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Entry
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- *104155 - ZINC FINGER HOMEOBOX 3; ZFHX3
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- OMIM
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</form>
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*104155</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<li role="presentation">
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<li role="presentation">
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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</li>
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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="#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 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/104155">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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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=ENSG00000140836;t=ENST00000268489" 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=463" 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=104155" 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=ENSG00000140836;t=ENST00000268489" 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_001164766,NM_001386735,NM_006885,NR_163978,XM_017023251,XM_024450291,XM_047434165,XM_047434166,XM_047434167,XM_047434168,XM_047434169" 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_006885" 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=104155" 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=00075&isoform_id=00075_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/ZFHX3" 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/219430,976347,976349,3924672,20987426,34526297,38679302,108935822,118498345,119579570,119579572,119579573,119579574,258613987,1034594678,1370468505,1898478969,2217306104,2217306106,2217306108,2217306110,2217306114,2462549150,2462549152,2462549154,2462549156,2462549158,2462549160,2462549162,2462549164" 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/Q15911" 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=463" 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=ENSG00000140836;t=ENST00000268489" 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=ZFHX3" 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=ZFHX3" 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+463" 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/ZFHX3" 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:463" 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/463" 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=chr16&hgg_gene=ENST00000268489.10&hgg_start=72782885&hgg_end=73891930&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=104155[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=104155[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/ZFHX3/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/ENSG00000140836" 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=ZFHX3" 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=ZFHX3" 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=ZFHX3" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=ZFHX3&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/PA162409676" 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:777" 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/FBgn0004607.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:99948" 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/ZFHX3#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:99948" 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/463/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=463" 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=WBGene00022518;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-030131-7577" 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:463" 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=ZFHX3&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>
|
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<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> 715755008<br />
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">ICD+</a>
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</div>
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<div>
|
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
|
104155
|
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</span>
|
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
|
<span class="mim-font">
|
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ZINC FINGER HOMEOBOX 3; ZFHX3
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</span>
|
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</h3>
|
|
</div>
|
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<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">
|
|
AT MOTIF-BINDING FACTOR 1; ATBF1<br />
|
|
AT-BINDING TRANSCRIPTION FACTOR 1<br />
|
|
ALPHA-FETOPROTEIN ENHANCER-BINDING PROTEIN
|
|
</span>
|
|
</h4>
|
|
</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=ZFHX3" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">ZFHX3</a></em></strong>
|
|
</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/16/630?start=-3&limit=10&highlight=630">16q22.2-q22.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:72782885-73891930&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'})">16:72,782,885-73,891,930</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
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|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<br />
|
|
</div>
|
|
<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
|
|
<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=613055,176807,600223" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
|
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/16/630?start=-3&limit=10&highlight=630">
|
|
16q22.2-q22.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
{Atrial fibrillation 8, susceptibility to}
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/613055"> 613055 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
|
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|
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|
|
</tr>
|
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|
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|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Prostate cancer, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/176807"> 176807 </a>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Spinocerebellar ataxia 4
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/600223"> 600223 </a>
|
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<p>ZFHX3 is a transcriptional regulator that interacts with AT motifs in target genes. ZFHX3 is involved in regulation of circadian rhythm (<a href="#10" class="mim-tip-reference" title="Parsons, M. J., Brancaccio, M., Sethi, S., Maywood, E. S., Satija, R., Edwards, J. K., Jagannath, A., Couch, Y., Finelli, M. J., Smyllie, N. J., Esapa, C., Butler, R., and 11 others. <strong>The regulatory factor ZFHX3 modifies circadian function in SCN via an AT motif-driven axis.</strong> Cell 162: 607-621, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26232227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26232227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26232227[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.2015.06.060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26232227">Parsons et al., 2015</a>) and appetite and body weight (<a href="#9" class="mim-tip-reference" title="Nolan, P. M., Banks, G., Bourbia, N., Wilcox, A. G., Bentley, L., Moir, L., Kent, L., Hillier, R., Wilson, D., Barrett, P., Dumbell, R. <strong>A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice.</strong> FASEB J. 37: e23189, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37713040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37713040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37713040[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/10.1096/fj.202201829R" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37713040">Nolan et al., 2023</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26232227+37713040" 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>Tissue-specific expression of the human alpha-fetoprotein (AFP) gene (<a href="/entry/104150">104150</a>) is strongly stimulated by an enhancer present 3.3 to 4.9 kb upstream of the transcription initiation site. One of the enhancer elements contains an AT-rich core sequence (AT motif). To determine the nuclear factor in hepatoma cell lines that interacts with the human AFP enhancer AT motif, <a href="#8" class="mim-tip-reference" title="Morinaga, T., Yasuda, H., Hashimoto, T., Higashio, K., Tamaoki, T. <strong>A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers.</strong> Molec. Cell. Biol. 11: 6041-6049, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1719379/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1719379</a>] [<a href="https://doi.org/10.1128/mcb.11.12.6041-6049.1991" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1719379">Morinaga et al. (1991)</a> screened a hepatoma cDNA expression library with an AFP enhancer fragment that bore the AT motif. They succeeded in isolating a cDNA that can code for an AT motif-binding factor, which they termed ATBF1. This was the largest DNA-binding protein identified to that time and the first protein shown to contain multiple homeodomains and multiple zinc finger motifs. The protein had a predicted mass of 306 kD and contained 4 homeodomains and 17 zinc finger motifs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1719379" 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="#2" class="mim-tip-reference" title="Dong, X.-Y., Sun, X., Guo, P., Li, Q., Sasahara, M., Ishii, Y., Dong, J.-T. <strong>ATBF1 inhibits estrogen receptor (ER) function by selectively competing with AIB1 for binding to the ER in ER-positive breast cancer cells.</strong> J. Biol. Chem. 285: 32801-32809, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20720010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20720010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20720010[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.M110.128330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20720010">Dong et al. (2010)</a> stated that full-length human ATBF1 contains 3,703 amino acids and that it has an ATPase A motif, 2 DEAH box-like sequences, 4 homeodomains, and 23 zinc finger motifs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20720010" 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 confocal imaging in adult wildtype mouse heart tissue, <a href="#6" class="mim-tip-reference" title="Jameson, H. S., Hanley, A., Hill, M. C., Xiao, L., Ye, J., Bapat, A., Ronzier, E., Hall, A. W., Hucker, W. J., Clauss, S., Barazza, M., Silber, E., Mina, J. A., Tucker, N. R., Mills, R. W., Dong, J.-T., Milan, D. J., Ellinor, P. T. <strong>Loss of the atrial fibrillation-related gene, Zfhx3, results in atrial dilation and arrhythmias.</strong> Circ. Res. 133: 313-329, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37449401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37449401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37449401[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/10.1161/CIRCRESAHA.123.323029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37449401">Jameson et al. (2023)</a> demonstrated expression of Zfhx3 primarily in atria. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37449401" 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 fluorescence in situ hybridization, <a href="#17" class="mim-tip-reference" title="Yamada, K., Miura, Y., Scheidl, T., Yoshida, M. C., Tamaoki, T. <strong>Assignment of the human ATBF1 transcription factor gene to chromosome 16q22.3-q23.1.</strong> Genomics 29: 552-553, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8666409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8666409</a>] [<a href="https://doi.org/10.1006/geno.1995.9967" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8666409">Yamada et al. (1995)</a> mapped the ATBF1 gene to 16q22.3-q23.1. <a href="#16" class="mim-tip-reference" title="Yamada, K., Ma, D., Miura, Y., Ido, A., Tamaoki, T., Yoshida, M. C. <strong>Assignment of the ATBF1 transcription factor gene (Atbf1) to mouse chromosome band 8E1 by in situ hybridization.</strong> Cytogenet. Cell Genet. 