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Entry
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- *606557 - BAF CHROMATIN REMODELING COMPLEX SUBUNIT BCL11A; BCL11A
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*606557</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<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="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</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/606557">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div 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=ENSG00000119866;t=ENST00000642384" 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=53335" 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=606557" 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=ENSG00000119866;t=ENST00000642384" 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_001363864,NM_001365609,NM_001405708,NM_001405709,NM_001405710,NM_001405711,NM_001405712,NM_001405713,NM_001405714,NM_001405715,NM_001405716,NM_001405717,NM_001405718,NM_001405719,NM_001405720,NM_001405721,NM_001405722,NM_001405723,NM_001405724,NM_001405725,NM_001405726,NM_001405727,NM_001405728,NM_001405729,NM_001405730,NM_001405731,NM_001405732,NM_001405733,NM_001405734,NM_001405735,NM_001405736,NM_018014,NM_022893,NM_138559,NR_175964,XM_024452963,XM_047444761" 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_022893" 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=606557" 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=05949&isoform_id=05949_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/BCL11A" 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/11558482,11558484,11558486,12150278,18089267,20336305,20336307,20336313,29691173,40881359,44887724,51475128,62702279,62822235,119620440,119620441,119620442,119620443,119620444,119620445,119620446,193786207,193787324,194387108,194390132,302313165,302313167,359391714,929654655,1370477963,1394533403,1475409038,2217328902,2234200078,2234200088,2234200103,2234200114,2234200118,2234200122,2234200126,2234200128,2234200155,2234200157,2234200163,2234200168,2234200170,2234200172,2234200182,2234200189,2234200196,2234200202,2234200204,2234200219,2234200231,2234200234,2234200245,2234200247,2234200252,2234200256,2234200258,2234200268,2234200270,2462574342" 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/Q9H165" 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=53335" 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=ENSG00000119866;t=ENST00000642384" 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=BCL11A" 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=BCL11A" 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+53335" 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/BCL11A" 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:53335" 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/53335" 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=chr2&hgg_gene=ENST00000642384.2&hgg_start=60450520&hgg_end=60553924&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:13221" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:13221" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=606557[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=606557[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/BCL11A/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/ENSG00000119866" 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=BCL11A" 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=BCL11A" 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=BCL11A" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://lovd.bx.psu.edu/home.php?select_db=BCL11A" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=BCL11A&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/PA25300" 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:13221" 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/FBgn0029939.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:106190" 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/BCL11A#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:106190" 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/53335/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=53335" 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=WBGene00017430;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-060421-4643" 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://reactome.org/content/query?q=BCL11A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
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<span class="text-danger"><strong>*</strong></span>
|
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606557
|
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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BAF CHROMATIN REMODELING COMPLEX SUBUNIT BCL11A; BCL11A
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</span>
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</h3>
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</div>
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<div>
|
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<br />
|
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
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<em>Alternative titles; symbols</em>
|
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</span>
|
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</p>
|
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</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
B-CELL CLL/LYMPHOMA 11A<br />
|
|
CTIP1, MOUSE, HOMOLOG OF; CTIP1<br />
|
|
EVI9, MOUSE, HOMOLOG OF; EVI9<br />
|
|
KIAA1809<br />
|
|
FLJ10173
|
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</span>
|
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</h4>
|
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</div>
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</div>
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<div>
|
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=BCL11A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">BCL11A</a></em></strong>
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</span>
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</p>
|
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</div>
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<div>
|
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<a id="cytogeneticLocation" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
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<strong>
|
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<em>
|
|
Cytogenetic location: <a href="/geneMap/2/275?start=-3&limit=10&highlight=275">2p16.1</a>
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|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr2:60450520-60553924&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'})">2:60,450,520-60,553,924</a> </span>
|
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</em>
|
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</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
|
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</p>
|
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</div>
|
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<div>
|
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<br />
|
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</div>
|
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<div>
|
|
<a id="geneMap" class="mim-anchor"></a>
|
|
<div style="margin-bottom: 10px;">
|
|
<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</div>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
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<th>
|
|
Location
|
|
</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>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
|
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</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/2/275?start=-3&limit=10&highlight=275">
|
|
2p16.1
|
|
</a>
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Dias-Logan syndrome
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/617101"> 617101 </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>
|
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|
|
</span>
|
|
</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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<div class="btn-group">
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<p>The BCL11A gene encodes a zinc finger protein that regulates transcription through interaction with COUP-TF proteins (see <a href="/entry/132890">132890</a>), as well as direct, sequence-dependent DNA binding (<a href="#21" class="mim-tip-reference" title="Wiegreffe, C., Simon, R., Peschkes, K., Kling, C., Strehle, M., Cheng, J., Srivatsa, S., Liu, P., Jenkins, N. A., Copeland, N. G., Tarabykin, V., Britsch, S. <strong>Bcl11a (Ctip1) controls migration of cortical projection neurons through regulation of Sema3c.</strong> Neuron 87: 311-325, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26182416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26182416</a>] [<a href="https://doi.org/10.1016/j.neuron.2015.06.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26182416">Wiegreffe et al., 2015</a>). It is highly expressed in the brain, B-lymphocytes, and the adult erythroid lineage (summary by <a href="#7" class="mim-tip-reference" title="Funnell, A. P. W., Prontera, P., Ottaviani, V., Piccione, M., Giambona, A., Maggio, A., Ciaffoni, F., Stehling-Sun, S., Marra, M., Masiello, F., Varricchio, L., Stamatoyannolpoulos, J. A., Migliaccio, A. R., Papayannopoulou, T. <strong>2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment.</strong> Blood 126: 89-93, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26019277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26019277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26019277[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/10.1182/blood-2015-04-638528" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26019277">Funnell et al., 2015</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=26182416+26019277" 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 screening a fetal brain cDNA library with mouse Evi9 as probe, <a href="#17" class="mim-tip-reference" title="Saiki, Y., Yamazaki, Y., Yoshida, M., Katoh, O., Nakamura, T. <strong>Human EVI9, a homologue of the mouse myeloid leukemia gene, is expressed in the hematopoietic progenitors and down-regulated during myeloid differentiation of HL60 cells.</strong> Genomics 70: 387-391, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11161790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11161790</a>] [<a href="https://doi.org/10.1006/geno.2000.6385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11161790">Saiki et al. (2000)</a> isolated a cDNA encoding EVI9, also termed BCL11A, and a shorter splice variant, EVI9C. Sequence analysis predicted that the 797-amino acid BCL11A protein, which is 99% identical to the mouse protein apart from an additional 35 N-terminal residues, contains 3 C2H2-type zinc finger motifs, a proline-rich region, and an acidic domain. Northern blot analysis revealed highest expression in brain, spleen, and testis. RT-PCR analysis detected expression in most hematopoietic cells but downregulation during monocytic differentiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11161790" 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 screening for cDNAs encoding large proteins in brain, <a href="#15" class="mim-tip-reference" title="Nagase, T., Nakayama, M., Nakajima, D., Kikuno, R., Ohara, O. <strong>Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro.</strong> DNA Res. 8: 85-95, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11347906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11347906</a>] [<a href="https://doi.org/10.1093/dnares/8.2.85" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11347906">Nagase et al. (2001)</a> identified a partial cDNA, which they called KIAA1809, encoding a deduced 800-amino acid zinc finger protein, predicted to be 97% and 100% identical to mouse Evi9 and human BCL11A, respectively, and involved in nucleic acid management. RT-PCR analysis detected wide expression that was highest in spleen and adult and fetal brain, and undetectable in liver and skeletal muscle. Within brain, expression was highest in caudate nucleus followed by hippocampus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11347906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Wiegreffe, C., Simon, R., Peschkes, K., Kling, C., Strehle, M., Cheng, J., Srivatsa, S., Liu, P., Jenkins, N. A., Copeland, N. G., Tarabykin, V., Britsch, S. <strong>Bcl11a (Ctip1) controls migration of cortical projection neurons through regulation of Sema3c.</strong> Neuron 87: 311-325, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26182416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26182416</a>] [<a href="https://doi.org/10.1016/j.neuron.2015.06.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26182416">Wiegreffe et al. (2015)</a> stated that Bcl11a is expressed in the murine neocortex and is essential for morphogenesis and wiring of projection neurons in the dorsal spinal cord. They found that Bcl11a expression was restricted to projection neurons and some GABAergic interneurons in early mouse embryos. At postnatal day 2, Bcl11a was detected in late-born upper-layer projection neurons and deep-layer neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26182416" 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="Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others. <strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong> Am. J. Hum. Genet. 99: 253-274, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27453576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27453576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27453576[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.2016.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27453576">Dias et al. (2016)</a> noted that there are 3 BCL11A isoforms encoding 3 different proteins: a short (S) 243-residue protein, a long (L) 773-residue protein, and an extra-long (XL) 835-residue protein. The common N-terminal region of all 3 isoforms is required for homo- and heterodimerization of BCL11A isoforms, as well as for interaction with repressive nucleosome remodeling complexes. Bcl11a was expressed in the developing mouse brain, with highest expression in the forebrain. During the postnatal period, expression persisted in neurons in the central nervous system, including the cortex, hippocampus, olfactory bulb, and, to a lesser extent, the cerebellum. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27453576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using yeast 2-hybrid analysis, <a href="#1" class="mim-tip-reference" title="Avram, D., Fields, A., Top, K. P. O., Nevrivy, D. J., Ishmael, J. E., Leid, M. <strong>Isolation of a novel family of C2H2 zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors.