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Entry
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- *607102 - WT1 TRANSCRIPTION FACTOR; WT1
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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">*607102</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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<ul id="mimFloatingTocMenuItems" class="nav nav-pills nav-stacked mim-floating-toc-padding">
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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="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#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/607102">Table View</a>
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<li role="presentation">
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<a href="#seeAlso"><strong>See Also</strong></a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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</li>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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</nav>
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</div>
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<div 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=ENSG00000184937;t=ENST00000452863" 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=7490" 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=607102" 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=ENSG00000184937;t=ENST00000452863" 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_000378,NM_001198551,NM_001198552,NM_001367854,NM_001407044,NM_001407045,NM_001407046,NM_001407047,NM_001407048,NM_001407049,NM_001407050,NM_001407051,NM_001429031,NM_001429032,NM_001429033,NM_001429034,NM_024424,NM_024426,NR_160306,NR_176266" 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_024426" 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=607102" 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=06163&isoform_id=06163_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/WT1" 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/37978,139778,235959,237600,237602,237604,237606,300309,300311,312850,312852,340380,340382,807201,825731,23271272,28932926,37964181,110611793,116672765,116672767,119588626,119588627,119588628,119588629,119588630,119588631,119588632,158256904,158302666,193787461,309951097,309951099,549537251,575866908,849388780,1114633401,1327848670,1327848672,1327848674,1540583145,1585575741,2243992922,2243992924,2243992926,2243992928,2243993590,2243993889,2243996583,2243996598,2710271972,2710271974,2710271976,2710271978" 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/P19544" 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=7490" 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=ENSG00000184937;t=ENST00000452863" 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=WT1" 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=WT1" 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+7490" 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/WT1" 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:7490" 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/7490" 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=chr11&hgg_gene=ENST00000452863.10&hgg_start=32387775&hgg_end=32435539&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:12796" 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:12796" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/wt1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=607102[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=607102[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/WT1/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/ENSG00000184937" 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=WT1" 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=WT1" 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=WT1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=WT1&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/PA37395" 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:12796" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:98968" 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/WT1#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:98968" 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/7490/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=7490" 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://zfin.org/ZDB-GENE-050420-319" 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">
|
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<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:7490" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=WT1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 236385009, 25081006, 302849000, 445431000, 722461004<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
|
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607102
|
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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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WT1 TRANSCRIPTION FACTOR; WT1
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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="includedTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
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</span>
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</p>
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</div>
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<div>
|
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<span class="h3 mim-font">
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WT1/EWS FUSION GENE, INCLUDED
|
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
|
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=WT1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">WT1</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">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/11/284?start=-3&limit=10&highlight=284">11p13</a>
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|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:32387775-32435539&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'})">11:32,387,775-32,435,539</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
|
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</th>
|
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<th>
|
|
Phenotype
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=194080,136680,608978,156240,256370,194070" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
|
</a>
|
|
</span>
|
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|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