75: 30-31, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8995484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8995484</a>] [<a href="https://doi.org/10.1159/000134451" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8995484">Yamada et al. (1996)</a> used fluorescence in situ hybridization to assign the Atbf1 gene to mouse chromosome 8E1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8995484+8666409" 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="#12" class="mim-tip-reference" title="Qi, Y., Ranish, J. A., Zhu, X., Krones, A., Zhang, J., Aebersold, R., Rose, D. W., Rosenfeld, M. G., Carriere, C. <strong>Atbf1 is required for the Pit1 gene early activation.</strong> Proc. Nat. Acad. Sci. 105: 2481-2486, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18272476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18272476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18272476[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.0712196105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18272476">Qi et al. (2008)</a> identified 3 highly conserved regulatory elements in the promoter region of the mouse Pit1 gene (POU1F1; <a href="/entry/173110">173110</a>) and found that Atbf1 bound and activated Pit1 from 1 of these elements, EE-alpha. Pituitaries of mice with a hypomorphic Atbf1 allele showed decreased expression of the somatotrope marker, Gh (<a href="/entry/139250">139250</a>), and almost no expression of the thyrotrope marker, Tshb (<a href="/entry/188540">188540</a>). <a href="#12" class="mim-tip-reference" title="Qi, Y., Ranish, J. A., Zhu, X., Krones, A., Zhang, J., Aebersold, R., Rose, D. W., Rosenfeld, M. G., Carriere, C. <strong>Atbf1 is required for the Pit1 gene early activation.</strong> Proc. Nat. Acad. Sci. 105: 2481-2486, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18272476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18272476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18272476[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.0712196105" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18272476">Qi et al. (2008)</a> concluded that ATBF1 is required for early PIT1 transcriptional activation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18272476" 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="#2" class="mim-tip-reference" title="Dong, X.-Y., Sun, X., Guo, P., Li, Q., Sasahara, M., Ishii, Y., Dong, J.-T. <strong>ATBF1 inhibits estrogen receptor (ER) function by selectively competing with AIB1 for binding to the ER in ER-positive breast cancer cells.</strong> J. Biol. Chem. 285: 32801-32809, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20720010/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20720010</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20720010[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.M110.128330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20720010">Dong et al. (2010)</a> found that ATBF1 inhibited estrogen receptor (ER, or ESR1; <a href="/entry/133430">133430</a>)-mediated gene transcription, cell growth, and proliferation in ER-positive breast cancer cell lines. In vitro and in vivo immunoprecipitation experiments revealed that ATBF1 interacted directly with ER, and mutation analysis identified multiple domains in both proteins that mediated the interaction. ATBF1 inhibited ER function by selectively competing with the steroid receptor coactivator AIB1 (NCOA3; <a href="/entry/601937">601937</a>), but not GRIP1 (NCOA2; <a href="/entry/601993">601993</a>) or SRC1 (NCOA1; <a href="/entry/602691">602691</a>), for binding to ER. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20720010" 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="Jameson, H. S., Hanley, A., Hill, M. C., Xiao, L., Ye, J., Bapat, A., Ronzier, E., Hall, A. W., Hucker, W. J., Clauss, S., Barazza, M., Silber, E., Mina, J. A., Tucker, N. R., Mills, R. W., Dong, J.-T., Milan, D. J., Ellinor, P. T. <strong>Loss of the atrial fibrillation-related gene, Zfhx3, results in atrial dilation and arrhythmias.</strong> Circ. Res. 133: 313-329, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37449401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37449401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37449401[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/10.1161/CIRCRESAHA.123.323029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37449401">Jameson et al. (2023)</a> performed differential expression analysis as well as gene ontology and pathway enrichment analysis of left and right mouse atria from 6-month-old mice that were wildtype, heterozygous, or homozygous for ZFHX3 knockout. Their findings suggested that ZFHX3 plays a role in the regulation of gene signaling pathways involved in cardiac pathophysiology. To determine which genes in atrial cardiomyocytes are putatively regulated directly by ZFHX3, the authors analyzed human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data obtained from each of the 4 cardiac chambers. Among the top enriched terms for the putative ZFHX3 cistrome were cardiac conduction, heart contraction, and Ca(2+) transport. Extracting atrial-enriched data peaks and performing motif enrichment analysis for ZFHX3 identified 4,174 ZFHX3 atrial cardiomyocyte-specific binding sites, of which 306 genes were identified as differentially expressed. Gene ontology analysis of those 306 direct ZFHX3 target genes uncovered enrichment for genes with roles in cardiac development, VEGF (<a href="/entry/192240">192240</a>) signaling, Wnt (see <a href="/entry/164820">164820</a>) signaling, calcium binding, and heart contraction. The directionality of expression was consistent with both positive and negative regulation by ZFHX3 in cardiomyocytes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37449401" 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>Atrial Fibrillation 8</em></strong>
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<p><a href="#6" class="mim-tip-reference" title="Jameson, H. S., Hanley, A., Hill, M. C., Xiao, L., Ye, J., Bapat, A., Ronzier, E., Hall, A. W., Hucker, W. J., Clauss, S., Barazza, M., Silber, E., Mina, J. A., Tucker, N. R., Mills, R. W., Dong, J.-T., Milan, D. J., Ellinor, P. T. <strong>Loss of the atrial fibrillation-related gene, Zfhx3, results in atrial dilation and arrhythmias.</strong> Circ. Res. 133: 313-329, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37449401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37449401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37449401[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/10.1161/CIRCRESAHA.123.323029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37449401">Jameson et al. (2023)</a> defined the atrial fibrillation-8 (ATFB8; <a href="/entry/613055">613055</a>) locus using SNPs in strong linkage disequilibrium with an ATFB8-associated SNP (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs2106261;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs2106261</a>) previously identified by <a href="#1" class="mim-tip-reference" title="Benjamin, E. J., Rice, K. M., Arking, D. E., Pfeufer, A., van Noord, C., Smith, A. V., Schnabel, R. B., Bis, J. C., Boerwinkle, E., Sinner, M. F., Dehghan, A., Lubitz, S. A., and 44 others. <strong>Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.</strong> Nature Genet. 41: 879-881, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19597492/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19597492</a>] [<a href="https://doi.org/10.1038/ng.416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19597492">Benjamin et al. (2009)</a>, located in an intron of the ZFHX3 gene. <a href="#6" class="mim-tip-reference" title="Jameson, H. S., Hanley, A., Hill, M. C., Xiao, L., Ye, J., Bapat, A., Ronzier, E., Hall, A. W., Hucker, W. J., Clauss, S., Barazza, M., Silber, E., Mina, J. A., Tucker, N. R., Mills, R. W., Dong, J.-T., Milan, D. J., Ellinor, P. T. <strong>Loss of the atrial fibrillation-related gene, Zfhx3, results in atrial dilation and arrhythmias.</strong> Circ. Res. 133: 313-329, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37449401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37449401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37449401[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/10.1161/CIRCRESAHA.123.323029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37449401">Jameson et al. (2023)</a> obtained a 74-kb region containing 52 common variants with a minor allele frequency greater than 1% in individuals of European descent. Intersecting the 52 ATFB-associated SNPs on 16q22 with the DNaseI hypersensitivity signal in human cardiomyocytes identified 6 candidate SNPs that overlapped with active chromatin marks. The authors then assessed the effect of the 6 candidates on gene expression in human pluripotent stem cell-derived cardiomyocytes (PSC-CMs), and found only 1 SNP (C-A, <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12931021;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12931021</a>; <a href="#0002">104155.0002</a>) in the ZFHX3 gene that exhibited differential activity dependent on genotype. The authors concluded that ZFHX3 is the causal gene at the ATFB8 locus at 16q22, with <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12931021;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12931021</a> being a functional SNP mediating the genetic association with increased risk of atrial fibrillation correlated to reduced ZFHX3 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19597492+37449401" 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>Spinocerebellar Ataxia 4</em></strong>
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</p>
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<div class="mim-changed mim-change"><p>In 2024, 3 different research groups (<a href="#14" class="mim-tip-reference" title="Wallenius, J., Kafantari, E., Jhaveri, E., Gorcenco, S., Ameur, A., Karremo, C., Dobloug, S., Karrman, K., de Koning, T., Ilinca, A., Landqvist Waldo, M., Arvidsson, A., Persson, S., Englund, E., Ehrencrona, H., Puschmann, A. <strong>Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease.</strong> Am. J. Hum. Genet. 111: 1-14, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38035881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38035881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38035881[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.2023.11.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38035881">Wallenius et al., 2024</a>, <a href="#3" class="mim-tip-reference" title="Figueroa, K. P., Gross, C., Buena-Atienza, E., Paul, S., Gandelman, M., Kakar, N., Sturm, M., Casadei, N., Admard, J., Park, J., Zuhlke, C., Hellenbroich, Y., and 18 others. <strong>A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.</strong> Nature Genet. 56: 1080-1089, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38684900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38684900</a>] [<a href="https://doi.org/10.1038/s41588-024-01719-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38684900">Figueroa et al., 2024</a>, and <a href="#11" class="mim-tip-reference" title="Paucar, M., Nilsson, D., Engvall, M., Laffita-Mesa, J., Soderhall, C., Skorpil, M., Halldin, C., Fazio, P., Lagerstedt-Robinson, K., Solders, G., Angeria, M., Varrone, A., Risling, M., Jiao, H., Nennesmo, I., Wedell, A., Svenningsson, P. <strong>Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs.</strong> J. Intern. Med. 296: 234-248, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38973251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38973251</a>] [<a href="https://doi.org/10.1111/joim.13815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38973251">Paucar et al., 2024</a>) independently identified a heterozygous GGC(n) trinucleotide repeat expansion in the ZFHX3 gene (<a href="#0003">104155.0003</a>) as the cause of autosomal dominant spinocerebellar ataxia-4 (SCA4; <a href="/entry/600223">600223</a>) that had been mapped to chromosome 16q22. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=38684900+38035881+38973251" 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></div>