</strong> J. Biol. Chem. 275: 10315-10322, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10744719/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10744719</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10744719[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.275.14.10315" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10744719">Avram et al. (2000)</a> identified mouse Ctip1 and Ctip2 (BCL11B; <a href="/entry/606558">606558</a>) as proteins expressed in brain that interacted with Arp1 (NR2F2; <a href="/entry/107773">107773</a>). Cotransfection experiments in HEK293 cells showed that Ctip1 potentiated Arp1-mediated transcriptional repression independently of trichostatin A-sensitive histone deacetylation. Confocal microscopy demonstrated punctate nuclear expression of Ctip1 and recruitment of Arp1 to these foci. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10744719" 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>Evi9 is a common site of retroviral integration in murine myeloid leukemias in the BXH2 mouse strain. <a href="#16" class="mim-tip-reference" title="Nakamura, T., Yamazaki, Y., Saiki, Y., Moriyama, M., Largaespada, D. A., Jenkins, N. A., Copeland, N. G. <strong>Evi9 encodes a novel zinc finger protein that physically interacts with BCL6, a known human B-cell proto-oncogene product.</strong> Molec. Cell Biol. 20: 3178-3186, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10757802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10757802</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10757802[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.20.9.3178-3186.2000" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10757802">Nakamura et al. (2000)</a> showed that mouse Evi9 can interact with the human BCL6 (<a href="/entry/109565">109565</a>) protooncogene product. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10757802" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Sankaran, V. G., Menne, T. F., Xu, J., Akie, T. E., Lettre, G., Van Handel, B., Mikkola, H. K. A., Hirschhorn, J. N., Cantor, A. B., Orkin, S. H. <strong>Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A.</strong> Science 322: 1839-1842, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056937</a>] [<a href="https://doi.org/10.1126/science.1165409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19056937">Sankaran et al. (2008)</a> found that the high fetal hemoglobin (HbF) BCL11A genotype is associated with reduced BCL11A expression. Abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Downregulation of BCL11A expression in primary adult erythroid cells led to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, <a href="#18" class="mim-tip-reference" title="Sankaran, V. G., Menne, T. F., Xu, J., Akie, T. E., Lettre, G., Van Handel, B., Mikkola, H. K. A., Hirschhorn, J. N., Cantor, A. B., Orkin, S. H. <strong>Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A.</strong> Science 322: 1839-1842, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056937</a>] [<a href="https://doi.org/10.1126/science.1165409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19056937">Sankaran et al. (2008)</a> found that BCL11A occupies several discrete sites in the beta-globin gene cluster. <a href="#18" class="mim-tip-reference" title="Sankaran, V. G., Menne, T. F., Xu, J., Akie, T. E., Lettre, G., Van Handel, B., Mikkola, H. K. A., Hirschhorn, J. N., Cantor, A. B., Orkin, S. H. <strong>Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A.</strong> Science 322: 1839-1842, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056937</a>] [<a href="https://doi.org/10.1126/science.1165409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19056937">Sankaran et al. (2008)</a> concluded that BCL11A is a potential therapeutic target for reactivation of HbF in beta-hemoglobin disorders. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19056937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Sankaran, V. G., Xu, J., Ragoczy, T., Ippolito, G. C., Walkley, C. R., Maika, S. D., Fujiwara, Y., Ito, M., Groudine, M., Bender, M. A., Tucker, P. W., Orkin, S. H. <strong>Developmental and species-divergent globin switching are driven by BCL11A.</strong> Nature 460: 1093-1097, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19657335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19657335</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19657335[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19657335">Sankaran et al. (2009)</a> demonstrated that in transgenic mice containing the human beta-globin (HBG) locus, the HBG genes behaved as murine embryonic globin genes, revealing a limitation of the model and demonstrating that critical differences in the trans-acting milieu have arisen during mammalian evolution. <a href="#19" class="mim-tip-reference" title="Sankaran, V. G., Xu, J., Ragoczy, T., Ippolito, G. C., Walkley, C. R., Maika, S. D., Fujiwara, Y., Ito, M., Groudine, M., Bender, M. A., Tucker, P. W., Orkin, S. H. <strong>Developmental and species-divergent globin switching are driven by BCL11A.</strong> Nature 460: 1093-1097, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19657335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19657335</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19657335[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19657335">Sankaran et al. (2009)</a> showed that the expression of BCL11A, a repressor of human gamma-globin expression identified by genomewide association studies (see <a href="/entry/142335">142335</a>), differs between mouse and human. Developmental silencing of the mouse embryonic globin and human gamma-globin genes fails to occur in mice in the absence of BCL11A. Thus, <a href="#19" class="mim-tip-reference" title="Sankaran, V. G., Xu, J., Ragoczy, T., Ippolito, G. C., Walkley, C. R., Maika, S. D., Fujiwara, Y., Ito, M., Groudine, M., Bender, M. A., Tucker, P. W., Orkin, S. H. <strong>Developmental and species-divergent globin switching are driven by BCL11A.</strong> Nature 460: 1093-1097, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19657335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19657335</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19657335[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19657335">Sankaran et al. (2009)</a> concluded that BCL11A is a critical mediator of species-divergent globin switching. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19657335" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Borg, J., Papadopoulos, P., Georgitsi, M., Gutierrez, L., Grech, G., Fanis, P., Phylactides, M., Verkerk, A. J. M. H., van der Spek, P. J., Scerri, C. A., Cassar, W., Galdies, R., and 10 others. <strong>Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin.</strong> Nature Genet. 42: 801-805, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20676099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20676099</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20676099[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.630" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20676099">Borg et al. (2010)</a> demonstrated that KLF1 (<a href="/entry/600599">600599</a>) binds to and activates the promoter region of the BCL11A gene, which is a repressor of the HbF genes HBG1 (<a href="/entry/142200">142200</a>) and HBG2 (<a href="/entry/142250">142250</a>). Chromatin immunoprecipitation (ChIP) assays of erythroid progenitors from adult peripheral blood showed strong binding of KLF1 to the BCL11A promoter, whereas such binding was not observed in human fetal liver erythroid progenitors. These findings indicated that KLF1 acts as a dual regulator of fetal-to-adult globin switching in humans by acting as a preferential activator of the HBB gene and by activating expression of BCL11A, which in turn represses the HBG1 and HBG2 genes. <a href="#23" class="mim-tip-reference" title="Zhou, D., Liu, K., Sun, C.-W., Pawlik, K. M., Townes, T. M. <strong>KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching.</strong> Nature Genet. 42: 742-744, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20676097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20676097</a>] [<a href="https://doi.org/10.1038/ng.637" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20676097">Zhou et al. (2010)</a> also found that wildtype murine Klf1 binds to a CACCC box in the promoter region of Bcl11a. Studies in adult human progenitor blood cells showed that knockdown of KLF1 resulted in decreased BCL11A expression and upregulation of gamma-globin genes, similar to mouse studies. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=20676099+20676097" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bauer, D. E., Kamran, S. C., Lessard, S., Xu, J., Fujiwara, Y., Lin, C., Shao, Z., Canver, M. C., Smith, E. C., Pinello, L., Sabo, P. J., Vierstra, J., Voit, R. A., Yuan, G.-C., Porteus, M. H., Stamatoyannopoulos, J. A., Lettre, G., Orkin, S. H. <strong>An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.</strong> Science 342: 253-257, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24115442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24115442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24115442[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/10.1126/science.1242088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24115442">Bauer et al. (2013)</a> found that common genetic variation at BCL11A associated with fetal hemoglobin level lies in noncoding sequences decorated by an erythroid enhancer chromatin signature. Fine mapping uncovered a motif-disrupting common variant associated with reduced transcription factor binding, modestly diminished BCL11A expression, and elevated fetal hemoglobin. The surrounding sequences functioned in vivo as a developmental stage-specific, lineage-restricted enhancer. Genome engineering revealed that the enhancer is required in erythroid but not beta-lymphoid cells for BCL11A expression. <a href="#3" class="mim-tip-reference" title="Bauer, D. E., Kamran, S. C., Lessard, S., Xu, J., Fujiwara, Y., Lin, C., Shao, Z., Canver, M. C., Smith, E. C., Pinello, L., Sabo, P. J., Vierstra, J., Voit, R. A., Yuan, G.-C., Porteus, M. H., Stamatoyannopoulos, J. A., Lettre, G., Orkin, S. H. <strong>An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.</strong> Science 342: 253-257, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24115442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24115442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24115442[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/10.1126/science.1242088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24115442">Bauer et al. (2013)</a> concluded that these findings illustrated how genomewide association studies may expose functional variants of modest impact within causal elements essential for appropriate gene expression, and proposed that the BCL11A enhancer represents an attractive target for therapeutic genome engineering for the beta-hemoglobinopathies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24115442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Canver, M. C., Smith, E. C., Sher, F., Pinello, L., Sanjana, N. E., Shalem, O., Chen, D. D., Schupp, P. G., Vinjamur, D. S., Garcia, S. P., Luc, S., Kurita, R., Nakamura, Y., Fujiwara, Y., Maeda, T., Yuan, G.-C., Zhang, F., Orkin, S. H., Bauer, D. E. <strong>BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis.</strong> Nature 527: 192-197, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26375006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26375006</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26375006[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature15521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26375006">Canver et al. (2015)</a> developed pooled CRISPR-Cas9 guide RNA libraries to perform in situ saturating mutagenesis of the human and mouse BCL11A enhancers. This approach revealed critical minimal features and discrete vulnerabilities of these enhancers. Despite conserved function of the composite enhancers, their architecture diverges. The crucial human sequences appear to be primate-specific. Through editing of primary human progenitors and mouse transgenesis, <a href="#5" class="mim-tip-reference" title="Canver, M. C., Smith, E. C., Sher, F., Pinello, L., Sanjana, N. E., Shalem, O., Chen, D. D., Schupp, P. G., Vinjamur, D. S., Garcia, S. P., Luc, S., Kurita, R., Nakamura, Y., Fujiwara, Y., Maeda, T., Yuan, G.-C., Zhang, F., Orkin, S. H., Bauer, D. E. <strong>BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis.</strong> Nature 527: 192-197, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26375006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26375006</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26375006[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature15521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26375006">Canver et al. (2015)</a> validated the BCL11A erythroid enhancer as a target for fetal hemoglobin reinduction. The authors concluded that the detailed enhancer map would inform therapeutic genome editing, and the screening approach described was generally applicable to functional interrogation of noncoding genomic elements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26375006" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Martyn, G. E., Wienert, B., Yang, L., Shah, M., Norton, L. J., Burdach, J., Kurita, R., Nakamura, Y., Pearson, R. C. M., Funnell, A. P. W., Quinlan, K. G. R., Crossley, M. <strong>Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding.</strong> Nature Genet. 50: 498-503, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29610478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29610478</a>] [<a href="https://doi.org/10.1038/s41588-018-0085-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29610478">Martyn et al. (2018)</a> carried out an in vitro screen for candidate repressors of the gamma-globin gene and found that the C-terminal zinc finger region of BCL11A bound to a site -115 bp upstream of the transcription start site in the gamma-globin gene promoter in electrophoretic mobility shift assays. All tested hereditary persistence of fetal hemoglobin (HPFH; <a href="/entry/141749">141749</a>)-associated gamma-globin promoter point mutations disrupted binding with BCL11A. CRISPR-Cas9 genome editing and chromatin immunoprecipitation studies in human erythroid HUDEP-2 cells showed that BCL11A bound to the site at -115 bp of the gamma-globin gene promoter in vivo and that HPFH-associated mutations in the gamma-globin promoter disrupted in vivo BCL11A binding and raised gamma-globin gene expression. Further analysis with chromatin immunoprecipitation-PCR revealed that binding of BCL11A did not affect binding of the other gamma-globin repressor, ZBTB7A (<a href="/entry/605878">605878</a>), to the gamma-globin promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29610478" 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>Independently, <a href="#9" class="mim-tip-reference" title="Liu, N., Hargreaves, V. V., Zhu, Q., Kurland, J. V., Hong, J., Kim, W., Sher, F., Macias-Trevino, C., Rogers, J. M., Kurita, R., Nakamura, Y., Yuan, G.