation frequencies averaged 82%, and for individuals with at least 50 repeats, 98%. The extraordinarily high mutation frequency levels are most consistent with a process that occurs throughout germline mitotic divisions, rather than resulting from a single meiotic event. A statistical model based on incomplete processing of Okazaki fragments during DNA replication was found to provide an excellent fit to the data, but variation in parameter values among individuals suggests that the molecular mechanism might be more complex. </p><p>Large intergenerational repeat expansions of the CAG trinucleotide repeat in the HD gene are well documented for the male germline. Laccone and Christian (2000) described a recurrent large expansion of a maternal allele with 36 CAG repeats (to 66 and 57 repeats, respectively, in 2 daughters) associated with onset of Huntington disease in the second and third decade in a family without history of HD. The findings gave evidence of gonadal mosaicism in the unaffected mother. Laccone and Christian (2000) hypothesized that large expansions also occur in the female germline and that a negative selection of oocytes with long repeats may explain the different instability behavior of the male and female germlines. </p><p>Kovtun et al. (2000) followed the fate of the CAG trinucleotide repeat, during transmission, in a transgene containing the exon 1 portion of the human Huntington disease gene. Similar to humans, the mouse transmits expansions predominantly through the male germline. However, the CAG repeat size of the mutant human HD gene is different in male and female progeny from identical fathers. Males predominantly expanded the repeat, whereas females predominantly contracted the repeat. In contrast to the classic definition of imprinting, CAG expansion is influenced by the gender of the embryo. The authors hypothesized that there may be X- or Y-encoded factors that influence repair or replication of DNA in the embryo, and that gender dependence in the embryo may explain why expansion in HD from premutation to disease primarily occurs through the paternal line. </p><p>Yoon et al. (2003) performed single-molecule DNA analysis of testicular germ cells isolated by laser capture microdissection from 2 HD patients, showing that trinucleotide repeat expansion mutations were present before the end of the first present meiotic division, and some mutations were present even before meiosis began. Most of the larger Huntington disease mutations were found in the postmeiotic cell population, suggesting that expansions may continue to occur during meiosis and/or after meiosis is complete. </p><p>Kennedy et al. (2003) showed dramatic mutation length increases (gains of 16 to 1,000 CAG repeats) in human striatal cells early in the disease course, most likely before the onset of pathologic cell loss. Studies of knockin HD mice indicated that the size of the initial CAG repeat mutation may influence both onset and tissue-specific patterns of age-dependent, expansion-biased mutation length variability. Given that CAG repeat length strongly correlates with clinical severity, Kennedy et al. (2003) suggested that somatic increases of mutation length may play a major role in the progressive nature and cell-selective aspects of both adult-onset and juvenile-onset HD pathogenesis. </p><p>Cannella et al. (2005) reported a triplet size increase in an intermediate-sized allele (34 CAG) of the huntingtin gene carried by a lymphoblast cell culture after 30 passages. This finding demonstrated that the huntingtin gene shows somatic as well as germline instability and has a propensity for somatic CAG variation in human cells even with repeat numbers under the expanded edge (i.e., intermediate alleles being defined as containing between 29 and 35 CAG repeats). Factors potentially cis acting with this particular mutation included a CCG polymorphic stretch, deletion of the glutamic acid residue at position 2642, and the 4-codon segment between CAG and CCG polymorphisms. </p><p>Kovtun et al. (2007) demonstrated that the age-dependent somatic CAG expansion associated with Huntington disease (Kennedy et al., 2003) occurs in the process of removing oxidized base lesions, and is remarkably dependent on the single-base excision repair enzyme 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1; 601982). Both in vivo and in vitro results supported a 'toxic oxidation' model in which OGG1 initiates an escalating oxidation-excision cycle that leads to progressive age-dependent expansion. Kovtun et al. (2007) concluded that age-dependent CAG expansion provides a direct molecular link between oxidative damage and toxicity in postmitotic neurons through a DNA damage response, and error-prone repair of single-strand breaks. </p><p>Wright et al. (2019) assessed the effect of a sequence variant downstream of the CAG repeat in the HTT gene, a change from (CAG)n-CAA-CAG to (CAG)n-CAG-CAG, in 16 patients with HD from 6 families. The variant resulted in complete loss of interrupting (LOI) adenine nucleotides in this region. The LOI was associated with increased somatic CAG tract instability and increased repeat size as assessed in patient blood and sperm. Patients who were carriers of the LOI variant had an average of disease onset 25 years earlier than predicted by models. This effect was particularly seen in patients who were carriers of reduced penetrance alleles of 36 to 39 CAG repeat lengths in the HTT gene. </p><p><strong><em>Lopes-Maciel-Rodan Syndrome</em></strong></p><p>