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<div class="mim-changed mim-change"><p>In 8 affected individuals from 5 Swedish families with SCA4, <a href="#14" class="mim-tip-reference" title="Wallenius, J., Kafantari, E., Jhaveri, E., Gorcenco, S., Ameur, A., Karremo, C., Dobloug, S., Karrman, K., de Koning, T., Ilinca, A., Landqvist Waldo, M., Arvidsson, A., Persson, S., Englund, E., Ehrencrona, H., Puschmann, A. <strong>Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease.</strong> Am. J. Hum. Genet. 111: 1-14, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38035881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38035881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38035881[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.2023.11.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38035881">Wallenius et al. (2024)</a> identified a heterozygous 3-bp (GGC) repeat expansion in the last coding exon (exon 10) of the ZFHX3 gene (<a href="#0003">104155.0003</a>); the GGC repeat encoded a glycine residue. All families originated from Skane, the southernmost region of Sweden, and haplotype analysis indicated a founder effect. Two of the families had previously been reported (see <a href="#7" class="mim-tip-reference" title="Moller, E., Hindfelt, B., Olsson, J. E. <strong>HLA-determination in families with hereditary ataxia.</strong> Tissue Antigens 12: 357-366, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/85351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">85351</a>] [<a href="https://doi.org/10.1111/j.1399-0039.1978.tb01345.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="85351">Moller et al., 1978</a> and <a href="#15" class="mim-tip-reference" title="Wictorin, K., Bradvik, B., Nilsson, K., Soller, M., van Westen, D., Bynke, G., Bauer, P., Schols, L., Puschmann, A. <strong>Autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism: a novel entity?</strong> Parkinsonism Relat. Disord. 20: 748-754, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24787759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24787759</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2014.03.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24787759">Wictorin et al., 2014</a>). The repeat was expanded to greater than 40 repeats (range 42 to 74) in affected individuals, whereas the most common nonexpanded repeat length was reported as 21 repeats (range 14 to 26) in controls. The nonexpanded repeat in controls consisted of 20 glycine residues interrupted by a single serine. All nonexpanded alleles had interruptions within the GGC repeat; the interruptions were predominantly synonymous GGT and a nonsynonymous AGT (serine). Pathogenic expanded alleles did not contain interruptions: GGC was the only repeat unit. Genetic anticipation was observed, and there was a correlation between longer repeat expansions and earlier age at symptom onset. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=38035881+24787759+85351" 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></div>
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<div class="mim-changed mim-change"><p>In affected members of 8 families with SCA4, <a href="#3" class="mim-tip-reference" title="Figueroa, K. P., Gross, C., Buena-Atienza, E., Paul, S., Gandelman, M., Kakar, N., Sturm, M., Casadei, N., Admard, J., Park, J., Zuhlke, C., Hellenbroich, Y., and 18 others. <strong>A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.</strong> Nature Genet. 56: 1080-1089, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38684900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38684900</a>] [<a href="https://doi.org/10.1038/s41588-024-01719-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38684900">Figueroa et al. (2024)</a> identified a heterozygous a GGC(n) repeat expansion in the last coding exon (exon 10) of the ZFHX3 gene (<a href="#0003">104155.0003</a>). The repeat, which was found by long-read genome sequencing, segregated with the disorder in the families in an autosomal dominant pattern of inheritance. The normal allele had 21 repeats, whereas the pathogenic GGC repeat was over 45 repeats (up to 61 repeats) and was translated into a polyG domain in-frame with the rest of the ZFHX3 protein as demonstrated in patient fibroblasts. There was a significant inverse correlation between age at onset and repeat expansion length. One of the families was a large multigenerational family from Utah previously reported by <a href="#5" class="mim-tip-reference" title="Gardner, K., Alderson, K., Galster, B., Kaplan, C., Leppert, M., Ptacek, L. <strong>Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA4) in a Utah kindred. (Abstract)</strong> Neurology 44: A361 only, 1994."None>Gardner et al. (1994)</a> and <a href="#4" class="mim-tip-reference" title="Flanigan, K., Gardner, K., Alderson, K., Galster, B., Otterud, B., Leppert, M. F., Kaplan, C., Ptacek, L. J. <strong>Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1.</strong> Am. J. Hum. Genet. 59: 392-399, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755926</a>]" pmid="8755926">Flanigan et al. (1996)</a> who could be traced to a common ancestor in southern Sweden around the start of the 19th century. The 7 other families were from Germany (Lubeck, Munchen, Magdeburg 1 and 2, Essen 1 and 2, and Hamburg). Haplotype analysis showed that several of the families shared a common repeat expansion haplotype. Fibroblast samples from 4 SCA4 patients in the Utah family showed evidence of abnormal autophagy compared to controls. Wildtype ATXN2 was upregulated in all patient samples. Induced pluripotent stem cells (iPSCs) generated from one SCA4 patient from the Utah family with 21/53 repeats contained increased polyG-expanded ZFHX3 protein levels, but became rapidly apoptotic upon induction of differentiation to neurons, whereas control iPSCs easily differentiated into neurons under similar conditions. Neuropathologic examination of 1 patient detected neuronal intranuclear inclusions (NII) in the cerebellum that were immunoreactive to ZFHX3, ubiquitin, and p62. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=38684900+8755926" 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></div>
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<div class="mim-changed mim-change"><p>Using a combination of methods, including long-read sequencing, <a href="#11" class="mim-tip-reference" title="Paucar, M., Nilsson, D., Engvall, M., Laffita-Mesa, J., Soderhall, C., Skorpil, M., Halldin, C., Fazio, P., Lagerstedt-Robinson, K., Solders, G., Angeria, M., Varrone, A., Risling, M., Jiao, H., Nennesmo, I., Wedell, A., Svenningsson, P. <strong>Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs.</strong> J. Intern. Med. 296: 234-248, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38973251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38973251</a>] [<a href="https://doi.org/10.1111/joim.13815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38973251">Paucar et al. (2024)</a> identified a heterozygous GGC(n) repeat expansion in the coding region of the ZFHX3 gene (<a href="#0003">104155.0003</a>) in affected member of 3 multigenerational Swedish families with SCA4. The pathogenic repeat ranged from 46 to 64 copies. The majority of normal alleles contained 21 copies, with a maximum of 26 copies. Functional studies of the variant were not performed, but neuropathologic studies of 4 patients showed intranuclear inclusions positive for ubiquitin and p62. Polyglycine-positive inclusions were found in neurons in 1 patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38973251" 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></div>
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<p><strong><em>Somatic Mutations</em></strong>
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<p>The long arm of chromosome 16 is frequently deleted in human cancers. <a href="#13" class="mim-tip-reference" title="Sun, X., Frierson, H. F., Chen, C., Li, C., Ran, Q., Otto, K. B., Cantarel, B. L., Vessella, R. L., Gao, A. C., Petros, J., Miura, Y., Simons, J. W., Dong, J.-T. <strong>Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer.</strong> Nature Genet. 37: 407-412, 2005. Note: Erratum: Nature Genet. 37: 652 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15750593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15750593</a>] [<a href="https://doi.org/10.1038/ng1528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15750593">Sun et al. (2005)</a> presented evidence that the ATBF1 gene is a good candidate for the 16q22 tumor suppressor gene. They narrowed the region of deletion at 16q22 to 861 kb containing ATBF1. ATBF1 mRNA was abundant in normal prostates but more scarce in approximately half of prostate cancers tested. In 24 (36%) of 66 cancers examined, <a href="#13" class="mim-tip-reference" title="Sun, X., Frierson, H. F., Chen, C., Li, C., Ran, Q., Otto, K. B., Cantarel, B. L., Vessella, R. L., Gao, A. C., Petros, J., Miura, Y., Simons, J. W., Dong, J.-T. <strong>Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer.</strong> Nature Genet. 37: 407-412, 2005. Note: Erratum: Nature Genet. 37: 652 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15750593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15750593</a>] [<a href="https://doi.org/10.1038/ng1528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15750593">Sun et al. (2005)</a> identified 22 unique somatic mutations (see, e.g., <a href="#0001">104155.0001</a>), many of which impaired ATBF1 function. Furthermore, ATBF1 inhibited cell proliferation. <a href="#13" class="mim-tip-reference" title="Sun, X., Frierson, H. F., Chen, C., Li, C., Ran, Q., Otto, K. B., Cantarel, B. L., Vessella, R. L., Gao, A. C., Petros, J., Miura, Y., Simons, J. W., Dong, J.-T. <strong>Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer.</strong> Nature Genet. 37: 407-412, 2005. Note: Erratum: Nature Genet. 37: 652 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15750593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15750593</a>] [<a href="https://doi.org/10.1038/ng1528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15750593">Sun et al. (2005)</a> concluded that loss of ATBF1 is one mechanism that defines the absence of growth control in prostate cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15750593" 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="#10" class="mim-tip-reference" title="Parsons, M. J., Brancaccio, M., Sethi, S., Maywood, E. S., Satija, R., Edwards, J. K., Jagannath, A., Couch, Y., Finelli, M. J., Smyllie, N. J., Esapa, C., Butler, R., and 11 others. <strong>The regulatory factor ZFHX3 modifies circadian function in SCN via an AT motif-driven axis.</strong> Cell 162: 607-621, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26232227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26232227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26232227[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.2015.06.060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26232227">Parsons et al. (2015)</a> identified a mutant mouse line, termed 'short circuit' (Sci), with a shorter circadian period compared with the population mean. The Sci phenotype was inherited in a dominant fashion. The authors identified the Sci mutation as a val1963-to-phe (V1963F) substitution in a highly conserved region upstream of zinc finger motif-17 in Zhfx3a. Genotype and phenotype correlation demonstrated that the mutation caused homozygous lethality during embryonic development; therefore, only Zfhx3 Sci/+ adult animals could be assessed phenotypically. Transcriptional analysis revealed that the Zhfx3 V1963F mutant downregulated neuropeptide genes with AT motifs in their promoter sequences, including Avp (<a href="/entry/192340">192340</a>) and Vip (<a href="/entry/192320">192320</a>). Further analysis identified the AT motif as a clock-regulated transcriptional axis and showed that Zfhx3 V1963F had diminished ability to activate transcription via AT motifs. Ex vivo or in vivo knockdown of Zfhx3 lengthened the circadian period in mice, confirming the role of Zfhx3 in regulating circadian period. Immunoprecipitation analysis in suprachiasmatic nucleus tissue from wildtype mice showed that Zfhx3 interacted directly with the Avp and Vip promoters in close proximity to AT consensus motifs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26232227" 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="Nolan, P. M., Banks, G., Bourbia, N., Wilcox, A. G., Bentley, L., Moir, L., Kent, L., Hillier, R., Wilson, D., Barrett, P., Dumbell, R. <strong>A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice.</strong> FASEB J. 37: e23189, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37713040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37713040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37713040[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/10.1096/fj.202201829R" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37713040">Nolan et al. (2023)</a> found that Zfhx3 Sci/+ mice were smaller and leaner than wildtype. Zfhx3 Sci/+ mice had lower circulating anabolic hormone concentrations and consumed less food in proportion to body weight. Early differences in body weight were due to impaired lean mass gain by Zfhx3 Sci/+ female mice, but fat mass did not differ. In situ hybridization in Sci/+ mouse brain detected increased mRNA expression of somatostatin (SST; <a href="/entry/182450">182450</a>) and decreased mRNA expression of growth hormone-releasing hormone (GHRH; <a href="/entry/139190">139190</a>) and growth hormone receptor (GHR; <a href="/entry/600946">600946</a>) in the arcuate nucleus (ARC). Similarly, ARC expression of orexigenic neuropeptide Y (NPY; <a href="/entry/162640">162640</a>) was decreased and ventricular ependymal expression of the orphan G protein-coupled receptor Gpr50 (<a href="/entry/300207">300207</a>) was decreased. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37713040" 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="Jameson, H. S., Hanley, A., Hill, M. C., Xiao, L., Ye, J., Bapat, A., Ronzier, E., Hall, A. W., Hucker, W. J., Clauss, S., Barazza, M., Silber, E., Mina, J. A., Tucker, N. R., Mills, R. W., Dong, J.-T., Milan, D. J., Ellinor, P. T. <strong>Loss of the atrial fibrillation-related gene, Zfhx3, results in atrial dilation and arrhythmias.</strong> Circ. Res. 133: 313-329, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37449401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37449401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37449401[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/10.1161/CIRCRESAHA.123.323029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37449401">Jameson et al. (2023)</a> generated mice that were heterozygous or homozygous for cardiomyocyte-restricted loss of Zfhx3, and observed a high incidence of premature death in the mutant mice, at age 10 months in the knockout mice and 12 months in the heterozygotes, compared to wildtype littermates. Cardiac MRI at age 3 months showed a significantly reduced ejection fraction and significantly increased left atrial size in the knockout mice compared to controls. By 9 to 11 months of age, Zfhx3 knockout mice displayed massively dilated hearts with large thrombi in both the left and right atria and significantly increased fibrosis of the atrial wall and left ventricle. In addition, the mutant mice exhibited a premorbid phenotype indicating advanced heart failure, including diffuse edema/anasarca, abdominal distention presumably due to ascites, tachypnea, and muscle wasting. In vivo cardiac electrophysiology testing at age 3 months demonstrated a gene-dose response in inducible atrial arrhythmias by programmed stimulation in the mice, with the knockout mice having a higher incidence of atrial arrhythmias/atrial fibrillation than heterozygotes or wildtype mice. The knockout mice were also more prone to arrhythmia induction and showed an increased frequency of atrial arrhythmias. Ex vivo optical mapping in knockout mouse hearts demonstrated significantly slower right atrial conduction, and knockout left atrial cardiomyocytes showed abnormal calcium handling compared to wildtype. The authors concluded that loss of Zfhx3 causes conditions that predispose to increased automaticity, resulting in the observed increased susceptibility to atrial arrhythmias/atrial fibrillation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37449401" 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="https://www.ncbi.nlm.nih.gov/clinvar?term=104155[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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<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> rs727502780 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs727502780;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/rs727502780?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=rs727502780" 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=rs727502780" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In 4 cases of low- to midgrade primary prostate cancer (<a href="/entry/176807">176807</a>), <a href="#13" class="mim-tip-reference" title="Sun, X., Frierson, H. F., Chen, C., Li, C., Ran, Q., Otto, K. B., Cantarel, B. L., Vessella, R. L., Gao, A. C., Petros, J., Miura, Y., Simons, J. W., Dong, J.-T. <strong>Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer.</strong> Nature Genet. 37: 407-412, 2005. Note: Erratum: Nature Genet. 37: 652 only, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15750593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15750593</a>] [<a href="https://doi.org/10.1038/ng1528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15750593">Sun et al. (2005)</a> identified a 24-bp deletion in exon 10 of the ATBF1 gene, 10814del24, resulting in loss of 8 amino acids, beginning with codon 3381, in a glutamine-rich domain. The deletion was also identified in a microdissected high-grade primary metastasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15750593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Among 6 candidate SNPs within the atrial fibrillation-associated locus on chromosome 16q22 (ATFB8; <a href="/entry/613055">613055</a>), <a href="#6" class="mim-tip-reference" title="Jameson, H. S., Hanley, A., Hill, M. C., Xiao, L., Ye, J., Bapat, A., Ronzier, E., Hall, A. W., Hucker, W. J., Clauss, S., Barazza, M., Silber, E., Mina, J. A., Tucker, N. R., Mills, R. W., Dong, J.-T., Milan, D. J., Ellinor, P. T. <strong>Loss of the atrial fibrillation-related gene, Zfhx3, results in atrial dilation and arrhythmias.</strong> Circ. Res. 133: 313-329, 2023.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37449401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37449401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37449401[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/10.1161/CIRCRESAHA.123.323029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="37449401">Jameson et al. (2023)</a> identified only 1 SNP, a C-to-A transversion in the ZFHX3 gene (<a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12931021;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12931021</a>C-A), that exhibited differential activity dependent on genotype, with the nonrisk C allele being 3.9-fold more active than the risk-associated A allele. Chromatin immunoprecipitation analysis in pluripotent stem cell-derived cardiomyocytes (PSC-CMs) confirmed the genotype-dependent regulatory activity at <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12931021;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12931021</a>. Using CRISPR-Cas9 to delete a 219-bp region harboring <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12931021;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12931021</a> in PSC-CMs, the authors observed that the deleted cells expressed a significantly lower level of ZFHX3 than wildtype cells. In addition, analysis of isogenic PSC-CMs demonstrated a dose relationship between nonrisk C allele number and greater ZFHX3 expression. The authors concluded that <a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs12931021;toggle_HGVS_names=open" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'dbSNP\', \'domain\': \'ensembl.org\'})">rs12931021</a> is a functional SNP mediating the genetic association with increased risk of atrial fibrillation correlated to reduced ZFHX3 expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37449401" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 8 affected individuals from 5 Swedish families with autosomal dominant spinocerebellar ataxia-4 (SCA4; <a href="/entry/600223">600223</a>), <a href="#14" class="mim-tip-reference" title="Wallenius, J., Kafantari, E., Jhaveri, E., Gorcenco, S., Ameur, A., Karremo, C., Dobloug, S., Karrman, K., de Koning, T., Ilinca, A., Landqvist Waldo, M., Arvidsson, A., Persson, S., Englund, E., Ehrencrona, H., Puschmann, A. <strong>Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease.</strong> Am. J. Hum. Genet. 111: 1-14, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38035881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38035881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38035881[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.2023.11.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38035881">Wallenius et al. (2024)</a> identified a heterozygous 3-bp (GGC) repeat expansion in the last coding exon (exon 10) of the ZFHX3 gene; the GGC repeat encoded a glycine residue. All families originated from Skane, the southernmost region of Sweden, and haplotype analysis indicated a founder effect. Two of the families had previously been reported (see <a href="#7" class="mim-tip-reference" title="Moller, E., Hindfelt, B., Olsson, J. E. <strong>HLA-determination in families with hereditary ataxia.</strong> Tissue Antigens 12: 357-366, 1978.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/85351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">85351</a>] [<a href="https://doi.org/10.1111/j.1399-0039.1978.tb01345.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="85351">Moller et al., 1978</a> and <a href="#15" class="mim-tip-reference" title="Wictorin, K., Bradvik, B., Nilsson, K., Soller, M., van Westen, D., Bynke, G., Bauer, P., Schols, L., Puschmann, A. <strong>Autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism: a novel entity?</strong> Parkinsonism Relat. Disord. 20: 748-754, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24787759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24787759</a>] [<a href="https://doi.org/10.1016/j.parkreldis.2014.03.029" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24787759">Wictorin et al., 2014</a>). The repeat was expanded to greater than 40 repeats (range 42 to 74) in affected individuals, whereas the most common nonexpanded repeat length was reported as 21 repeats (range 14 to 26) in controls. The nonexpanded repeat in controls consisted of 20 glycine residues interrupted by a single serine. All nonexpanded alleles had interruptions within the GGC repeat; the interruptions were predominantly synonymous GGT and a nonsynonymous AGT (serine). Pathogenic expanded alleles did not contain interruptions: GGC was the only repeat unit. Genetic anticipation was observed, and there was a correlation between longer repeat expansions and earlier age at symptom onset. Long-read sequencing in a patient from family 1 who had onset at age 37 years showed 57 uninterrupted GGC repeats, whereas a patient in a later generation in family 1 who had onset at 15 years of age had 74 uninterrupted GGC repeats. Functional studies of the variant and studies of patient cells were not performed. However, postmortem examination of a patient who died at 28 years of age showed mild cerebellar atrophy with neuronal loss and gliosis, a loss of pigmented cells in the substantia nigra, and moderate cell loss in the locus ceruleus. Nerve cells of the myenteric plexus in the esophagus contained p62 (SQSTM1; <a href="/entry/601530">601530</a>)-immunoreactive inclusions. Alpha-synuclein (SNCA; <a href="/entry/163890">163890</a>) immunoreactivity was seen in brainstem and medulla oblongata neurons, in the hippocampus, and in myenteric ganglion cells in the gastrointestinal tract. Lewy bodies were not observed. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=38035881+24787759+85351" 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="mim-changed mim-change"><p>In affected members of 8 families with SCA4, <a href="#3" class="mim-tip-reference" title="Figueroa, K. P., Gross, C., Buena-Atienza, E., Paul, S., Gandelman, M., Kakar, N., Sturm, M., Casadei, N., Admard, J., Park, J., Zuhlke, C., Hellenbroich, Y., and 18 others. <strong>A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.</strong> Nature Genet. 56: 1080-1089, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38684900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38684900</a>] [<a href="https://doi.org/10.1038/s41588-024-01719-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38684900">Figueroa et al. (2024)</a> identified a heterozygous a GGC(n) repeat expansion in the last coding exon (exon 10) of the ZFHX3 gene. The repeat, which was found by long-read genome sequencing, segregated with the disorder in the families in an autosomal dominant pattern of inheritance. The normal allele had 21 repeats, whereas the pathogenic GGC repeat was over 45 repeats (up to 61 repeats) and was translated into a polyG domain in-frame with the rest of the ZFHX3 protein as demonstrated in patient fibroblasts. There was a significant inverse correlation between age at onset and repeat expansion length. One of the families was a large multigenerational family from Utah previously reported by <a href="#5" class="mim-tip-reference" title="Gardner, K., Alderson, K., Galster, B., Kaplan, C., Leppert, M., Ptacek, L. <strong>Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA4) in a Utah kindred. (Abstract)</strong> Neurology 44: A361 only, 1994."None>Gardner et al. (1994)</a> and <a href="#4" class="mim-tip-reference" title="Flanigan, K., Gardner, K., Alderson, K., Galster, B., Otterud, B., Leppert, M. F., Kaplan, C., Ptacek, L. J. <strong>Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1.</strong> Am. J. Hum. Genet. 59: 392-399, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755926</a>]" pmid="8755926">Flanigan et al. (1996)</a> who could be traced to a common ancestor in southern Sweden around the start of the 19th century. The 7 other families were from Germany (Lubeck, Munchen, Magdeburg 1 and 2, Essen 1 and 2, and Hamburg). Haplotype analysis showed that several of the families shared a common repeat expansion haplotype. Fibroblast samples from 4 SCA4 patients in the Utah family showed evidence of abnormal autophagy compared to controls. Wildtype ATXN2 was upregulated in all patient samples. Induced pluripotent stem cells (iPSCs) generated from one SCA4 patient from the Utah family with 21/53 repeats contained increased polyG-expanded ZFHX3 protein levels, but became rapidly apoptotic upon induction of differentiation to neurons, whereas control iPSCs easily differentiated into neurons under similar conditions. Neuropathologic examination of 1 patient detected neuronal intranuclear inclusions (NII) in the cerebellum that were immunoreactive to ZFHX3, ubiquitin, and p62. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=38684900+8755926" 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></div>