-C., Bauer, D. E., Xu, J., Bulyk, M. L., Orkin, S. H. <strong>Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch.</strong> Cell 173: 430-442, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29606353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29606353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29606353[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.2018.03.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29606353">Liu et al. (2018)</a> found that BCL11A directly bound DNA in a sequence-specific manner through its C-terminal zinc finger domain. They identified the preferred binding motif for BCL11A as TGACCA. This motif is present in the promoters of all embryonic- and fetal-expressed globin genes of humans and mice. Some patients with HPFH have mutations in this motif and, consequently, BCL11A cannot bind DNA in these individuals. Mapping of BCL11A chromatin occupancy confirmed TGACCA as the preferred in vivo binding sequence for BCL11A. Chromatin localization of BCL11A in globin loci revealed that the BCL11A motif appeared within globin loci, and high-resolution localization of BCL11A demonstrated that BCL11A preferentially bound the distal TGACCA motif in the gamma-globin promoters. In HUDEP-2 cells, mutation of the distal TGACCA motif in all 4 gamma-globin promoters resulted in failure of BCL11A to bind to the motif and reactivation of gamma-globin expression. <a href="#9" class="mim-tip-reference" title="Liu, N., Hargreaves, V. V., Zhu, Q., Kurland, J. V., Hong, J., Kim, W., Sher, F., Macias-Trevino, C., Rogers, J. M., Kurita, R., Nakamura, Y., Yuan, G.-C., Bauer, D. E., Xu, J., Bulyk, M. L., Orkin, S. H. <strong>Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch.</strong> Cell 173: 430-442, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29606353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29606353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29606353[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.2018.03.016" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29606353">Liu et al. (2018)</a> concluded that direct promoter repression by BCL11A controls the fetal-to-adult hemoglobin switch. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29606353" 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="Basak, A., Munschauer, M., Lareau, C. A., Montbleau, K. E., Ulirsch, J. C., Hartigan, C. R., Schenone, M., Lian, J., Wang, Y., Huang, Y., Wu, X., Gehrke, L., and 9 others. <strong>Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.</strong> Nature Genet. 52: 138-145, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31959994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31959994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31959994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-019-0568-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31959994">Basak et al. (2020)</a> showed that BCL11A is regulated at the level of mRNA translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, <a href="#2" class="mim-tip-reference" title="Basak, A., Munschauer, M., Lareau, C. A., Montbleau, K. E., Ulirsch, J. C., Hartigan, C. R., Schenone, M., Lian, J., Wang, Y., Huang, Y., Wu, X., Gehrke, L., and 9 others. <strong>Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.</strong> Nature Genet. 52: 138-145, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31959994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31959994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31959994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-019-0568-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31959994">Basak et al. (2020)</a> demonstrated that the RNA-binding protein LIN28B (<a href="/entry/611044">611044</a>), which is developmentally expressed in a pattern reciprocal to that of BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, <a href="#2" class="mim-tip-reference" title="Basak, A., Munschauer, M., Lareau, C. A., Montbleau, K. E., Ulirsch, J. C., Hartigan, C. R., Schenone, M., Lian, J., Wang, Y., Huang, Y., Wu, X., Gehrke, L., and 9 others. <strong>Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.</strong> Nature Genet. 52: 138-145, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31959994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31959994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31959994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-019-0568-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31959994">Basak et al. (2020)</a> showed that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independently of its role in regulating LET7 microRNAs (see <a href="/entry/605386">605386</a>), and that BCL11A is the major target of LIN28B-mediated fetal hemoglobin (HbF) induction. <a href="#2" class="mim-tip-reference" title="Basak, A., Munschauer, M., Lareau, C. A., Montbleau, K. E., Ulirsch, J. C., Hartigan, C. R., Schenone, M., Lian, J., Wang, Y., Huang, Y., Wu, X., Gehrke, L., and 9 others. <strong>Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.</strong> Nature Genet. 52: 138-145, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31959994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31959994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31959994[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-019-0568-7" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31959994">Basak et al. (2020)</a> concluded that their results revealed a mechanism underlying human hemoglobin switching that illuminated new therapeutic opportunities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31959994" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using CRISPR technology, <a href="#10" class="mim-tip-reference" title="Liu, N., Xu, S., Yao, Q., Zhu, Q., Kai, Y., Hsu, J., Sakon, P., Pinello, L., Yuan, G.-C., Bauer, D. E., Orkin, S. H. <strong>Transcription factor competition at the gamma-globin promoters controls hemoglobin switching.</strong> Nature Genet. 53: 511-520, 2021. Note: Erratum: Nature Genet. 53: 586 only, 2021.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/33649594/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">33649594</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=33649594[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41588-021-00798-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="33649594">Liu et al. (2021)</a> identified an activator element at the gamma-globin promoters near the BCL11A-binding site. They noted that the gamma-globin promoters contain duplicated BCL11A-binding sites that overlap CCAAT motifs. Knockdown, chromatin immunoprecipitation, and base-editing analyses revealed that NFY (see <a href="/entry/189903">189903</a>) activated gamma-globin expression through direct binding to the proximal CCAAT box, whereas BCL11A functioned through the distal binding motif. BCL11A and NFY competed for binding at the gamma-globin promoters to regulate expression of gamma-globin, thereby controlling the switch from fetal to adult hemoglobin. Mutation or deletion of the distal BCL11A-binding motif promoted NFY complex occupancy at the proximal CCAAT motif and activated robust gamma-globin expression, and thus assembly of adult hemoglobin. In contrast, binding of BCL11A to the distal motif constituted a steric barrier to NFY binding at the proximal CCAAT motif, leading to repression of gamma-globin expression, and thus inhibiting the switch from fetal to adult hemoglobin. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=33649594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By FISH, <a href="#17" class="mim-tip-reference" title="Saiki, Y., Yamazaki, Y., Yoshida, M., Katoh, O., Nakamura, T. <strong>Human EVI9, a homologue of the mouse myeloid leukemia gene, is expressed in the hematopoietic progenitors and down-regulated during myeloid differentiation of HL60 cells.</strong> Genomics 70: 387-391, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11161790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11161790</a>] [<a href="https://doi.org/10.1006/geno.2000.6385" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11161790">Saiki et al. (2000)</a> mapped the BCL11A gene to chromosome 2p13, where some cases of lymphoblastic leukemia have displayed chromosomal translocations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11161790" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#14" class="mim-tip-reference" title="Menzel, S., Garner, C., Gut, I., Matsuda, F., Yamaguchi, M., Heath, S., Foglio, M., Zelenika, D., Boland, A., Rooks, H., Best, S., Spector, T. D., Farrall, M., Lathrop, M., Thein, S. L. <strong>A QTL influencing F cell production maps to a gene encoding a zinc-finger protein on chromosome 2p15.</strong> Nature Genet. 39: 1197-1199, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17767159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17767159</a>] [<a href="https://doi.org/10.1038/ng2108" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17767159">Menzel et al. (2007)</a> stated the location of the BCL11A gene as 2p15. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17767159" 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="#20" class="mim-tip-reference" title="Satterwhite, E., Sonoki, T., Willis, T. G., Harder, L., Nowak, R., Arriola, E. L., Liu, H., Price, H. P., Gesk, S., Steinemann, D., Schlegelberger, B., Oscier, D. G., Siebert, R., Tucker, P. W., Dyer, M. J. S. <strong>The BCL11 gene family: involvement of BCL11A in lymphoid malignancies.</strong> Blood 98: 3413-3420, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719382</a>] [<a href="https://doi.org/10.1182/blood.v98.12.3413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11719382">Satterwhite et al. (2001)</a> reported the recurrent involvement and deregulated expression of BCL11A in 4 cases of B-cell malignancy with the translocation t(2;14)(p13;q32.3). They noted that this translocation is a rare cytogenetic abnormality in the clinically aggressive subset of B-cell chronic lymphocytic leukemia (<a href="/entry/151400">151400</a>)/immunocytoma. FISH analysis showed colocalization of BCL11A and REL (<a href="/entry/164910">164910</a>) in B-cell non-Hodgkin lymphoma (<a href="/entry/605027">605027</a>). <a href="#20" class="mim-tip-reference" title="Satterwhite, E., Sonoki, T., Willis, T. G., Harder, L., Nowak, R., Arriola, E. L., Liu, H., Price, H. P., Gesk, S., Steinemann, D., Schlegelberger, B., Oscier, D. G., Siebert, R., Tucker, P. W., Dyer, M. J. S. <strong>The BCL11 gene family: involvement of BCL11A in lymphoid malignancies.</strong> Blood 98: 3413-3420, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719382</a>] [<a href="https://doi.org/10.1182/blood.v98.12.3413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11719382">Satterwhite et al. (2001)</a> also identified a BCL11A homolog, BCL11B (<a href="/entry/606558">606558</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11719382" 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>Comparative genomic hybridization studies showed gains in chromosome region 2p as the most common imbalance in classical Hodgkin lymphoma. The minimal region of gain contained 2 candidate oncogenes, REL and BCL11A. <a href="#12" class="mim-tip-reference" title="Martin-Subero, J. I., Gesk, S., Harder, L., Sonoki, T., Tucker, P. W., Schlegelberger, B., Grote, W., Novo, F. J., Calasanz, M. J., Hansmann, M. L., Dyer, M. J. S., Siebert, R. <strong>Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma.</strong> Blood 99: 1474-1477, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11830502/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11830502</a>] [<a href="https://doi.org/10.1182/blood.v99.4.1474" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11830502">Martin-Subero et al. (2002)</a> examined the involvement of REL and BCL11A loci in 44 primary cases of classic Hodgkin lymphoma by combined immunophenotyping and interphase cytogenetics. A median 2p13 copy number above the tetraploid range was detected in 24 (55%) cases. One case displayed selective amplification of the REL locus not affecting BCL11A. Two other cases showed evidence of breakpoints in the region spanned by the REL probe. These data indicated that REL rather than BCL11A may be the target of the 2p13 alterations in classic Hodgkin lymphoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11830502" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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In 9 unrelated patients with intellectual developmental disorder with persistence of fetal hemoglobin (<a href="/entry/617101">617101</a>), <a href="#6" class="mim-tip-reference" title="Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others. <strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong> Am. J. Hum. Genet. 99: 253-274, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27453576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27453576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27453576[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.2016.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27453576">Dias et al. (2016)</a> identified 9 different de novo heterozygous mutations in the BCL11A gene (see, e.g., <a href="#0001">606557.0001</a>-<a href="#0006">606557.0006</a>). The mutations, which included 3 missense and 6 truncating mutations, were found by exome sequencing. In vitro functional expression assays showed that all the missense mutations occurred in the N-terminal region, which encodes a dimerization site, and resulted in defective dimerization, localization, and transcriptional activity, consistent with a loss of function. The findings suggested that the disorder may result from a haploinsufficiency mechanism. In addition, all patients had increased HbF, indicating the importance of BCL11A for transcriptional repression of HbF. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27453576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of an association between variation in the BCL11A gene and fetal hemoglobin (HbF) levels, see HBFQTL5 (<a href="/entry/142335">142335</a>).</p><p>For discussion of an association between deletion of the BCL11A gene and defects in language development, see <a href="/entry/612513">612513</a> and DYX3 (<a href="/entry/604254">604254</a>).</p>