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In an 18-year-old girl with Lopes-Maciel-Rodan syndrome (LOMARS; 617435), Lopes et al. (2016) identified compound heterozygous missense mutations in the HTT gene (P703L, 613004.0002 and T1260M, 613004.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but Lopes et al. (2016) noted that the HTT gene interacts with MECP2 (300005), which is mutant in Rett syndrome (RTT; 312750). The patient filled diagnostic criteria for RTT, suggesting a common molecular pathogenesis. </p><p>In 3 sibs, born of parents of Ecuadorian descent, with LOMARS, Rodan et al. (2016) identified compound heterozygous mutations in the HTT gene (613004.0004 and 613004.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed. </p><p>Jung et al. (2021) performed functional studies in fibroblasts from the parents and 1 affected sib and in lymphoblastoid cell lines from another affected sib from the family described by Rodan et al. (2016) with LOMARS. The 2 affected sibs inherited F2719L (613004.0005) from the mother and c.4469+1G-A (613004.0004) from the father. There was reduced HTT mRNA in the cells from the father and the affected sibs, and RT-PCR studies demonstrated that the c.4469+1G-A mutation resulted in skipping of exon 34, with a subsequent frameshift and premature termination. Studies in the maternal cells showed that the F2719L mutation resulted in reduced protein stability. Jung et al. (2021) concluded that LOMARS is due to biallelic hypomorphic loss-of-function mutations in HTT, and that heterozygosity for a loss-of-function mutation in HTT is not disease causing. </p>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Nasir et al. (1995) created a targeted disruption in exon 5 of Hdh, the murine homolog of the HTT gene, using homologous recombination. They found that homozygotes died before embryonic day 8.5 and initiated gastrulation, but did not proceed to the formation of somites or to organogenesis. Mice heterozygous for the mutation displayed increased motor activity and cognitive deficits. Neuropathologic assessment of 2 heterozygous mice showed a significant neuronal loss in the subthalamic nucleus. These studies showed that the HD gene is essential for postimplantation development and that it may play an important role in normal functioning of the basal ganglia. </p><p>To distinguish between 'loss-of-function' and 'gain-of-function' models of HD, Duyao et al. (1995) inactivated the mouse Hdh by gene targeting. Mice heterozygous for Hdh inactivation were phenotypically normal, whereas homozygosity resulted in embryonic death. Homozygotes displayed abnormal gastrulation at embryonic day 7.5 and were resorbing by day 8.5. The authors concluded that huntingtin is critical early in embryonic development, before the emergence of the nervous system. That Hdh inactivation did not mimic adult HD neuropathology suggested to the authors that the human disease involves a gain of function. </p><p>Zeitlin et al. (1995) also used targeted gene disruption of Hdh and found that mice nullizygous for the Hdh gene showed developmental retardation and disorganization as embryos and died between days 8.5 and 10.5 of gestation. Based on the observation that the level of the regionalized apoptotic cell death in the embryonic ectoderm, a layer expressing the Hdh gene, was much higher than normal in the null mutants, Zeitlin et al. (1995) proposed that huntingtin is involved in processes counterbalancing the operation of an apoptotic pathway. </p><p>Hodgson et al. (1996) reported results of their studies designed to rescue the embryonic lethality phenotype that results from targeted disruption of the murine HD gene. They generated viable offspring that were homozygous for the disrupted murine HD gene and that expressed human huntingtin derived from a YAC transgene. These results indicated that the YAC transgene was expressed prior to 7.5 days' gestation and that the human huntingtin protein was functional in a murine background. </p><p>MacDonald et al. (1996) reviewed the work with targeted inactivation of the mouse Hdh gene. </p><p>It is known that huntingtin plays a fundamental role in development, since gene targeted Hd -/- mouse embryos died shortly after gastrulation. Metzler et al. (2000) analyzed expression of huntingtin in a variety of hematopoietic cell types, and in vitro hematopoiesis was assessed using an Hd +/- and several Hd -/- embryonic stem (ES) cell lines. Although wildtype and the 2 mutant cell lines