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<div class="mim-changed mim-change"><p>Using a combination of methods, including long-read sequencing, <a href="#11" class="mim-tip-reference" title="Paucar, M., Nilsson, D., Engvall, M., Laffita-Mesa, J., Soderhall, C., Skorpil, M., Halldin, C., Fazio, P., Lagerstedt-Robinson, K., Solders, G., Angeria, M., Varrone, A., Risling, M., Jiao, H., Nennesmo, I., Wedell, A., Svenningsson, P. <strong>Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs.</strong> J. Intern. Med. 296: 234-248, 2024.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38973251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38973251</a>] [<a href="https://doi.org/10.1111/joim.13815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="38973251">Paucar et al. (2024)</a> identified a heterozygous GGC(n) repeat expansion in the coding region of the ZFHX3 gene in affected member of 3 multigenerational Swedish families with SCA4. The pathogenic repeat ranged from 46 to 64 copies. The majority of normal alleles contained 21 copies, with a maximum of 26 copies. Functional studies of the variant were not performed, but neuropathologic studies of 4 patients showed intranuclear inclusions positive for ubiquitin and p62. Polyglycine-positive inclusions were found in neurons in 1 patient. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38973251" 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></div>
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[<a href="https://doi.org/10.1074/jbc.M110.128330" target="_blank">Full Text</a>]
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Figueroa, K. P., Gross, C., Buena-Atienza, E., Paul, S., Gandelman, M., Kakar, N., Sturm, M., Casadei, N., Admard, J., Park, J., Zuhlke, C., Hellenbroich, Y., and 18 others.
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<strong>A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.</strong>
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Nature Genet. 56: 1080-1089, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38684900/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38684900</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38684900" 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/s41588-024-01719-5" target="_blank">Full Text</a>]
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Flanigan, K., Gardner, K., Alderson, K., Galster, B., Otterud, B., Leppert, M. F., Kaplan, C., Ptacek, L. J.
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<strong>Autosomal dominant spinocerebellar ataxia with sensory axonal neuropathy (SCA4): clinical description and genetic localization to chromosome 16q22.1.</strong>
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Am. J. Hum. Genet. 59: 392-399, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8755926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8755926</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8755926" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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Gardner, K., Alderson, K., Galster, B., Kaplan, C., Leppert, M., Ptacek, L.
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<strong>Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA4) in a Utah kindred. (Abstract)</strong>
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Neurology 44: A361 only, 1994.
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Jameson, H. S., Hanley, A., Hill, M. C., Xiao, L., Ye, J., Bapat, A., Ronzier, E., Hall, A. W., Hucker, W. J., Clauss, S., Barazza, M., Silber, E., Mina, J. A., Tucker, N. R., Mills, R. W., Dong, J.-T., Milan, D. J., Ellinor, P. T.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37449401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37449401</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37449401[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37449401" 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/10.1161/CIRCRESAHA.123.323029" target="_blank">Full Text</a>]
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Moller, E., Hindfelt, B., Olsson, J. E.
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<strong>HLA-determination in families with hereditary ataxia.</strong>
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Tissue Antigens 12: 357-366, 1978.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/85351/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">85351</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=85351" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/j.1399-0039.1978.tb01345.x" target="_blank">Full Text</a>]
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Morinaga, T., Yasuda, H., Hashimoto, T., Higashio, K., Tamaoki, T.
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<strong>A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers.</strong>
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[<a href="https://doi.org/10.1128/mcb.11.12.6041-6049.1991" target="_blank">Full Text</a>]
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Nolan, P. M., Banks, G., Bourbia, N., Wilcox, A. G., Bentley, L., Moir, L., Kent, L., Hillier, R., Wilson, D., Barrett, P., Dumbell, R.
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<strong>A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice.</strong>
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FASEB J. 37: e23189, 2023.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/37713040/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">37713040</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=37713040[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=37713040" 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/10.1096/fj.202201829R" target="_blank">Full Text</a>]
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<a id="Parsons2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Parsons, M. J., Brancaccio, M., Sethi, S., Maywood, E. S., Satija, R., Edwards, J. K., Jagannath, A., Couch, Y., Finelli, M. J., Smyllie, N. J., Esapa, C., Butler, R., and 11 others.
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|
<strong>The regulatory factor ZFHX3 modifies circadian function in SCN via an AT motif-driven axis.</strong>
|
|
Cell 162: 607-621, 2015.
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26232227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26232227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26232227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26232227" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2015.06.060" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Paucar2024" class="mim-anchor"></a>
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<div class="mim-changed mim-change">
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<p class="mim-text-font">
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Paucar, M., Nilsson, D., Engvall, M., Laffita-Mesa, J., Soderhall, C., Skorpil, M., Halldin, C., Fazio, P., Lagerstedt-Robinson, K., Solders, G., Angeria, M., Varrone, A., Risling, M., Jiao, H., Nennesmo, I., Wedell, A., Svenningsson, P.
|
|
<strong>Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs.</strong>
|
|
J. Intern. Med. 296: 234-248, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38973251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38973251</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38973251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1111/joim.13815" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Qi2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Qi, Y., Ranish, J. A., Zhu, X., Krones, A., Zhang, J., Aebersold, R., Rose, D. W., Rosenfeld, M. G., Carriere, C.
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|
<strong>Atbf1 is required for the Pit1 gene early activation.</strong>
|
|
Proc. Nat. Acad. Sci. 105: 2481-2486, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18272476/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18272476</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18272476[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18272476" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.0712196105" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Sun2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sun, X., Frierson, H. F., Chen, C., Li, C., Ran, Q., Otto, K. B., Cantarel, B. L., Vessella, R. L., Gao, A. C., Petros, J., Miura, Y., Simons, J. W., Dong, J.-T.
|
|
<strong>Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer.</strong>
|
|
Nature Genet. 37: 407-412, 2005. Note: Erratum: Nature Genet. 37: 652 only, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15750593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15750593</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15750593" 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/ng1528" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Wallenius2024" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wallenius, J., Kafantari, E., Jhaveri, E., Gorcenco, S., Ameur, A., Karremo, C., Dobloug, S., Karrman, K., de Koning, T., Ilinca, A., Landqvist Waldo, M., Arvidsson, A., Persson, S., Englund, E., Ehrencrona, H., Puschmann, A.
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<strong>Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease.</strong>
|
|
Am. J. Hum. Genet. 111: 1-14, 2024.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/38035881/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">38035881</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=38035881[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=38035881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2023.11.008" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Wictorin2014" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Wictorin, K., Bradvik, B., Nilsson, K., Soller, M., van Westen, D., Bynke, G., Bauer, P., Schols, L., Puschmann, A.
|
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<strong>Autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism: a novel entity?</strong>
|
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Parkinsonism Relat. Disord. 20: 748-754, 2014.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24787759/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24787759</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24787759" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.parkreldis.2014.03.029" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Yamada1996" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamada, K., Ma, D., Miura, Y., Ido, A., Tamaoki, T., Yoshida, M. C.
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<strong>Assignment of the ATBF1 transcription factor gene (Atbf1) to mouse chromosome band 8E1 by in situ hybridization.</strong>
|
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Cytogenet. Cell Genet. 75: 30-31, 1996.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8995484/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8995484</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8995484" 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/10.1159/000134451" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Yamada1995" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamada, K., Miura, Y., Scheidl, T., Yoshida, M. C., Tamaoki, T.