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<p><a href="#11" class="mim-tip-reference" title="Liu, P., Keller, J. R., Ortiz, M., Tessarollo, L., Rachel, R. A., Nakamura, T., Jenkins, N. A., Copeland, N. G. <strong>Bcl11a is essential for normal lymphoid development.</strong> Nature Immun. 4: 525-532, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717432</a>] [<a href="https://doi.org/10.1038/ni925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717432">Liu et al. (2003)</a> deleted exon 1 of the Bcl11a gene by gene targeting in embryonic stem cells to generate Bcl11a-deficient mice. Unlike heterozygotes, which were viable and fertile, the Bcl11a -/- mice died within 3 to 4 hours after birth. Flow cytometric and RT-PCR analyses of Bcl11a -/- fetal liver cells demonstrated an absence of B-lymphocyte markers and T-cell alpha/beta receptors, but normal development of macrophage-granulocyte and erythroid lineages and an increase in thymic gamma/delta T cells. Transfer of mutant fetal liver cells resulted in the development of clonal T-cell leukemia with substantially increased expression of Notch1 (<a href="/entry/190198">190198</a>) but not of Notch2 (<a href="/entry/600275">600275</a>) or Hes1 (<a href="/entry/139605">139605</a>), a downstream target of Notch1. TdT-mediated dUTP-biotin nick-end labeling (TUNEL) analysis indicated decreased apoptosis in mutant thymi, suggesting a cause for the abnormal development of fetal thymocytes in Bcl11a-deficient mice. <a href="#11" class="mim-tip-reference" title="Liu, P., Keller, J. R., Ortiz, M., Tessarollo, L., Rachel, R. A., Nakamura, T., Jenkins, N. A., Copeland, N. G. <strong>Bcl11a is essential for normal lymphoid development.</strong> Nature Immun. 4: 525-532, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717432/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717432</a>] [<a href="https://doi.org/10.1038/ni925" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717432">Liu et al. (2003)</a> concluded that Bcl11a, like Notch1, is crucial for the early steps in both B- and T-lymphocyte development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717432" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Xu, J., Peng, C., Sankaran, V. G., Shao, Z., Esrick, E. B., Chong, B. G., Ippolito, G. C., Fujiwara, Y., Ebert, B. L., Tucker, P. W., Orkin, S. H. <strong>Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.</strong> Science 334: 993-996, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21998251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21998251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21998251[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/10.1126/science.1211053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21998251">Xu et al. (2011)</a> showed that the repressor BCL11A is required in vivo for silencing of gamma-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, <a href="#22" class="mim-tip-reference" title="Xu, J., Peng, C., Sankaran, V. G., Shao, Z., Esrick, E. B., Chong, B. G., Ippolito, G. C., Fujiwara, Y., Ebert, B. L., Tucker, P. W., Orkin, S. H. <strong>Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.</strong> Science 334: 993-996, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21998251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21998251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21998251[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/10.1126/science.1211053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21998251">Xu et al. (2011)</a> demonstrated that inactivation of BCL11A in sickle cell disease (<a href="/entry/603903">603903</a>) transgenic mice corrects the hematologic and pathologic defects associated with sickle cell disease through high-level pancellular HbF induction. Thus, <a href="#22" class="mim-tip-reference" title="Xu, J., Peng, C., Sankaran, V. G., Shao, Z., Esrick, E. B., Chong, B. G., Ippolito, G. C., Fujiwara, Y., Ebert, B. L., Tucker, P. W., Orkin, S. H. <strong>Correction of sickle cell disease in adult mice by interference with fetal hemoglobin silencing.</strong> Science 334: 993-996, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21998251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21998251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21998251[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/10.1126/science.1211053" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21998251">Xu et al. (2011)</a> concluded that interference with HbF silencing by manipulation of a single target protein is sufficient to reverse sickle cell disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21998251" 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 conditional knockout of Bcl11a in mouse spinal cord, <a href="#8" class="mim-tip-reference" title="John, A., Brylka, H., Wiegreffe, C., Simon, R., Liu, P., Juttner, R., Crenshaw, E. B., III, Luyten, F. P., Jenkins, N. A., Copeland, N. G., Birchmeier, C., Britsch, S. <strong>Bcl11a is required for neuronal morphogenesis and sensory circuit formation in dorsal spinal cord development.</strong> Development 139: 1831-1841, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22491945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22491945</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22491945[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/10.1242/dev.072850" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22491945">John et al. (2012)</a> found that Bcl11a was required for terminal differentiation and morphogenesis of dorsal spinal neurons. Immunohistologic analysis and postsynaptic current recordings revealed that Bcl11a was also required in spinal target neurons, but was dispensable in presynaptic sensory neurons, for correct wiring and differentiation in superficial dorsal horn. Mutation of Bcl11a in spinal neurons disrupted their maturation and morphogenesis, and disrupted differentiation of dorsal spinal neurons observed in Bcl11a mutant mice interfered with their correct innervation by cutaneous sensory neurons. Microarray analysis in dorsal horn of Bcl11a mutant mouse embryos demonstrated that dysregulated Frzb expression could, in part, account for disrupted sensory innervation of Bcl11a mutant spinal cord. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22491945" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using conditional knockout mice, <a href="#21" class="mim-tip-reference" title="Wiegreffe, C., Simon, R., Peschkes, K., Kling, C., Strehle, M., Cheng, J., Srivatsa, S., Liu, P., Jenkins, N. A., Copeland, N. G., Tarabykin, V., Britsch, S. <strong>Bcl11a (Ctip1) controls migration of cortical projection neurons through regulation of Sema3c.</strong> Neuron 87: 311-325, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26182416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26182416</a>] [<a href="https://doi.org/10.1016/j.neuron.2015.06.023" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26182416">Wiegreffe et al. (2015)</a> found that Bcl11a was required for the neuronal cell polarity switch from multipolar to bipolar morphology and for migration of upper-layer projection neurons. Bcl11a -/- neurons showed reduced radial orientation of the Golgi apparatus, randomly changed their orientation, and exhibited repetitively slowed migration, suggesting that they unsuccessfully probed their environment for directional cues. Microarray gene expression and chromatin immunoprecipitation analyses revealed that Bcl11a directly repressed expression of the guidance cue Sema3c (<a href="/entry/602645">602645</a>) by binding to regulatory elements in intron 2 of the Sema3c gene. Overexpression of Sema3c in wildtype mouse cortical neurons recapitulated the Bcl11a-knockout phenotype, whereas knockout of both Sema3c and Bcl11a rescued the Bcl11a-knockout phenotype. Bcl11a also had a Sema3c-independent role in late differentiation and survival of upper-layer cortical neurons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26182416" 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="Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others. <strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong> Am. J. Hum. Genet. 99: 253-274, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27453576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27453576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27453576[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.2016.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27453576">Dias et al. (2016)</a> found that haploinsufficiency of Bcl11a in the mouse resulted in microcephaly with decreased brain volume, particularly affecting the limbic system, and abnormal behavior, including impaired long-term social memory and increased locomotion. Haploinsufficient mice also showed significant transcriptional deregulation in the cortex and hippocampus, with effects on genes involved in ion transport, membrane trafficking, and neuronal signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27453576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>ALLELIC VARIANTS (<a href="/help/faq#1_4"></strong>
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<strong>6 Selected Examples</a>):</strong>
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<a href="/allelicVariants/606557" class="btn btn-default" role="button"> Table View </a>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=606557[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<strong>.0001 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886037864 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037864;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886037864" 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=rs886037864" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000239897" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000239897" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000239897</a>
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<p>In a girl with intellectual developmental disorder with persistence of fetal hemoglobin (<a href="/entry/617101">617101</a>), <a href="#6" class="mim-tip-reference" title="Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others. <strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong> Am. J. Hum. Genet. 99: 253-274, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27453576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27453576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27453576[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.2016.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27453576">Dias et al. (2016)</a> identified a de novo heterozygous c.139A-C transversion (c.139A-C, NM_022893.3) in exon 2 of the BCL11A gene, resulting in a thr47-to-pro (T47P) substitution in the N-terminal region. The mutation was found by exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27453576" 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 id="0002" class="mim-anchor"></a>
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<strong>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886037865 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037865;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886037865" 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=rs886037865" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000240280" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240280" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240280</a>
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<p>In a boy with intellectual developmental disorder with persistence of fetal hemoglobin (<a href="/entry/617101">617101</a>), <a href="#6" class="mim-tip-reference" title="Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others. <strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong> Am. J. Hum. Genet. 99: 253-274, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27453576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27453576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27453576[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.2016.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27453576">Dias et al. (2016)</a> identified a de novo heterozygous c.143G-T transversion (c.143G-T, NM_022893.3) in exon 2 of the BCL11A gene, resulting in a cys48-to-phe (C48F) substitution in the N-terminal region. The mutation was found by exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27453576" 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 id="0003" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0003 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</strong>
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BCL11A, HIS66GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886037866 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037866;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886037866" 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=rs886037866" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000240572" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240572" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240572</a>
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</div>
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<span class="mim-text-font">
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<p>In a girl with intellectual developmental disorder with persistence of fetal hemoglobin (<a href="/entry/617101">617101</a>), <a href="#6" class="mim-tip-reference" title="Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others. <strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong> Am. J. Hum. Genet. 99: 253-274, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27453576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27453576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27453576[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.2016.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27453576">Dias et al. (2016)</a> identified a de novo heterozygous c.198C-A transversion (c.198C-A, NM_022893.3) in exon 2 of the BCL11A gene, resulting in a his66-to-gln (H66Q) substitution in the N-terminal region. The mutation was found by exome sequencing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27453576" 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 id="0004" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0004 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</strong>
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BCL11A, GLN177TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1553403736 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1553403736;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1553403736" 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=rs1553403736" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000598781 OR RCV000856831" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000598781, RCV000856831" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000598781...</a>
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<span class="mim-text-font">