formed primary embryoid bodies (EBs) with similar efficiency, the number of hematopoietic progenitors detected at various stages of the in vitro differentiation were reduced in both of the heterozygous and the homozygous ES cell lines examined. Expression analyses of hematopoietic markers within the EBs revealed that primitive and definitive hematopoiesis occurs in the absence of huntingtin. However, further analysis using a suspension culture in the presence of hematopoietic cytokines demonstrated a highly significant gene dosage-dependent decrease in proliferation and/or survival of Hd +/- and Hd -/- cells. Enrichment for the CD34+ (142230) cells within the EB confirmed that the impairment is intrinsic to the hematopoietic cells. These observations suggested that huntingtin expression is required for the generation and expansion of hematopoietic cells and provides an alternative system in which to assess the function of huntingtin. </p><p>Clabough and Zeitlin (2006) found that mice with targeted deletion of the short CAG triplet repeat (7Q) in the Htt gene showed no gross phenotypic differences compared to control littermates. However, adult mice showed mild learning and memory deficits and slightly better motor coordination compared to wildtype mice. Fibroblast cultures derived from the 7Q-deletion mice had increased levels of ATP and senesced earlier compared to wildtype fibroblasts. The findings indicated that the polyQ stretch is not required for an essential function of HTT, but may be required for modulating longevity in culture or modulating a function involved in regulating energy homeostasis. </p><p>To determine whether caspase cleavage of HTT is a key event in the neuronal dysfunction and selective neurodegeneration in HD, Graham et al. (2006) generated YAC mice expressing caspase-3 (CASP3; 600636)- and caspase-6 (CASP6; 601532)-resistant mutant human HTT. Mice expressing mutant HTT resistant to cleavage by caspase-6, but not by caspase-3, maintained normal neuronal function and did not develop neurodegeneration. Furthermore, caspase-6-resistant mutant HTT mice were protected against neurotoxicity induced by multiple stressors, including NMDA, quinolinic acid, and staurosporine. Graham et al. (2006) concluded that proteolysis of HTT at the caspase-6 cleavage site is a crucial and rate-limiting step in the pathogenesis of HD. </p><p>Dietrich et al. (2009) inactivated the mouse Hdh gene in Wnt1 (164820) cell lineages, which contribute to development of the midbrain, hindbrain, granular cells of the cerebellum, and dorsal midline-derived ependymal secretory structures, using the Cre-loxP system of recombination. Conditional inactivation of the Hdh gene in Wnt1 cell lineages resulted in congenital hydrocephalus, which was associated with increase in CSF production by the choroid plexus, and abnormal subcommissural organ. </p><p>Using synthetic antisense morpholinos to inhibit the translation of huntingtin mRNA during early zebrafish development, Henshall et al. (2009) determined the effects of huntingtin loss of function on the developing nervous system, observing distinct defects in morphology of neuromasts, olfactory placode, and branchial arches. There was impaired formation of the anterior-most region of the neural plate as indicated by reduced pre-placodal and telencephalic gene expression, with no effect on mid- or hindbrain formation. The authors suggested a specific 'rate-limiting' role for huntingtin in formation of the telencephalon and the pre-placodal region, and differing levels of requirement for huntingtin function in specific nerve cell types. </p><p>Yamanaka et al. (2010) performed a comprehensive analysis of altered DNA binding of multiple transcription factors using brains from R6/2 HD mice, which express an N-terminal fragment of mutant huntingtin (Nhtt). The authors observed a reduction of DNA binding of Brn2 (600494), a POU domain transcription factor involved in differentiation and function of hypothalamic neurosecretory neurons. Brn2 lost its function through 2 pathways, sequestration by mutant Nhtt and reduced transcription, leading to reduced expression of hypothalamic neuropeptides. In contrast, Brn1 (602480) was not sequestered by mutant Nhtt but was upregulated in R6/2 brain, except in hypothalamus. Yamanaka et al. (2010) concluded that functional suppression of Brn2 together with a region-specific lack of compensation by Brn1 may mediate hypothalamic cell dysfunction by mutant Nhtt. </p><p>Jiang et al. (2012) found that mutant Htt interacted with Sirt1 (604479) and interfered with Sirt1 deacetylase activity in a mouse model of HD. Overexpression of Sirt1 reversed neurodegeneration and molecular changes observed in HD mice. Independently, Jeong et al. (2012) presented similar findings, including interaction of Htt with Sirt1. They found that interaction between Torc1 (CRTC1; 607536) and Creb (123810) had a crucial role in Sirt1-mediated reversal of mutant Htt effects. </p><p>For a discussion of animal models of Huntington disease, see ANIMAL MODEL section in 143100.</p>