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<strong>Assignment of the human ATBF1 transcription factor gene to chromosome 16q22.3-q23.1.</strong>
|
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Genomics 29: 552-553, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8666409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8666409</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8666409" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1006/geno.1995.9967" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 12/13/2024
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 11/19/2024<br>Cassandra L. Kniffin - updated : 12/11/2023<br>Marla J. F. O'Neill - updated : 11/16/2023<br>Patricia A. Hartz - updated : 1/11/2012<br>Patricia A. Hartz - updated : 4/1/2008<br>Victor A. McKusick - updated : 3/29/2005
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 1/22/1992
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="editHistory" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/07/2025
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 12/13/2024<br>ckniffin : 12/13/2024<br>mgross : 11/19/2024<br>alopez : 12/15/2023<br>alopez : 12/15/2023<br>ckniffin : 12/11/2023<br>alopez : 12/06/2023<br>carol : 11/17/2023<br>alopez : 11/16/2023<br>carol : 05/07/2022<br>carol : 05/06/2022<br>carol : 07/24/2020<br>carol : 01/22/2015<br>terry : 8/31/2012<br>mgross : 2/24/2012<br>terry : 1/11/2012<br>alopez : 9/30/2009<br>wwang : 11/24/2008<br>mgross : 4/1/2008<br>terry : 4/1/2008<br>alopez : 4/14/2005<br>tkritzer : 4/1/2005<br>terry : 3/29/2005<br>terry : 1/15/1997<br>mark : 10/25/1995<br>supermim : 3/16/1992<br>carol : 1/22/1992
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</span>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<div class="container visible-print-block">
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<div class="row">
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<div class="col-md-8 col-md-offset-1">
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>*</strong> 104155
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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ZINC FINGER HOMEOBOX 3; ZFHX3
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<div >
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
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</span>
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</p>
|
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</div>
|
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<div>
|
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<h4>
|
|
<span class="mim-font">
|
|
AT MOTIF-BINDING FACTOR 1; ATBF1<br />
|
|
AT-BINDING TRANSCRIPTION FACTOR 1<br />
|
|
ALPHA-FETOPROTEIN ENHANCER-BINDING PROTEIN
|
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: ZFHX3</em></strong>
|
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 715755008;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: 16q22.2-q22.3
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 16:72,782,885-73,891,930 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</h4>
|
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<div>
|
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<table class="table table-bordered table-condensed small mim-table-padding">
|
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<thead>
|
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<tr class="active">
|
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<th>
|
|
Location
|
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</th>
|
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<th>
|
|
Phenotype
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</th>
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<th>
|
|
Phenotype <br /> MIM number
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</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
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<tbody>
|
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<tr>
|
|
<td rowspan="3">
|
|
<span class="mim-font">
|
|
16q22.2-q22.3
|
|
</span>
|
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</td>
|
|
|
|
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<td>
|
|
<span class="mim-font">
|
|
{Atrial fibrillation 8, susceptibility to}
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613055
|
|
</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
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</td>
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</tr>
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<tr>
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<td>
|
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<span class="mim-font">
|
|
Prostate cancer, somatic
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</span>
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</td>
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<td>
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<span class="mim-font">
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176807
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Spinocerebellar ataxia 4
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</span>
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</td>
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<td>
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<span class="mim-font">
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600223
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>ZFHX3 is a transcriptional regulator that interacts with AT motifs in target genes. ZFHX3 is involved in regulation of circadian rhythm (Parsons et al., 2015) and appetite and body weight (Nolan et al., 2023). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Tissue-specific expression of the human alpha-fetoprotein (AFP) gene (104150) is strongly stimulated by an enhancer present 3.3 to 4.9 kb upstream of the transcription initiation site. One of the enhancer elements contains an AT-rich core sequence (AT motif). To determine the nuclear factor in hepatoma cell lines that interacts with the human AFP enhancer AT motif, Morinaga et al. (1991) screened a hepatoma cDNA expression library with an AFP enhancer fragment that bore the AT motif. They succeeded in isolating a cDNA that can code for an AT motif-binding factor, which they termed ATBF1. This was the largest DNA-binding protein identified to that time and the first protein shown to contain multiple homeodomains and multiple zinc finger motifs. The protein had a predicted mass of 306 kD and contained 4 homeodomains and 17 zinc finger motifs. </p><p>Dong et al. (2010) stated that full-length human ATBF1 contains 3,703 amino acids and that it has an ATPase A motif, 2 DEAH box-like sequences, 4 homeodomains, and 23 zinc finger motifs. </p><p>By confocal imaging in adult wildtype mouse heart tissue, Jameson et al. (2023) demonstrated expression of Zfhx3 primarily in atria. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>By fluorescence in situ hybridization, Yamada et al. (1995) mapped the ATBF1 gene to 16q22.3-q23.1. Yamada et al. (1996) used fluorescence in situ hybridization to assign the Atbf1 gene to mouse chromosome 8E1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Qi et al. (2008) identified 3 highly conserved regulatory elements in the promoter region of the mouse Pit1 gene (POU1F1; 173110) and found that Atbf1 bound and activated Pit1 from 1 of these elements, EE-alpha. Pituitaries of mice with a hypomorphic Atbf1 allele showed decreased expression of the somatotrope marker, Gh (139250), and almost no expression of the thyrotrope marker, Tshb (188540). Qi et al. (2008) concluded that ATBF1 is required for early PIT1 transcriptional activation. </p><p>Dong et al. (2010) found that ATBF1 inhibited estrogen receptor (ER, or ESR1; 133430)-mediated gene transcription, cell growth, and proliferation in ER-positive breast cancer cell lines. In vitro and in vivo immunoprecipitation experiments revealed that ATBF1 interacted directly with ER, and mutation analysis identified multiple domains in both proteins that mediated the interaction. ATBF1 inhibited ER function by selectively competing with the steroid receptor coactivator AIB1 (NCOA3; 601937), but not GRIP1 (NCOA2; 601993) or SRC1 (NCOA1; 602691), for binding to ER. </p><p>Jameson et al. (2023) performed differential expression analysis as well as gene ontology and pathway enrichment analysis of left and right mouse atria from 6-month-old mice that were wildtype, heterozygous, or homozygous for ZFHX3 knockout. Their findings suggested that ZFHX3 plays a role in the regulation of gene signaling pathways involved in cardiac pathophysiology. To determine which genes in atrial cardiomyocytes are putatively regulated directly by ZFHX3, the authors analyzed human cardiac single-nucleus ATAC (assay for transposase-accessible chromatin)-sequencing data obtained from each of the 4 cardiac chambers. Among the top enriched terms for the putative ZFHX3 cistrome were cardiac conduction, heart contraction, and Ca(2+) transport. Extracting atrial-enriched data peaks and performing motif enrichment analysis for ZFHX3 identified 4,174 ZFHX3 atrial cardiomyocyte-specific binding sites, of which 306 genes were identified as differentially expressed. Gene ontology analysis of those 306 direct ZFHX3 target genes uncovered enrichment for genes with roles in cardiac development, VEGF (192240) signaling, Wnt (see 164820) signaling, calcium binding, and heart contraction. The directionality of expression was consistent with both positive and negative regulation by ZFHX3 in cardiomyocytes. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Atrial Fibrillation 8</em></strong></p><p>
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Jameson et al. (2023) defined the atrial fibrillation-8 (ATFB8; 613055) locus using SNPs in strong linkage disequilibrium with an ATFB8-associated SNP (rs2106261) previously identified by Benjamin et al. (2009), located in an intron of the ZFHX3 gene. Jameson et al. (2023) obtained a 74-kb region containing 52 common variants with a minor allele frequency greater than 1% in individuals of European descent. Intersecting the 52 ATFB-associated SNPs on 16q22 with the DNaseI hypersensitivity signal in human cardiomyocytes identified 6 candidate SNPs that overlapped with active chromatin marks. The authors then assessed the effect of the 6 candidates on gene expression in human pluripotent stem cell-derived cardiomyocytes (PSC-CMs), and found only 1 SNP (C-A, rs12931021; 104155.0002) in the ZFHX3 gene that exhibited differential activity dependent on genotype. The authors concluded that ZFHX3 is the causal gene at the ATFB8 locus at 16q22, with rs12931021 being a functional SNP mediating the genetic association with increased risk of atrial fibrillation correlated to reduced ZFHX3 expression. </p><p><strong><em>Spinocerebellar Ataxia 4</em></strong></p><p>