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<p>In a girl with intellectual developmental disorder with persistence of fetal hemoglobin (<a href="/entry/617101">617101</a>), <a href="#6" class="mim-tip-reference" title="Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others. <strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong> Am. J. Hum. Genet. 99: 253-274, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27453576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27453576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27453576[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.2016.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27453576">Dias et al. (2016)</a> identified a de novo heterozygous c.529C-T transition (c.198C-A, NM_022893.3) in the BCL11A gene, resulting in a gln177-to-ter (Q177X) substitution. The mutation was found by exome sequencing. The findings were consistent with haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27453576" 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 id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</strong>
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BCL11A, 3-BP INS, 1775TGG
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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> rs886037867 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037867;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/rs886037867?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=rs886037867" 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=rs886037867" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000240288" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240288" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240288</a>
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<p>In a girl with intellectual developmental disorder with persistence of fetal hemoglobin (<a href="/entry/617101">617101</a>), <a href="#6" class="mim-tip-reference" title="Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others. <strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong> Am. J. Hum. Genet. 99: 253-274, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27453576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27453576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27453576[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.2016.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27453576">Dias et al. (2016)</a> identified a de novo heterozygous 3-bp insertion (c.1775_1776insTGG, NM_022893.3), resulting in a frameshift and premature termination (Glu593GlyfsTer9). The mutation was found by exome sequencing. The findings were consistent with haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27453576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</strong>
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BCL11A, GLN52TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs886037868 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs886037868;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs886037868" 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=rs886037868" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000240553" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000240553" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000240553</a>
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<p>In a girl with intellectual developmental disorder with persistence of fetal hemoglobin (<a href="/entry/617101">617101</a>), <a href="#6" class="mim-tip-reference" title="Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others. <strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong> Am. J. Hum. Genet. 99: 253-274, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27453576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27453576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27453576[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.2016.05.030" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="27453576">Dias et al. (2016)</a> identified a de novo heterozygous c.154C-T transition (c.154C-T, NM_022893.3) in the BCL11A gene, resulting in a gln52-to-ter (Q52X) substitution. The mutation was found by exome sequencing. The findings were consistent with haploinsufficiency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=27453576" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="Avram2000" class="mim-anchor"></a>
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Avram, D., Fields, A., Top, K. P. O., Nevrivy, D. J., Ishmael, J. E., Leid, M.
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<strong>Isolation of a novel family of C2H2 zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors.</strong>
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[<a href="https://doi.org/10.1074/jbc.275.14.10315" target="_blank">Full Text</a>]
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<a id="Basak2020" class="mim-anchor"></a>
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Basak, A., Munschauer, M., Lareau, C. A., Montbleau, K. E., Ulirsch, J. C., Hartigan, C. R., Schenone, M., Lian, J., Wang, Y., Huang, Y., Wu, X., Gehrke, L., and 9 others.
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<strong>Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.</strong>
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Nature Genet. 52: 138-145, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31959994/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31959994</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31959994[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=31959994" 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/s41588-019-0568-7" target="_blank">Full Text</a>]
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<a id="Bauer2013" class="mim-anchor"></a>
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Bauer, D. E., Kamran, S. C., Lessard, S., Xu, J., Fujiwara, Y., Lin, C., Shao, Z., Canver, M. C., Smith, E. C., Pinello, L., Sabo, P. J., Vierstra, J., Voit, R. A., Yuan, G.-C., Porteus, M. H., Stamatoyannopoulos, J. A., Lettre, G., Orkin, S. H.
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<strong>An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.</strong>
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Science 342: 253-257, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24115442/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24115442</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24115442[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=24115442" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1242088" target="_blank">Full Text</a>]
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<a id="Borg2010" class="mim-anchor"></a>
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Borg, J., Papadopoulos, P., Georgitsi, M., Gutierrez, L., Grech, G., Fanis, P., Phylactides, M., Verkerk, A. J. M. H., van der Spek, P. J., Scerri, C. A., Cassar, W., Galdies, R., and 10 others.
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<strong>Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin.</strong>
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Nature Genet. 42: 801-805, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20676099/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20676099</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20676099[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=20676099" 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/ng.630" target="_blank">Full Text</a>]
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<a id="Canver2015" class="mim-anchor"></a>
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Canver, M. C., Smith, E. C., Sher, F., Pinello, L., Sanjana, N. E., Shalem, O., Chen, D. D., Schupp, P. G., Vinjamur, D. S., Garcia, S. P., Luc, S., Kurita, R., Nakamura, Y., Fujiwara, Y., Maeda, T., Yuan, G.-C., Zhang, F., Orkin, S. H., Bauer, D. E.
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<strong>BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis.</strong>
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Nature 527: 192-197, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26375006/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26375006</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26375006[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=26375006" 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/nature15521" target="_blank">Full Text</a>]
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<a id="Dias2016" class="mim-anchor"></a>
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<div class="">
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Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others.
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<strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong>
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Am. J. Hum. Genet. 99: 253-274, 2016.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/27453576/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">27453576</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=27453576[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=27453576" 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.2016.05.030" target="_blank">Full Text</a>]
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<a id="Funnell2015" class="mim-anchor"></a>
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Funnell, A. P. W., Prontera, P., Ottaviani, V., Piccione, M., Giambona, A., Maggio, A., Ciaffoni, F., Stehling-Sun, S., Marra, M., Masiello, F., Varricchio, L., Stamatoyannolpoulos, J. A., Migliaccio, A. R., Papayannopoulou, T.
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<strong>2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment.</strong>
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Blood 126: 89-93, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26019277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26019277</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26019277[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=26019277" 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/10.1182/blood-2015-04-638528" target="_blank">Full Text</a>]
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<a id="John2012" class="mim-anchor"></a>
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John, A., Brylka, H., Wiegreffe, C., Simon, R., Liu, P., Juttner, R., Crenshaw, E. B., III, Luyten, F. P., Jenkins, N. A., Copeland, N. G., Birchmeier, C., Britsch, S.
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<strong>Bcl11a is required for neuronal morphogenesis and sensory circuit formation in dorsal spinal cord development.</strong>
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Development 139: 1831-1841, 2012.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22491945/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22491945</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22491945[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=22491945" 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/10.1242/dev.072850" target="_blank">Full Text</a>]
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<a id="Liu2018" class="mim-anchor"></a>
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Liu, N., Hargreaves, V. V., Zhu, Q., Kurland, J. V., Hong, J., Kim, W., Sher, F., Macias-Trevino, C., Rogers, J. M., Kurita, R., Nakamura, Y., Yuan, G.-C., Bauer, D. E., Xu, J., Bulyk, M. L., Orkin, S. H.
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<strong>Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch.</strong>
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Cell 173: 430-442, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29606353/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29606353</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29606353[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=29606353" 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.2018.03.016" target="_blank">Full Text</a>]
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<a id="Liu2021" class="mim-anchor"></a>
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Liu, N., Xu, S., Yao, Q., Zhu, Q., Kai, Y., Hsu, J., Sakon, P., Pinello, L., Yuan, G.-C., Bauer, D. E., Orkin, S. H.
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[<a href="https://doi.org/10.1038/s41588-021-00798-y" target="_blank">Full Text</a>]
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<div class="">
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[<a href="https://doi.org/10.1038/ni925" target="_blank">Full Text</a>]
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<div class="">
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[<a href="https://doi.org/10.1182/blood.v99.4.1474" target="_blank">Full Text</a>]
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Martyn, G. E., Wienert, B., Yang, L., Shah, M., Norton, L. J., Burdach, J., Kurita, R., Nakamura, Y., Pearson, R. C. M., Funnell, A. P. W., Quinlan, K. G. R., Crossley, M.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29610478/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29610478</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29610478" 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/s41588-018-0085-0" target="_blank">Full Text</a>]
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<a id="Menzel2007" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17767159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17767159</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17767159" 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/ng2108" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11347906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11347906</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11347906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/dnares/8.2.85" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10757802/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10757802</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10757802[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=10757802" 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/10.1128/MCB.20.9.3178-3186.2000" target="_blank">Full Text</a>]
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<a id="Saiki2000" class="mim-anchor"></a>
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Saiki, Y., Yamazaki, Y., Yoshida, M., Katoh, O., Nakamura, T.
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<strong>Human EVI9, a homologue of the mouse myeloid leukemia gene, is expressed in the hematopoietic progenitors and down-regulated during myeloid differentiation of HL60 cells.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11161790/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11161790</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11161790" 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.2000.6385" target="_blank">Full Text</a>]
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<a id="Sankaran2008" class="mim-anchor"></a>
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<div class="">
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Sankaran, V. G., Menne, T. F., Xu, J., Akie, T. E., Lettre, G., Van Handel, B., Mikkola, H. K. A., Hirschhorn, J. N., Cantor, A. B., Orkin, S. H.