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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>5 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 HUNTINGTON 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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HTT, (CAG)n REPEAT EXPANSION
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<br />
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ClinVar: RCV000030659
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</span>
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<span class="mim-text-font">
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<p>Huntington disease (HD; 143100) is caused by expansion of a polymorphic trinucleotide repeat (CAG)n, encoding glutamine, located in the N-terminal coding region of the HTT gene. In normal individuals, the range of repeat numbers is 9 to 36. In those with HD, the repeat number is above 37 (Duyao et al., 1993). </p><p>The trinucleotide repeat expansion was identified in affected members of 75 families with HD by the Huntington's Disease Collaborative Research Group (1993). The families came from a variety of ethnic backgrounds and demonstrated a variety of 4p16.3 haplotypes. </p><p>Gellera et al. (1996) noted that the unstable (CAG)n repeat lies immediately upstream from a moderately polymorphic polyproline-encoding (CCG)n repeat. They noted further that a number of reports in the literature indicated that in normal subjects the number of (CAG)n repeats ranges from 9 to 36, while in HD patients it ranges from 37 to 100. The downstream (CCG)n repeat may vary in size between 7 and 12 repeats in both affected and normal individuals. They reported the occurrence of a CAA trinucleotide deletion (nucleotides 433-435) in HD chromosomes in 2 families that, because of its position within the conventional antisense primer hd447, hampered HD mutation detection if only the (CAG)n tract were amplified. Therefore, Gellera et al. (1996) stressed the importance of using a series of 3 diagnostic PCR reactions: one that amplified the (CAG)n tract alone, one that amplified the (CCG)n tract alone, and one that amplified the whole region. </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>.0002 LOPES-MACIEL-RODAN SYNDROME</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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HTT, PRO703LEU
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<br />
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SNP: rs768047421,
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gnomAD: rs768047421,
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ClinVar: RCV000477706, RCV001851126, RCV004760523
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 18-year-old girl (proband 2) with Lopes-Maciel-Rodan syndrome (LOMARS; 617435), Lopes et al. (2016) identified compound heterozygous mutations in the HTT gene: a c.2108C-T transition (c.2108C-T, NM_002111), resulting in a pro703-to-leu (P703L) substitution, and a c.3779C-T transition, resulting in a thr1260-to-met (T1260M; 613004.0003) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The T1260M variant was present at a low frequency in the dbSNP database (0.0276/138). Functional studies of the variants and studies of patient cells were not performed. </p>
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</span>
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</div>
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<div>
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<br />
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 LOPES-MACIEL-RODAN SYNDROME</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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HTT, THR1260MET ({dbSNP rs34315806})
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<br />
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SNP: rs34315806,
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gnomAD: rs34315806,
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ClinVar: RCV000477735, RCV001662450, RCV001777163
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the c.3779C-T transition (c.3779C-T, NM_002111) in the HTT gene, resulting in a thr1260-to-met (T1260M) substitution, that was found in compound heterozygous state in a patient with Lopes-Maciel-Rodan syndrome (LOMARS; 617435) by Lopes et al. (2016), see 613004.0002. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0004 LOPES-MACIEL-RODAN SYNDROME</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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HTT, IVS34DS, G-A, +1
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<br />
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SNP: rs1060505027,
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ClinVar: RCV000477676, RCV000490292