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In 2024, 3 different research groups (Wallenius et al., 2024, Figueroa et al., 2024, and Paucar et al., 2024) independently identified a heterozygous GGC(n) trinucleotide repeat expansion in the ZFHX3 gene (104155.0003) as the cause of autosomal dominant spinocerebellar ataxia-4 (SCA4; 600223) that had been mapped to chromosome 16q22. </p><p>In 8 affected individuals from 5 Swedish families with SCA4, Wallenius et al. (2024) identified a heterozygous 3-bp (GGC) repeat expansion in the last coding exon (exon 10) of the ZFHX3 gene (104155.0003); the GGC repeat encoded a glycine residue. All families originated from Skane, the southernmost region of Sweden, and haplotype analysis indicated a founder effect. Two of the families had previously been reported (see Moller et al., 1978 and Wictorin et al., 2014). The repeat was expanded to greater than 40 repeats (range 42 to 74) in affected individuals, whereas the most common nonexpanded repeat length was reported as 21 repeats (range 14 to 26) in controls. The nonexpanded repeat in controls consisted of 20 glycine residues interrupted by a single serine. All nonexpanded alleles had interruptions within the GGC repeat; the interruptions were predominantly synonymous GGT and a nonsynonymous AGT (serine). Pathogenic expanded alleles did not contain interruptions: GGC was the only repeat unit. Genetic anticipation was observed, and there was a correlation between longer repeat expansions and earlier age at symptom onset. </p><p>In affected members of 8 families with SCA4, Figueroa et al. (2024) identified a heterozygous a GGC(n) repeat expansion in the last coding exon (exon 10) of the ZFHX3 gene (104155.0003). The repeat, which was found by long-read genome sequencing, segregated with the disorder in the families in an autosomal dominant pattern of inheritance. The normal allele had 21 repeats, whereas the pathogenic GGC repeat was over 45 repeats (up to 61 repeats) and was translated into a polyG domain in-frame with the rest of the ZFHX3 protein as demonstrated in patient fibroblasts. There was a significant inverse correlation between age at onset and repeat expansion length. One of the families was a large multigenerational family from Utah previously reported by Gardner et al. (1994) and Flanigan et al. (1996) who could be traced to a common ancestor in southern Sweden around the start of the 19th century. The 7 other families were from Germany (Lubeck, Munchen, Magdeburg 1 and 2, Essen 1 and 2, and Hamburg). Haplotype analysis showed that several of the families shared a common repeat expansion haplotype. Fibroblast samples from 4 SCA4 patients in the Utah family showed evidence of abnormal autophagy compared to controls. Wildtype ATXN2 was upregulated in all patient samples. Induced pluripotent stem cells (iPSCs) generated from one SCA4 patient from the Utah family with 21/53 repeats contained increased polyG-expanded ZFHX3 protein levels, but became rapidly apoptotic upon induction of differentiation to neurons, whereas control iPSCs easily differentiated into neurons under similar conditions. Neuropathologic examination of 1 patient detected neuronal intranuclear inclusions (NII) in the cerebellum that were immunoreactive to ZFHX3, ubiquitin, and p62. </p><p>Using a combination of methods, including long-read sequencing, Paucar et al. (2024) identified a heterozygous GGC(n) repeat expansion in the coding region of the ZFHX3 gene (104155.0003) in affected member of 3 multigenerational Swedish families with SCA4. The pathogenic repeat ranged from 46 to 64 copies. The majority of normal alleles contained 21 copies, with a maximum of 26 copies. Functional studies of the variant were not performed, but neuropathologic studies of 4 patients showed intranuclear inclusions positive for ubiquitin and p62. Polyglycine-positive inclusions were found in neurons in 1 patient. </p><p><strong><em>Somatic Mutations</em></strong></p><p>
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The long arm of chromosome 16 is frequently deleted in human cancers. Sun et al. (2005) presented evidence that the ATBF1 gene is a good candidate for the 16q22 tumor suppressor gene. They narrowed the region of deletion at 16q22 to 861 kb containing ATBF1. ATBF1 mRNA was abundant in normal prostates but more scarce in approximately half of prostate cancers tested. In 24 (36%) of 66 cancers examined, Sun et al. (2005) identified 22 unique somatic mutations (see, e.g., 104155.0001), many of which impaired ATBF1 function. Furthermore, ATBF1 inhibited cell proliferation. Sun et al. (2005) concluded that loss of ATBF1 is one mechanism that defines the absence of growth control in prostate cancer. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Parsons et al. (2015) identified a mutant mouse line, termed 'short circuit' (Sci), with a shorter circadian period compared with the population mean. The Sci phenotype was inherited in a dominant fashion. The authors identified the Sci mutation as a val1963-to-phe (V1963F) substitution in a highly conserved region upstream of zinc finger motif-17 in Zhfx3a. Genotype and phenotype correlation demonstrated that the mutation caused homozygous lethality during embryonic development; therefore, only Zfhx3 Sci/+ adult animals could be assessed phenotypically. Transcriptional analysis revealed that the Zhfx3 V1963F mutant downregulated neuropeptide genes with AT motifs in their promoter sequences, including Avp (192340) and Vip (192320). Further analysis identified the AT motif as a clock-regulated transcriptional axis and showed that Zfhx3 V1963F had diminished ability to activate transcription via AT motifs. Ex vivo or in vivo knockdown of Zfhx3 lengthened the circadian period in mice, confirming the role of Zfhx3 in regulating circadian period. Immunoprecipitation analysis in suprachiasmatic nucleus tissue from wildtype mice showed that Zfhx3 interacted directly with the Avp and Vip promoters in close proximity to AT consensus motifs. </p><p>Nolan et al. (2023) found that Zfhx3 Sci/+ mice were smaller and leaner than wildtype. Zfhx3 Sci/+ mice had lower circulating anabolic hormone concentrations and consumed less food in proportion to body weight. Early differences in body weight were due to impaired lean mass gain by Zfhx3 Sci/+ female mice, but fat mass did not differ. In situ hybridization in Sci/+ mouse brain detected increased mRNA expression of somatostatin (SST; 182450) and decreased mRNA expression of growth hormone-releasing hormone (GHRH; 139190) and growth hormone receptor (GHR; 600946) in the arcuate nucleus (ARC). Similarly, ARC expression of orexigenic neuropeptide Y (NPY; 162640) was decreased and ventricular ependymal expression of the orphan G protein-coupled receptor Gpr50 (300207) was decreased. </p><p>Jameson et al. (2023) generated mice that were heterozygous or homozygous for cardiomyocyte-restricted loss of Zfhx3, and observed a high incidence of premature death in the mutant mice, at age 10 months in the knockout mice and 12 months in the heterozygotes, compared to wildtype littermates. Cardiac MRI at age 3 months showed a significantly reduced ejection fraction and significantly increased left atrial size in the knockout mice compared to controls. By 9 to 11 months of age, Zfhx3 knockout mice displayed massively dilated hearts with large thrombi in both the left and right atria and significantly increased fibrosis of the atrial wall and left ventricle. In addition, the mutant mice exhibited a premorbid phenotype indicating advanced heart failure, including diffuse edema/anasarca, abdominal distention presumably due to ascites, tachypnea, and muscle wasting. In vivo cardiac electrophysiology testing at age 3 months demonstrated a gene-dose response in inducible atrial arrhythmias by programmed stimulation in the mice, with the knockout mice having a higher incidence of atrial arrhythmias/atrial fibrillation than heterozygotes or wildtype mice. The knockout mice were also more prone to arrhythmia induction and showed an increased frequency of atrial arrhythmias. Ex vivo optical mapping in knockout mouse hearts demonstrated significantly slower right atrial conduction, and knockout left atrial cardiomyocytes showed abnormal calcium handling compared to wildtype. The authors concluded that loss of Zfhx3 causes conditions that predispose to increased automaticity, resulting in the observed increased susceptibility to atrial arrhythmias/atrial fibrillation. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<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>3 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 PROSTATE CANCER, SOMATIC</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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ZFHX3, 24-BP DEL, NT10814
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<br />
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SNP: rs727502780,
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gnomAD: rs727502780,
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ClinVar: RCV000019797, RCV000996316, RCV002247371
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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 4 cases of low- to midgrade primary prostate cancer (176807), Sun et al. (2005) identified a 24-bp deletion in exon 10 of the ATBF1 gene, 10814del24, resulting in loss of 8 amino acids, beginning with codon 3381, in a glutamine-rich domain. The deletion was also identified in a microdissected high-grade primary metastasis. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 ATRIAL FIBRILLATION 8, SUSCEPTIBILITY TO</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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ZFHX3, C-A ({dbSNP rs12931021})
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<br />
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SNP: rs12931021,
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gnomAD: rs12931021,
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ClinVar: RCV003444097
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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>Among 6 candidate SNPs within the atrial fibrillation-associated locus on chromosome 16q22 (ATFB8; 613055), Jameson et al. (2023) identified only 1 SNP, a C-to-A transversion in the ZFHX3 gene (rs12931021C-A), that exhibited differential activity dependent on genotype, with the nonrisk C allele being 3.9-fold more active than the risk-associated A allele. Chromatin immunoprecipitation analysis in pluripotent stem cell-derived cardiomyocytes (PSC-CMs) confirmed the genotype-dependent regulatory activity at rs12931021. Using CRISPR-Cas9 to delete a 219-bp region harboring rs12931021 in PSC-CMs, the authors observed that the deleted cells expressed a significantly lower level of ZFHX3 than wildtype cells. In addition, analysis of isogenic PSC-CMs demonstrated a dose relationship between nonrisk C allele number and greater ZFHX3 expression. The authors concluded that rs12931021 is a functional SNP mediating the genetic association with increased risk of atrial fibrillation correlated to reduced ZFHX3 expression. </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>.0003 SPINOCEREBELLAR ATAXIA 4</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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ZFHX3, (GGC)n REPEAT EXPANSION
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<br />
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ClinVar: RCV003449001
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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 8 affected individuals from 5 Swedish families with autosomal dominant spinocerebellar ataxia-4 (SCA4; 600223), Wallenius et al. (2024) identified a heterozygous 3-bp (GGC) repeat expansion in the last coding exon (exon 10) of the ZFHX3 gene; the GGC repeat encoded a glycine residue. All families originated from Skane, the southernmost region of Sweden, and haplotype analysis indicated a founder effect. Two of the families had previously been reported (see Moller et al., 1978 and Wictorin et al., 2014). The repeat was expanded to greater than 40 repeats (range 42 to 74) in affected individuals, whereas the most common nonexpanded repeat length was reported as 21 repeats (range 14 to 26) in controls. The nonexpanded repeat in controls consisted of 20 glycine residues interrupted by a single serine. All nonexpanded alleles had interruptions within the GGC repeat; the interruptions were predominantly synonymous GGT and a nonsynonymous AGT (serine). Pathogenic expanded alleles did not contain interruptions: GGC was the only repeat unit. Genetic anticipation was observed, and there was a correlation between longer repeat expansions and earlier age at symptom onset. Long-read sequencing in a patient from family 1 who had onset at age 37 years showed 57 uninterrupted GGC repeats, whereas a patient in a later generation in family 1 who had onset at 15 years of age had 74 uninterrupted GGC repeats. Functional studies of the variant and studies of patient cells were not performed. However, postmortem examination of a patient who died at 28 years of age showed mild cerebellar atrophy with neuronal loss and gliosis, a loss of pigmented cells in the substantia nigra, and moderate cell loss in the locus ceruleus. Nerve cells of the myenteric plexus in the esophagus contained p62 (SQSTM1; 601530)-immunoreactive inclusions. Alpha-synuclein (SNCA; 163890) immunoreactivity was seen in brainstem and medulla oblongata neurons, in the hippocampus, and in myenteric ganglion cells in the gastrointestinal tract. Lewy bodies were not observed. </p>