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<strong>Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19056937/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19056937</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19056937" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1165409" target="_blank">Full Text</a>]
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<a id="Sankaran2009" class="mim-anchor"></a>
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<div class="">
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Sankaran, V. G., Xu, J., Ragoczy, T., Ippolito, G. C., Walkley, C. R., Maika, S. D., Fujiwara, Y., Ito, M., Groudine, M., Bender, M. A., Tucker, P. W., Orkin, S. H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19657335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19657335</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19657335[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=19657335" 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/nature08243" target="_blank">Full Text</a>]
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<a id="Satterwhite2001" class="mim-anchor"></a>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11719382/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11719382</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11719382" 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/10.1182/blood.v98.12.3413" target="_blank">Full Text</a>]
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<a id="21" class="mim-anchor"></a>
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<a id="Wiegreffe2015" class="mim-anchor"></a>
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Wiegreffe, C., Simon, R., Peschkes, K., Kling, C., Strehle, M., Cheng, J., Srivatsa, S., Liu, P., Jenkins, N. A., Copeland, N. G., Tarabykin, V., Britsch, S.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26182416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26182416</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26182416" 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.neuron.2015.06.023" target="_blank">Full Text</a>]
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<a id="Xu2011" class="mim-anchor"></a>
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Xu, J., Peng, C., Sankaran, V. G., Shao, Z., Esrick, E. B., Chong, B. G., Ippolito, G. C., Fujiwara, Y., Ebert, B. L., Tucker, P. W., Orkin, S. H.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21998251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21998251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21998251[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=21998251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1211053" target="_blank">Full Text</a>]
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<a id="Zhou2010" class="mim-anchor"></a>
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<div class="">
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Zhou, D., Liu, K., Sun, C.-W., Pawlik, K. M., Townes, T. M.
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<strong>KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20676097/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20676097</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20676097" 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/ng.637" target="_blank">Full Text</a>]
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Bao Lige - updated : 07/21/2021
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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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Ada Hamosh - updated : 04/28/2020<br>Bao Lige - updated : 11/14/2018<br>Bao Lige - updated : 08/17/2018<br>Ada Hamosh - updated : 10/12/2016<br>Cassandra L. Kniffin - updated : 08/29/2016<br>Cassandra L. Kniffin - updated : 02/15/2016<br>Patricia A. Hartz - updated : 1/27/2016<br>Ada Hamosh - updated : 1/30/2014<br>Ada Hamosh - updated : 12/20/2011<br>Paul J. Converse - updated : 12/22/2010<br>Cassandra L. Kniffin - updated : 9/20/2010<br>Ada Hamosh - updated : 9/9/2009<br>Ada Hamosh - updated : 1/9/2009<br>Cassandra L. Kniffin - updated : 2/20/2008<br>Victor A. McKusick - updated : 10/18/2007<br>Paul J. Converse - updated : 5/15/2003<br>Victor A. McKusick - updated : 4/23/2002
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Creation Date:
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Paul J. Converse : 12/13/2001
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carol : 02/15/2022
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mgross : 07/21/2021<br>alopez : 04/28/2020<br>carol : 08/21/2019<br>mgross : 11/20/2018<br>mgross : 11/14/2018<br>mgross : 08/17/2018<br>mgross : 08/17/2018<br>alopez : 10/12/2016<br>carol : 09/08/2016<br>carol : 08/31/2016<br>alopez : 08/30/2016<br>alopez : 08/30/2016<br>ckniffin : 08/29/2016<br>ckniffin : 02/15/2016<br>mgross : 1/27/2016<br>carol : 9/8/2014<br>mcolton : 9/4/2014<br>ckniffin : 9/3/2014<br>alopez : 1/30/2014<br>alopez : 1/4/2012<br>terry : 12/20/2011<br>mgross : 2/2/2011<br>terry : 12/22/2010<br>wwang : 9/23/2010<br>ckniffin : 9/20/2010<br>terry : 1/20/2010<br>alopez : 9/11/2009<br>terry : 9/9/2009<br>ckniffin : 6/3/2009<br>alopez : 1/12/2009<br>terry : 1/9/2009<br>wwang : 3/6/2008<br>ckniffin : 2/20/2008<br>alopez : 10/23/2007<br>terry : 10/18/2007<br>carol : 10/27/2004<br>alopez : 6/3/2003<br>mgross : 5/15/2003<br>alopez : 5/3/2002<br>terry : 4/23/2002<br>carol : 12/13/2001<br>carol : 12/13/2001
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<strong>*</strong> 606557
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BAF CHROMATIN REMODELING COMPLEX SUBUNIT BCL11A; BCL11A
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B-CELL CLL/LYMPHOMA 11A<br />
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CTIP1, MOUSE, HOMOLOG OF; CTIP1<br />
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EVI9, MOUSE, HOMOLOG OF; EVI9<br />
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KIAA1809<br />
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FLJ10173
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<strong><em>HGNC Approved Gene Symbol: BCL11A</em></strong>
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Cytogenetic location: 2p16.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 2:60,450,520-60,553,924 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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2p16.1
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Dias-Logan syndrome
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617101
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Autosomal dominant
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>The BCL11A gene encodes a zinc finger protein that regulates transcription through interaction with COUP-TF proteins (see 132890), as well as direct, sequence-dependent DNA binding (Wiegreffe et al., 2015). It is highly expressed in the brain, B-lymphocytes, and the adult erythroid lineage (summary by Funnell et al., 2015). </p>
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<strong>Cloning and Expression</strong>
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<p>By screening a fetal brain cDNA library with mouse Evi9 as probe, Saiki et al. (2000) isolated a cDNA encoding EVI9, also termed BCL11A, and a shorter splice variant, EVI9C. Sequence analysis predicted that the 797-amino acid BCL11A protein, which is 99% identical to the mouse protein apart from an additional 35 N-terminal residues, contains 3 C2H2-type zinc finger motifs, a proline-rich region, and an acidic domain. Northern blot analysis revealed highest expression in brain, spleen, and testis. RT-PCR analysis detected expression in most hematopoietic cells but downregulation during monocytic differentiation. </p><p>By screening for cDNAs encoding large proteins in brain, Nagase et al. (2001) identified a partial cDNA, which they called KIAA1809, encoding a deduced 800-amino acid zinc finger protein, predicted to be 97% and 100% identical to mouse Evi9 and human BCL11A, respectively, and involved in nucleic acid management. RT-PCR analysis detected wide expression that was highest in spleen and adult and fetal brain, and undetectable in liver and skeletal muscle. Within brain, expression was highest in caudate nucleus followed by hippocampus. </p><p>Wiegreffe et al. (2015) stated that Bcl11a is expressed in the murine neocortex and is essential for morphogenesis and wiring of projection neurons in the dorsal spinal cord. They found that Bcl11a expression was restricted to projection neurons and some GABAergic interneurons in early mouse embryos. At postnatal day 2, Bcl11a was detected in late-born upper-layer projection neurons and deep-layer neurons. </p><p>Dias et al. (2016) noted that there are 3 BCL11A isoforms encoding 3 different proteins: a short (S) 243-residue protein, a long (L) 773-residue protein, and an extra-long (XL) 835-residue protein. The common N-terminal region of all 3 isoforms is required for homo- and heterodimerization of BCL11A isoforms, as well as for interaction with repressive nucleosome remodeling complexes. Bcl11a was expressed in the developing mouse brain, with highest expression in the forebrain. During the postnatal period, expression persisted in neurons in the central nervous system, including the cortex, hippocampus, olfactory bulb, and, to a lesser extent, the cerebellum. </p>
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<strong>Gene Function</strong>
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<p>Using yeast 2-hybrid analysis, Avram et al. (2000) identified mouse Ctip1 and Ctip2 (BCL11B; 606558) as proteins expressed in brain that interacted with Arp1 (NR2F2; 107773). Cotransfection experiments in HEK293 cells showed that Ctip1 potentiated Arp1-mediated transcriptional repression independently of trichostatin A-sensitive histone deacetylation. Confocal microscopy demonstrated punctate nuclear expression of Ctip1 and recruitment of Arp1 to these foci. </p><p>Evi9 is a common site of retroviral integration in murine myeloid leukemias in the BXH2 mouse strain. Nakamura et al. (2000) showed that mouse Evi9 can interact with the human BCL6 (109565) protooncogene product. </p><p>Sankaran et al. (2008) found that the high fetal hemoglobin (HbF) BCL11A genotype is associated with reduced BCL11A expression. Abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Downregulation of BCL11A expression in primary adult erythroid cells led to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, Sankaran et al. (2008) found that BCL11A occupies several discrete sites in the beta-globin gene cluster. Sankaran et al. (2008) concluded that BCL11A is a potential therapeutic target for reactivation of HbF in beta-hemoglobin disorders. </p><p>Sankaran et al. (2009) demonstrated that in transgenic mice containing the human beta-globin (HBG) locus, the HBG genes behaved as murine embryonic globin genes, revealing a limitation of the model and demonstrating that critical differences in the trans-acting milieu have arisen during mammalian evolution. Sankaran et al. (2009) showed that the expression of BCL11A, a repressor of human gamma-globin expression identified by genomewide association studies (see 142335), differs between mouse and human. Developmental silencing of the mouse embryonic globin and human gamma-globin genes fails to occur in mice in the absence of BCL11A. Thus, Sankaran et al. (2009) concluded that BCL11A is a critical mediator of species-divergent globin switching. </p><p>Borg et al. (2010) demonstrated that KLF1 (600599) binds to and activates the promoter region of the BCL11A gene, which is a repressor of the HbF genes HBG1 (142200) and HBG2 (142250). Chromatin immunoprecipitation (ChIP) assays of erythroid progenitors from adult peripheral blood showed strong binding of KLF1 to the BCL11A promoter, whereas such binding was not observed in human fetal liver erythroid progenitors. These findings indicated that KLF1 acts as a dual regulator of fetal-to-adult globin switching in humans by acting as a preferential activator of the HBB gene and by activating expression of BCL11A, which in turn represses the HBG1 and HBG2 genes. Zhou et al. (2010) also found that wildtype murine Klf1 binds to a CACCC box in the promoter region of Bcl11a. Studies in adult human progenitor blood cells showed that knockdown of KLF1 resulted in decreased BCL11A expression and upregulation of gamma-globin genes, similar to mouse studies. </p><p>Bauer et al. (2013) found that common genetic variation at BCL11A associated with fetal hemoglobin level lies in noncoding sequences decorated by an erythroid enhancer chromatin signature. Fine mapping uncovered