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In 3 sibs, born of parents of Ecuadorian descent, with Lopes-Maciel-Rodan syndrome (LOMARS; 617435), Rodan et al. (2016) identified compound heterozygous mutations in the HTT gene: a paternally inherited c.4469+1G-A transition in intron 34, predicted to result in abnormal gene splicing, and a maternally inherited c.8156T-A transversion, resulting in a phe2719-to-leu (F2719L; 613004.0005) substitution at a conserved residue. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was found in the Exome Sequencing Project or ExAC databases or in about 6,000 control individuals. Functional studies of the variants and studies of patient cells were not performed. </p><p>Jung et al. (2021) noted that the correct nucleotide change for the maternally inherited variant reported by Rodan et al. (2016) is c.8157T-A (c.8157T-A, NM_002111.8). They also noted that c.4469+1G-A (NM_002111.8) corresponds to c.4463+1G-A (GRCh38). </p><p>Jung et al. (2021) performed functional studies in fibroblasts from the parents and 1 affected sib and in lymphoblastoid cell lines from another affected sib from the family described by Rodan et al. (2016) with LOMARS. There was reduced HTT mRNA in cells from the father and the affected sibs, and RT-PCR studies demonstrated that the c.4469+1G-A mutation resulted in skipping of exon 34, with a subsequent frameshift and premature termination. Studies in the maternal cells showed that the F2719L mutation resulted in reduced protein stability. </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>.0005 LOPES-MACIEL-RODAN SYNDROME</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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HTT, PHE2719LEU
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<br />
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SNP: rs1060505028,
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ClinVar: RCV000477714
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>For discussion of the phe2719-to-leu (F2719L) substitution in the HTT gene that was found in compound heterozygous state in 3 sibs with Lopes-Maciel-Rodan syndrome (LOMARS; 617435) by Rodan et al. (2016), see 613004.0004. Rodan et al. (2016) reported the nucleotide change for this variant as a c.8156T-A transversion, but Jung et al. (2021) noted that the correct nucleotide change for this variant is c.8157T-A (c.8157T-A, NM_002111.8). </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>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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Altherr, M. R., Wasmuth, J. J., Seldin, M. F., Nadeau, J. H., Baehr, W., Pittler, S. J.
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<strong>Chromosome mapping of the rod photoreceptor cGMP phosphodiesterase beta-subunit gene in mouse and human: tight linkage to the Huntington disease region (4p16.3).</strong>
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Genomics 12: 750-754, 1992.
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[PubMed: 1315306]
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[Full Text: https://doi.org/10.1016/0888-7543(92)90305-c]
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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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Ambrose, C. M., Duyao, M. P., Barnes, G., Bates, G. P., Lin, C. S., Srinidhi, J., Baxendale, S., Hummerich, H., Lehrach, H., Altherr, M., Wasmuth, J., Buckler, A., Church, D., Housman, D., Berks, M., Micklem, G., Durbin, R., Dodge, A., Read, A., Gusella, J., MacDonald, M. E.
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<strong>Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat.</strong>
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Somat. Cell Molec. Genet. 20: 27-38, 1994.
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[PubMed: 8197474]
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[Full Text: https://doi.org/10.1007/BF02257483]
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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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Andrew, S. E., Goldberg, Y. P., Kremer, B., Telenius, H., Theilmann, J., Adam, S., Starr, E., Squitieri, F., Lin, B., Kalchman, M. A., Graham, R. K., Hayden, M. R.
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<strong>The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease.</strong>
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Nature Genet. 4: 398-403, 1993.
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[PubMed: 8401589]
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[Full Text: https://doi.org/10.1038/ng0893-398]
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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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Thank you in advance for your generous support, <br />
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Ada Hamosh, MD, MPH <br />
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Scientific Director, OMIM <br />
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