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<div class="mim-changed mim-change"><p>In affected members of 8 families with SCA4, Figueroa et al. (2024) identified a heterozygous a GGC(n) repeat expansion in the last coding exon (exon 10) of the ZFHX3 gene. The repeat, which was found by long-read genome sequencing, segregated with the disorder in the families in an autosomal dominant pattern of inheritance. The normal allele had 21 repeats, whereas the pathogenic GGC repeat was over 45 repeats (up to 61 repeats) and was translated into a polyG domain in-frame with the rest of the ZFHX3 protein as demonstrated in patient fibroblasts. There was a significant inverse correlation between age at onset and repeat expansion length. One of the families was a large multigenerational family from Utah previously reported by Gardner et al. (1994) and Flanigan et al. (1996) who could be traced to a common ancestor in southern Sweden around the start of the 19th century. The 7 other families were from Germany (Lubeck, Munchen, Magdeburg 1 and 2, Essen 1 and 2, and Hamburg). Haplotype analysis showed that several of the families shared a common repeat expansion haplotype. Fibroblast samples from 4 SCA4 patients in the Utah family showed evidence of abnormal autophagy compared to controls. Wildtype ATXN2 was upregulated in all patient samples. Induced pluripotent stem cells (iPSCs) generated from one SCA4 patient from the Utah family with 21/53 repeats contained increased polyG-expanded ZFHX3 protein levels, but became rapidly apoptotic upon induction of differentiation to neurons, whereas control iPSCs easily differentiated into neurons under similar conditions. Neuropathologic examination of 1 patient detected neuronal intranuclear inclusions (NII) in the cerebellum that were immunoreactive to ZFHX3, ubiquitin, and p62. </p></div>
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<div class="mim-changed mim-change"><p>Using a combination of methods, including long-read sequencing, Paucar et al. (2024) identified a heterozygous GGC(n) repeat expansion in the coding region of the ZFHX3 gene in affected member of 3 multigenerational Swedish families with SCA4. The pathogenic repeat ranged from 46 to 64 copies. The majority of normal alleles contained 21 copies, with a maximum of 26 copies. Functional studies of the variant were not performed, but neuropathologic studies of 4 patients showed intranuclear inclusions positive for ubiquitin and p62. Polyglycine-positive inclusions were found in neurons in 1 patient. </p></div>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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Benjamin, E. J., Rice, K. M., Arking, D. E., Pfeufer, A., van Noord, C., Smith, A. V., Schnabel, R. B., Bis, J. C., Boerwinkle, E., Sinner, M. F., Dehghan, A., Lubitz, S. A., and 44 others.
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<strong>Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry.</strong>
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Nature Genet. 41: 879-881, 2009.
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[PubMed: 19597492]
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[Full Text: https://doi.org/10.1038/ng.416]
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Dong, X.-Y., Sun, X., Guo, P., Li, Q., Sasahara, M., Ishii, Y., Dong, J.-T.
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<strong>ATBF1 inhibits estrogen receptor (ER) function by selectively competing with AIB1 for binding to the ER in ER-positive breast cancer cells.</strong>
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J. Biol. Chem. 285: 32801-32809, 2010.
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[PubMed: 20720010]
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[Full Text: https://doi.org/10.1074/jbc.M110.128330]
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Figueroa, K. P., Gross, C., Buena-Atienza, E., Paul, S., Gandelman, M., Kakar, N., Sturm, M., Casadei, N., Admard, J., Park, J., Zuhlke, C., Hellenbroich, Y., and 18 others.
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<strong>A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.</strong>
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Nature Genet. 56: 1080-1089, 2024.
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Gardner, K., Alderson, K., Galster, B., Kaplan, C., Leppert, M., Ptacek, L.
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<strong>Autosomal dominant spinocerebellar ataxia: clinical description of a distinct hereditary ataxia and genetic localization to chromosome 16 (SCA4) in a Utah kindred. (Abstract)</strong>
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Neurology 44: A361 only, 1994.
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Jameson, H. S., Hanley, A., Hill, M. C., Xiao, L., Ye, J., Bapat, A., Ronzier, E., Hall, A. W., Hucker, W. J., Clauss, S., Barazza, M., Silber, E., Mina, J. A., Tucker, N. R., Mills, R. W., Dong, J.-T., Milan, D. J., Ellinor, P. T.
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<strong>Loss of the atrial fibrillation-related gene, Zfhx3, results in atrial dilation and arrhythmias.</strong>
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Circ. Res. 133: 313-329, 2023.
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Moller, E., Hindfelt, B., Olsson, J. E.
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<strong>HLA-determination in families with hereditary ataxia.</strong>
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Tissue Antigens 12: 357-366, 1978.
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[PubMed: 85351]
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Morinaga, T., Yasuda, H., Hashimoto, T., Higashio, K., Tamaoki, T.
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<strong>A human alpha-fetoprotein enhancer-binding protein, ATBF1, contains four homeodomains and seventeen zinc fingers.</strong>
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Molec. Cell. Biol. 11: 6041-6049, 1991.
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[PubMed: 1719379]
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Nolan, P. M., Banks, G., Bourbia, N., Wilcox, A. G., Bentley, L., Moir, L., Kent, L., Hillier, R., Wilson, D., Barrett, P., Dumbell, R.
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<strong>A missense mutation in zinc finger homeobox-3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice.</strong>
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FASEB J. 37: e23189, 2023.
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[PubMed: 37713040]
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[Full Text: https://doi.org/10.1096/fj.202201829R]
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Parsons, M. J., Brancaccio, M., Sethi, S., Maywood, E. S., Satija, R., Edwards, J. K., Jagannath, A., Couch, Y., Finelli, M. J., Smyllie, N. J., Esapa, C., Butler, R., and 11 others.
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<strong>The regulatory factor ZFHX3 modifies circadian function in SCN via an AT motif-driven axis.</strong>
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Cell 162: 607-621, 2015.
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[PubMed: 26232227]
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Paucar, M., Nilsson, D., Engvall, M., Laffita-Mesa, J., Soderhall, C., Skorpil, M., Halldin, C., Fazio, P., Lagerstedt-Robinson, K., Solders, G., Angeria, M., Varrone, A., Risling, M., Jiao, H., Nennesmo, I., Wedell, A., Svenningsson, P.
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<strong>Spinocerebellar ataxia type 4 is caused by a GGC expansion in the ZFHX3 gene and is associated with prominent dysautonomia and motor neuron signs.</strong>
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J. Intern. Med. 296: 234-248, 2024.
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[PubMed: 38973251]
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[Full Text: https://doi.org/10.1111/joim.13815]
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Qi, Y., Ranish, J. A., Zhu, X., Krones, A., Zhang, J., Aebersold, R., Rose, D. W., Rosenfeld, M. G., Carriere, C.
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<strong>Atbf1 is required for the Pit1 gene early activation.</strong>
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Proc. Nat. Acad. Sci. 105: 2481-2486, 2008.
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[PubMed: 18272476]
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[Full Text: https://doi.org/10.1073/pnas.0712196105]
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Sun, X., Frierson, H. F., Chen, C., Li, C., Ran, Q., Otto, K. B., Cantarel, B. L., Vessella, R. L., Gao, A. C., Petros, J., Miura, Y., Simons, J. W., Dong, J.-T.
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<strong>Frequent somatic mutations of the transcription factor ATBF1 in human prostate cancer.</strong>
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Nature Genet. 37: 407-412, 2005. Note: Erratum: Nature Genet. 37: 652 only, 2005.
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[PubMed: 15750593]
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[Full Text: https://doi.org/10.1038/ng1528]
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Wallenius, J., Kafantari, E., Jhaveri, E., Gorcenco, S., Ameur, A., Karremo, C., Dobloug, S., Karrman, K., de Koning, T., Ilinca, A., Landqvist Waldo, M., Arvidsson, A., Persson, S., Englund, E., Ehrencrona, H., Puschmann, A.
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<strong>Exonic trinucleotide repeat expansions in ZFHX3 cause spinocerebellar ataxia type 4: A poly-glycine disease.</strong>
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Am. J. Hum. Genet. 111: 1-14, 2024.
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[PubMed: 38035881]
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[Full Text: https://doi.org/10.1016/j.ajhg.2023.11.008]
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Wictorin, K., Bradvik, B., Nilsson, K., Soller, M., van Westen, D., Bynke, G., Bauer, P., Schols, L., Puschmann, A.
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<strong>Autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism: a novel entity?</strong>
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Parkinsonism Relat. Disord. 20: 748-754, 2014.
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Yamada, K., Ma, D., Miura, Y., Ido, A., Tamaoki, T., Yoshida, M. C.
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<strong>Assignment of the ATBF1 transcription factor gene (Atbf1) to mouse chromosome band 8E1 by in situ hybridization.</strong>
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Cytogenet. Cell Genet. 75: 30-31, 1996.
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[PubMed: 8995484]
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[Full Text: https://doi.org/10.1159/000134451]
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Yamada, K., Miura, Y., Scheidl, T., Yoshida, M. C., Tamaoki, T.
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<strong>Assignment of the human ATBF1 transcription factor gene to chromosome 16q22.3-q23.1.</strong>
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Genomics 29: 552-553, 1995.
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[PubMed: 8666409]
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[Full Text: https://doi.org/10.1006/geno.1995.9967]
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