a motif-disrupting common variant associated with reduced transcription factor binding, modestly diminished BCL11A expression, and elevated fetal hemoglobin. The surrounding sequences functioned in vivo as a developmental stage-specific, lineage-restricted enhancer. Genome engineering revealed that the enhancer is required in erythroid but not beta-lymphoid cells for BCL11A expression. Bauer et al. (2013) concluded that these findings illustrated how genomewide association studies may expose functional variants of modest impact within causal elements essential for appropriate gene expression, and proposed that the BCL11A enhancer represents an attractive target for therapeutic genome engineering for the beta-hemoglobinopathies. </p><p>Canver et al. (2015) developed pooled CRISPR-Cas9 guide RNA libraries to perform in situ saturating mutagenesis of the human and mouse BCL11A enhancers. This approach revealed critical minimal features and discrete vulnerabilities of these enhancers. Despite conserved function of the composite enhancers, their architecture diverges. The crucial human sequences appear to be primate-specific. Through editing of primary human progenitors and mouse transgenesis, Canver et al. (2015) validated the BCL11A erythroid enhancer as a target for fetal hemoglobin reinduction. The authors concluded that the detailed enhancer map would inform therapeutic genome editing, and the screening approach described was generally applicable to functional interrogation of noncoding genomic elements. </p><p>Martyn et al. (2018) carried out an in vitro screen for candidate repressors of the gamma-globin gene and found that the C-terminal zinc finger region of BCL11A bound to a site -115 bp upstream of the transcription start site in the gamma-globin gene promoter in electrophoretic mobility shift assays. All tested hereditary persistence of fetal hemoglobin (HPFH; 141749)-associated gamma-globin promoter point mutations disrupted binding with BCL11A. CRISPR-Cas9 genome editing and chromatin immunoprecipitation studies in human erythroid HUDEP-2 cells showed that BCL11A bound to the site at -115 bp of the gamma-globin gene promoter in vivo and that HPFH-associated mutations in the gamma-globin promoter disrupted in vivo BCL11A binding and raised gamma-globin gene expression. Further analysis with chromatin immunoprecipitation-PCR revealed that binding of BCL11A did not affect binding of the other gamma-globin repressor, ZBTB7A (605878), to the gamma-globin promoter. </p><p>Independently, Liu et al. (2018) found that BCL11A directly bound DNA in a sequence-specific manner through its C-terminal zinc finger domain. They identified the preferred binding motif for BCL11A as TGACCA. This motif is present in the promoters of all embryonic- and fetal-expressed globin genes of humans and mice. Some patients with HPFH have mutations in this motif and, consequently, BCL11A cannot bind DNA in these individuals. Mapping of BCL11A chromatin occupancy confirmed TGACCA as the preferred in vivo binding sequence for BCL11A. Chromatin localization of BCL11A in globin loci revealed that the BCL11A motif appeared within globin loci, and high-resolution localization of BCL11A demonstrated that BCL11A preferentially bound the distal TGACCA motif in the gamma-globin promoters. In HUDEP-2 cells, mutation of the distal TGACCA motif in all 4 gamma-globin promoters resulted in failure of BCL11A to bind to the motif and reactivation of gamma-globin expression. Liu et al. (2018) concluded that direct promoter repression by BCL11A controls the fetal-to-adult hemoglobin switch. </p><p>Basak et al. (2020) showed that BCL11A is regulated at the level of mRNA translation during human hematopoietic development. Despite decreased BCL11A protein synthesis earlier in development, BCL11A mRNA continues to be associated with ribosomes. Through unbiased genomic and proteomic analyses, Basak et al. (2020) demonstrated that the RNA-binding protein LIN28B (611044), which is developmentally expressed in a pattern reciprocal to that of BCL11A, directly interacts with ribosomes and BCL11A mRNA. Furthermore, Basak et al. (2020) showed that BCL11A mRNA translation is suppressed by LIN28B through direct interactions, independently of its role in regulating LET7 microRNAs (see 605386), and that BCL11A is the major target of LIN28B-mediated fetal hemoglobin (HbF) induction. Basak et al. (2020) concluded that their results revealed a mechanism underlying human hemoglobin switching that illuminated new therapeutic opportunities. </p><p>Using CRISPR technology, Liu et al. (2021) identified an activator element at the gamma-globin promoters near the BCL11A-binding site. They noted that the gamma-globin promoters contain duplicated BCL11A-binding sites that overlap CCAAT motifs. Knockdown, chromatin immunoprecipitation, and base-editing analyses revealed that NFY (see 189903) activated gamma-globin expression through direct binding to the proximal CCAAT box, whereas BCL11A functioned through the distal binding motif. BCL11A and NFY competed for binding at the gamma-globin promoters to regulate expression of gamma-globin, thereby controlling the switch from fetal to adult hemoglobin. Mutation or deletion of the distal BCL11A-binding motif promoted NFY complex occupancy at the proximal CCAAT motif and activated robust gamma-globin expression, and thus assembly of adult hemoglobin. In contrast, binding of BCL11A to the distal motif constituted a steric barrier to NFY binding at the proximal CCAAT motif, leading to repression of gamma-globin expression, and thus inhibiting the switch from fetal to adult hemoglobin. </p>
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<strong>Mapping</strong>
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<p>By FISH, Saiki et al. (2000) mapped the BCL11A gene to chromosome 2p13, where some cases of lymphoblastic leukemia have displayed chromosomal translocations. </p><p>Menzel et al. (2007) stated the location of the BCL11A gene as 2p15. </p>
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<strong>Cytogenetics</strong>
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<p>Satterwhite et al. (2001) reported the recurrent involvement and deregulated expression of BCL11A in 4 cases of B-cell malignancy with the translocation t(2;14)(p13;q32.3). They noted that this translocation is a rare cytogenetic abnormality in the clinically aggressive subset of B-cell chronic lymphocytic leukemia (151400)/immunocytoma. FISH analysis showed colocalization of BCL11A and REL (164910) in B-cell non-Hodgkin lymphoma (605027). Satterwhite et al. (2001) also identified a BCL11A homolog, BCL11B (606558). </p><p>Comparative genomic hybridization studies showed gains in chromosome region 2p as the most common imbalance in classical Hodgkin lymphoma. The minimal region of gain contained 2 candidate oncogenes, REL and BCL11A. Martin-Subero et al. (2002) examined the involvement of REL and BCL11A loci in 44 primary cases of classic Hodgkin lymphoma by combined immunophenotyping and interphase cytogenetics. A median 2p13 copy number above the tetraploid range was detected in 24 (55%) cases. One case displayed selective amplification of the REL locus not affecting BCL11A. Two other cases showed evidence of breakpoints in the region spanned by the REL probe. These data indicated that REL rather than BCL11A may be the target of the 2p13 alterations in classic Hodgkin lymphoma. </p>
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<p><strong><em>Intellectual Developmental Disorder with Persistence of Fetal Hemoglobin</em></strong></p><p>
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In 9 unrelated patients with intellectual developmental disorder with persistence of fetal hemoglobin (617101), Dias et al. (2016) identified 9 different de novo heterozygous mutations in the BCL11A gene (see, e.g., 606557.0001-606557.0006). The mutations, which included 3 missense and 6 truncating mutations, were found by exome sequencing. In vitro functional expression assays showed that all the missense mutations occurred in the N-terminal region, which encodes a dimerization site, and resulted in defective dimerization, localization, and transcriptional activity, consistent with a loss of function. The findings suggested that the disorder may result from a haploinsufficiency mechanism. In addition, all patients had increased HbF, indicating the importance of BCL11A for transcriptional repression of HbF. </p><p><strong><em>Associations Pending Confirmation</em></strong></p><p>
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For discussion of an association between variation in the BCL11A gene and fetal hemoglobin (HbF) levels, see HBFQTL5 (142335).</p><p>For discussion of an association between deletion of the BCL11A gene and defects in language development, see 612513 and DYX3 (604254).</p>
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<p>Liu et al. (2003) deleted exon 1 of the Bcl11a gene by gene targeting in embryonic stem cells to generate Bcl11a-deficient mice. Unlike heterozygotes, which were viable and fertile, the Bcl11a -/- mice died within 3 to 4 hours after birth. Flow cytometric and RT-PCR analyses of Bcl11a -/- fetal liver cells demonstrated an absence of B-lymphocyte markers and T-cell alpha/beta receptors, but normal development of macrophage-granulocyte and erythroid lineages and an increase in thymic gamma/delta T cells. Transfer of mutant fetal liver cells resulted in the development of clonal T-cell leukemia with substantially increased expression of Notch1 (190198) but not of Notch2 (600275) or Hes1 (139605), a downstream target of Notch1. TdT-mediated dUTP-biotin nick-end labeling (TUNEL) analysis indicated decreased apoptosis in mutant thymi, suggesting a cause for the abnormal development of fetal thymocytes in Bcl11a-deficient mice. Liu et al. (2003) concluded that Bcl11a, like Notch1, is crucial for the early steps in both B- and T-lymphocyte development. </p><p>Xu et al. (2011) showed that the repressor BCL11A is required in vivo for silencing of gamma-globin expression in adult animals, yet dispensable for red cell production. BCL11A serves as a barrier to HbF reactivation by known HbF inducing agents. In a proof-of-principle test of BCL11A as a potential therapeutic target, Xu et al. (2011) demonstrated that inactivation of BCL11A in sickle cell disease (603903) transgenic mice corrects the hematologic and pathologic defects associated with sickle cell disease through high-level pancellular HbF induction. Thus, Xu et al. (2011) concluded that interference with HbF silencing by manipulation of a single target protein is sufficient to reverse sickle cell disease. </p><p>By conditional knockout of Bcl11a in mouse spinal cord, John et al. (2012) found that Bcl11a was required for terminal differentiation and morphogenesis of dorsal spinal neurons. Immunohistologic analysis and postsynaptic current recordings revealed that Bcl11a was also required in spinal target neurons, but was dispensable in presynaptic sensory neurons, for correct wiring and differentiation in superficial dorsal horn. Mutation of Bcl11a in spinal neurons disrupted their maturation and morphogenesis, and disrupted differentiation of dorsal spinal neurons observed in Bcl11a mutant mice interfered with their correct innervation by cutaneous sensory neurons. Microarray analysis in dorsal horn of Bcl11a mutant mouse embryos demonstrated that dysregulated Frzb expression could, in part, account for disrupted sensory innervation of Bcl11a mutant spinal cord. </p><p>Using conditional knockout mice, Wiegreffe et al. (2015) found that Bcl11a was required for the neuronal cell polarity switch from multipolar to bipolar morphology and for migration of upper-layer projection neurons. Bcl11a -/- neurons showed reduced radial orientation of the Golgi apparatus, randomly changed their orientation, and exhibited repetitively slowed migration, suggesting that they unsuccessfully probed their environment for directional cues. Microarray gene expression and chromatin immunoprecipitation analyses revealed that Bcl11a directly repressed expression of the guidance cue Sema3c (602645) by binding to regulatory elements in intron 2 of the Sema3c gene. Overexpression of Sema3c in wildtype mouse cortical neurons recapitulated the Bcl11a-knockout phenotype, whereas knockout of both Sema3c and Bcl11a rescued the Bcl11a-knockout phenotype. Bcl11a also had a Sema3c-independent role in late differentiation and survival of upper-layer cortical neurons. </p><p>Dias et al. (2016) found that haploinsufficiency of Bcl11a in the mouse resulted in microcephaly with decreased brain volume, particularly affecting the limbic system, and abnormal behavior, including impaired long-term social memory and increased locomotion. Haploinsufficient mice also showed significant transcriptional deregulation in the cortex and hippocampus, with effects on genes involved in ion transport, membrane trafficking, and neuronal signaling. </p>
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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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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>6 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</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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BCL11A, THR47PRO
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<br />
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SNP: rs886037864,
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ClinVar: RCV000239897
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a girl with intellectual developmental disorder with persistence of fetal hemoglobin (617101), Dias et al. (2016) identified a de novo heterozygous c.139A-C transversion (c.139A-C, NM_022893.3) in exon 2 of the BCL11A gene, resulting in a thr47-to-pro (T47P) substitution in the N-terminal region. The mutation was found by exome sequencing. </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 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</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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BCL11A, CYS48PHE
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<br />
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SNP: rs886037865,
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ClinVar: RCV000240280
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a boy with intellectual developmental disorder with persistence of fetal hemoglobin (617101), Dias et al. (2016) identified a de novo heterozygous c.143G-T transversion (c.143G-T, NM_022893.3) in exon 2 of the BCL11A gene, resulting in a cys48-to-phe (C48F) substitution in the N-terminal region. The mutation was found by exome sequencing. </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 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</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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BCL11A, HIS66GLN
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<br />
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SNP: rs886037866,
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ClinVar: RCV000240572
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a girl with intellectual developmental disorder with persistence of fetal hemoglobin (617101), Dias et al. (2016) identified a de novo heterozygous c.198C-A transversion (c.198C-A, NM_022893.3) in exon 2 of the BCL11A gene, resulting in a his66-to-gln (H66Q) substitution in the N-terminal region. The mutation was found by exome sequencing. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0004 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</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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BCL11A, GLN177TER
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<br />
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SNP: rs1553403736,
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ClinVar: RCV000598781, RCV000856831
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a girl with intellectual developmental disorder with persistence of fetal hemoglobin (617101), Dias et al. (2016) identified a de novo heterozygous c.529C-T transition (c.198C-A, NM_022893.3) in the BCL11A gene, resulting in a gln177-to-ter (Q177X) substitution. The mutation was found by exome sequencing. The findings were consistent with haploinsufficiency. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0005 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</strong>
|
|
</span>
|
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</h4>
|
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</div>
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<div>
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<span class="mim-text-font">
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BCL11A, 3-BP INS, 1775TGG
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<br />
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SNP: rs886037867,
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gnomAD: rs886037867,
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ClinVar: RCV000240288
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a girl with intellectual developmental disorder with persistence of fetal hemoglobin (617101), Dias et al. (2016) identified a de novo heterozygous 3-bp insertion (c.1775_1776insTGG, NM_022893.3), resulting in a frameshift and premature termination (Glu593GlyfsTer9). The mutation was found by exome sequencing. The findings were consistent with haploinsufficiency. </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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|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 INTELLECTUAL DEVELOPMENTAL DISORDER WITH PERSISTENCE OF FETAL HEMOGLOBIN</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
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|
|
BCL11A, GLN52TER
|
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|
|
|
<br />
|
|
|
|
SNP: rs886037868,
|
|
|
|
|
|
|
|
ClinVar: RCV000240553
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a girl with intellectual developmental disorder with persistence of fetal hemoglobin (617101), Dias et al. (2016) identified a de novo heterozygous c.154C-T transition (c.154C-T, NM_022893.3) in the BCL11A gene, resulting in a gln52-to-ter (Q52X) substitution. The mutation was found by exome sequencing. The findings were consistent with haploinsufficiency. </p>
|
|
</span>
|
|
</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>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
|
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<ol>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Avram, D., Fields, A., Top, K. P. O., Nevrivy, D. J., Ishmael, J. E., Leid, M.
|
|
<strong>Isolation of a novel family of C2H2 zinc finger proteins implicated in transcriptional repression mediated by chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan nuclear receptors.</strong>
|
|
J. Biol. Chem. 275: 10315-10322, 2000.
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[PubMed: 10744719]
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[Full Text: https://doi.org/10.1074/jbc.275.14.10315]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Basak, A., Munschauer, M., Lareau, C. A., Montbleau, K. E., Ulirsch, J. C., Hartigan, C. R., Schenone, M., Lian, J., Wang, Y., Huang, Y., Wu, X., Gehrke, L., and 9 others.
|
|
<strong>Control of human hemoglobin switching by LIN28B-mediated regulation of BCL11A translation.</strong>
|
|
Nature Genet. 52: 138-145, 2020.
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[PubMed: 31959994]
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[Full Text: https://doi.org/10.1038/s41588-019-0568-7]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bauer, D. E., Kamran, S. C., Lessard, S., Xu, J., Fujiwara, Y., Lin, C., Shao, Z., Canver, M. C., Smith, E. C., Pinello, L., Sabo, P. J., Vierstra, J., Voit, R. A., Yuan, G.-C., Porteus, M. H., Stamatoyannopoulos, J. A., Lettre, G., Orkin, S. H.
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|
<strong>An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level.</strong>
|
|
Science 342: 253-257, 2013.
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[PubMed: 24115442]
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[Full Text: https://doi.org/10.1126/science.1242088]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Borg, J., Papadopoulos, P., Georgitsi, M., Gutierrez, L., Grech, G., Fanis, P., Phylactides, M., Verkerk, A. J. M. H., van der Spek, P. J., Scerri, C. A., Cassar, W., Galdies, R., and 10 others.
|
|
<strong>Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin.</strong>
|
|
Nature Genet. 42: 801-805, 2010.
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[PubMed: 20676099]
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[Full Text: https://doi.org/10.1038/ng.630]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Canver, M. C., Smith, E. C., Sher, F., Pinello, L., Sanjana, N. E., Shalem, O., Chen, D. D., Schupp, P. G., Vinjamur, D. S., Garcia, S. P., Luc, S., Kurita, R., Nakamura, Y., Fujiwara, Y., Maeda, T., Yuan, G.-C., Zhang, F., Orkin, S. H., Bauer, D. E.
|
|
<strong>BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis.</strong>
|
|
Nature 527: 192-197, 2015.
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[PubMed: 26375006]
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[Full Text: https://doi.org/10.1038/nature15521]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Dias, C., Estruch, S. B., Graham, S. A., McRae, J., Sawiak, S. J., Hurst, J. A., Joss, S. K., Holder, S. E., Morton, J. E. V., Turner, C., Thevenon, J., Mellul, K., and 12 others.
|
|
<strong>BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.</strong>
|
|
Am. J. Hum. Genet. 99: 253-274, 2016.
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|
|
[PubMed: 27453576]
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[Full Text: https://doi.org/10.1016/j.ajhg.2016.05.030]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Funnell, A. P. W., Prontera, P., Ottaviani, V., Piccione, M., Giambona, A., Maggio, A., Ciaffoni, F., Stehling-Sun, S., Marra, M., Masiello, F., Varricchio, L., Stamatoyannolpoulos, J. A., Migliaccio, A. R., Papayannopoulou, T.
|
|
<strong>2p15-p16.1 microdeletions encompassing and proximal to BCL11A are associated with elevated HbF in addition to neurologic impairment.</strong>
|
|
Blood 126: 89-93, 2015.
|
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|
|
[PubMed: 26019277]
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[Full Text: https://doi.org/10.1182/blood-2015-04-638528]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
John, A., Brylka, H., Wiegreffe, C., Simon, R., Liu, P., Juttner, R., Crenshaw, E. B., III, Luyten, F. P., Jenkins, N. A., Copeland, N. G., Birchmeier, C., Britsch, S.
|
|
<strong>Bcl11a is required for neuronal morphogenesis and sensory circuit formation in dorsal spinal cord development.</strong>
|
|
Development 139: 1831-1841, 2012.
|
|
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|
|
[PubMed: 22491945]
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[Full Text: https://doi.org/10.1242/dev.072850]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Liu, N., Hargreaves, V. V., Zhu, Q., Kurland, J. V., Hong, J., Kim, W., Sher, F., Macias-Trevino, C., Rogers, J. M., Kurita, R., Nakamura, Y., Yuan, G.-C., Bauer, D. E., Xu, J., Bulyk, M. L., Orkin, S. H.
|
|
<strong>Direct promoter repression by BCL11A controls the fetal to adult hemoglobin switch.</strong>
|
|
Cell 173: 430-442, 2018.
|
|
|
|
|
|
[PubMed: 29606353]
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|
[Full Text: https://doi.org/10.1016/j.cell.2018.03.016]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Liu, N., Xu, S., Yao, Q., Zhu, Q., Kai, Y., Hsu, J., Sakon, P., Pinello, L., Yuan, G.-C., Bauer, D. E., Orkin, S. H.
|
|
<strong>Transcription factor competition at the gamma-globin promoters controls hemoglobin switching.</strong>
|
|
Nature Genet. 53: 511-520, 2021. Note: Erratum: Nature Genet. 53: 586 only, 2021.
|
|
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|
|
[PubMed: 33649594]
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|
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[Full Text: https://doi.org/10.1038/s41588-021-00798-y]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Liu, P., Keller, J. R., Ortiz, M., Tessarollo, L., Rachel, R. A., Nakamura, T., Jenkins, N. A., Copeland, N. G.
|
|
<strong>Bcl11a is essential for normal lymphoid development.</strong>
|
|
Nature Immun. 4: 525-532, 2003.
|
|
|
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|
|
[PubMed: 12717432]
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|
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[Full Text: https://doi.org/10.1038/ni925]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Martin-Subero, J. I., Gesk, S., Harder, L., Sonoki, T., Tucker, P. W., Schlegelberger, B., Grote, W., Novo, F. J., Calasanz, M. J., Hansmann, M. L., Dyer, M. J. S., Siebert, R.
|
|
<strong>Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma.</strong>
|
|
Blood 99: 1474-1477, 2002.
|
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|
|
[PubMed: 11830502]
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