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<th>
|
|
Inheritance
|
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</th>
|
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="6">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/284?start=-3&limit=10&highlight=284">
|
|
11p13
|
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</a>
|
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</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Denys-Drash syndrome
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/194080"> 194080 </a>
|
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|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The WT1 gene encodes a zinc finger DNA-binding protein that acts as a transcriptional activator or repressor depending on the cellular or chromosomal context (summary by <a href="#29" class="mim-tip-reference" title="Hossain, A., Saunders, G. F. <strong>The human sex-determining gene SRY is a direct target of WT1.</strong> J. Biol. Chem. 276: 16817-16823, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11278460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11278460</a>] [<a href="https://doi.org/10.1074/jbc.M009056200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11278460">Hossain and Saunders, 2001</a>). WT1 is required for normal formation of the genitourinary system and mesothelial tissues (summary by <a href="#79" class="mim-tip-reference" title="Wagner, K.-D., Wagner, N., Schley, G., Theres, H., Scholz, H. <strong>The Wilms' tumor suppressor Wt1 encodes a transcriptional activator of the class IV POU-domain factor Pou4f2 (Brn-3b).</strong> Gene 305: 217-223, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12609742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12609742</a>] [<a href="https://doi.org/10.1016/s0378-1119(02)01231-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12609742">Wagner et al., 2003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12609742+11278460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>To localize a candidate gene for Wilms tumor (<a href="/entry/194070">194070</a>), <a href="#69" class="mim-tip-reference" title="Rose, E. A., Glaser, T., Jones, C., Smith, C. L., Lewis, W. H., Call, K. M., Minden, M., Champagne, E., Bonetta, L., Yeger, H., Housman, D. E. <strong>Complete physical map of the WAGR region of 11p13 localizes a candidate Wilms' tumor gene.</strong> Cell 60: 495-508, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2154334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2154334</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90600-j" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2154334">Rose et al. (1990)</a> developed a physical map of the 11p13 region, deleted in individuals with Wilms tumor, by a combination of pulsed field gel electrophoresis and irradiation-reduced somatic cell hybrids of the Goss-Harris type. Restriction fragments contained in 11p13 were visualized directly using interspersed repeated DNA sequences as hybridization probes. The Wilms tumor locus was narrowed down to a region of less than 345 kb, and a transcript was identified with many of the characteristics expected for the Wilms tumor gene: a GC-rich region mapped to the 5-prime end of a transcription unit encoding a zinc finger protein. <a href="#8" class="mim-tip-reference" title="Call, K. M., Glaser, T., Ito, C. Y., Buckler, A. J., Pelletier, J., Haber, D. A., Rose, E. A., Kral, A., Yeger, H., Lewis, W. H., Jones, C., Housman, D. E. <strong>Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.</strong> Cell 60: 509-520, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2154335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2154335</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90601-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2154335">Call et al. (1990)</a> reported further on these characteristics. The 429-amino acid polypeptide had features suggesting a role in transcriptional regulation: the presence of 4 zinc finger domains and a region rich in proline and glutamine. The amino acid sequence of the predicted polypeptide showed significant homology to EGR1 (<a href="/entry/128990">128990</a>) and EGR2 (<a href="/entry/129010">129010</a>). The mRNA was expressed predominantly in the kidney and a subset of hematopoietic cells. <a href="#22" class="mim-tip-reference" title="Gessler, M., Poustka, A., Cavenee, W., Neve, R. L., Orkin, S. H., Bruns, G. A. P. <strong>Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping.</strong> Nature 343: 774-778, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2154702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2154702</a>] [<a href="https://doi.org/10.1038/343774a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2154702">Gessler et al. (1990)</a> likewise isolated a cDNA clone derived from an RNA highly expressed in fetal kidney which is predicted to encode a Kruppel-like zinc finger protein that is probably a transcription factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2154335+2154702+2154334" 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="#30" class="mim-tip-reference" title="Huang, A., Campbell, C. E., Bonetta, L., McAndrews-Hill, M. S., Chilton-MacNeill, S., Coppes, M. J., Law, D. J., Feinberg, A. P., Yeger, H., Williams, B. R. G. <strong>Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor.</strong> Science 250: 991-994, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2173145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2173145</a>] [<a href="https://doi.org/10.1126/science.2173145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2173145">Huang et al. (1990)</a> independently cloned WT1, which they designated WIT2, from a chromosomal region homozygously deleted in a Wilms tumor cell line. Northern blot analysis of fetal tissues detected a major 3.5-kb WT1 transcript expressed predominantly in kidney and spleen. Expression was much lower in 5-year-old and adult kidney. <a href="#30" class="mim-tip-reference" title="Huang, A., Campbell, C. E., Bonetta, L., McAndrews-Hill, M. S., Chilton-MacNeill, S., Coppes, M. J., Law, D. J., Feinberg, A. P., Yeger, H., Williams, B. R. G. <strong>Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor.</strong> Science 250: 991-994, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2173145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2173145</a>] [<a href="https://doi.org/10.1126/science.2173145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2173145">Huang et al. (1990)</a> determined that expression of WIT1 (<a href="/entry/607899">607899</a>), which is located on chromosome 11p13 and is transcribed in the opposite direction of WT1, mirrors expression of WT1 in normal and Wilms tumor tissues, but at lower abundance. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2173145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Dallosso, A. R., Hancock, A. L., Brown, K. W., Williams, A. C., Jackson, S., Malik, K. <strong>Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours.</strong> Hum. Molec. Genet. 13: 405-415, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681303</a>] [<a href="https://doi.org/10.1093/hmg/ddh038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681303">Dallosso et al. (2004)</a> identified a novel alternative WT1 transcript (AWT1) that retains exons 2 to 10 of WT1 but utilizes an alternative exon 1a located in intron 1 of WT1, replacing 147 amino acids of exon 1 with 4 amino acids of exon 1a. AWT1 encodes proteins of approximately 33 kD, comprising all exon 5 and exon 9 splicing variants previously characterized for WT1. AWT1 was coexpressed with WT1 in renal and hematopoietic cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14681303" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Florio, F., Cesaro, E., Montano, G., Izzo, P., Miles, C., Costanzo, P. <strong>Biochemical and functional interaction between ZNF224 and ZNF255, two members of the Kruppel-like zinc-finger protein family and WT1 protein isoforms.</strong> Hum. Molec. Genet. 19: 3544-3556, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20591825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20591825</a>] [<a href="https://doi.org/10.1093/hmg/ddq270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20591825">Florio et al. (2010)</a> stated that at least 24 different WT1 isoforms are produced by alternative splicing and the use of alternate translation initiation sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20591825" 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>WT1-Antisense/WIT1 Fusion Transcript</em></strong></p><p>
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<a href="#14" class="mim-tip-reference" title="Eccles, M. R., Grubb, G., Ogawa, O., Szeto, J., Reeve, A. E. <strong>Cloning of novel Wilms tumor gene (WT1) cDNAs; evidence for antisense transcription of WT1.</strong> Oncogene 9: 2059-2063, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8208551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8208551</a>]" pmid="8208551">Eccles et al. (1994)</a> and <a href="#9" class="mim-tip-reference" title="Campbell, C. E., Huang, A., Gurney, A. L., Kessler, P. M., Hewitt, J. A., Williams, B. R. G. <strong>Antisense transcripts and protein binding motifs within the Wilms tumour (WT1) locus.</strong> Oncogene 9: 583-595, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8290269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8290269</a>]" pmid="8290269">Campbell et al. (1994)</a> identified a cDNA clone transcribed in the opposite direction of WT1 that includes sequences from WIT1 and WT1 and may include WT1 intronic sequences. By Northern blot analysis and RNase protection analyses, <a href="#14" class="mim-tip-reference" title="Eccles, M. R., Grubb, G., Ogawa, O., Szeto, J., Reeve, A. E. <strong>Cloning of novel Wilms tumor gene (WT1) cDNAs; evidence for antisense transcription of WT1.</strong> Oncogene 9: 2059-2063, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8208551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8208551</a>]" pmid="8208551">Eccles et al. (1994)</a> detected this transcript expressed at 7 to 10 kb in fetal kidney. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8208551+8290269" 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>WT1 is a zinc finger DNA-binding protein that acts as a transcriptional activator or repressor depending on the cellular or chromosomal context. It has 4 major isoforms, due to the insertion of 3 amino acids (KTS) between zinc fingers 3 and 4, and the insertion of an alternatively spliced 17-amino acid segment encoded by exon 5 in the middle of the protein (<a href="#29" class="mim-tip-reference" title="Hossain, A., Saunders, G. F. <strong>The human sex-determining gene SRY is a direct target of WT1.</strong> J. Biol. Chem. 276: 16817-16823, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11278460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11278460</a>] [<a href="https://doi.org/10.1074/jbc.M009056200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11278460">Hossain and Saunders, 2001</a>). The conservation in structure and relative levels of the 4 WT1 mRNA species suggests that each encoded polypeptide makes a significant contribution to normal gene function. The control of cellular proliferation and differentiation exerted by the WT1 gene products may involve interactions between the 4 polypeptides with distinct targets and functions (<a href="#24" class="mim-tip-reference" title="Haber, D. A., Sohn, R. L., Buckler, A. J., Pelletier, J., Call, K. M., Housman, D. E. <strong>Alternative splicing and genomic structure of the Wilms tumor gene WT1.</strong> Proc. Nat. Acad. Sci. 88: 9618-9622, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1658787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1658787</a>] [<a href="https://doi.org/10.1073/pnas.88.21.9618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1658787">Haber et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1658787+11278460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The WT1 protein that was isolated by <a href="#8" class="mim-tip-reference" title="Call, K. M., Glaser, T., Ito, C. Y., Buckler, A. J., Pelletier, J., Haber, D. A., Rose, E. A., Kral, A., Yeger, H., Lewis, W. H., Jones, C., Housman, D. E. <strong>Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.</strong> Cell 60: 509-520, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2154335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2154335</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90601-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2154335">Call et al. (1990)</a> and <a href="#22" class="mim-tip-reference" title="Gessler, M., Poustka, A., Cavenee, W., Neve, R. L., Orkin, S. H., Bruns, G. A. P. <strong>Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping.</strong> Nature 343: 774-778, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2154702/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2154702</a>] [<a href="https://doi.org/10.1038/343774a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2154702">Gessler et al. (1990)</a> as the likely 'cause' of Wilms tumor was used by <a href="#66" class="mim-tip-reference" title="Pritchard-Jones, K., Fleming, S., Davidson, D., Bickmore, W., Porteous, D., Gosden, C., Bard, J., Buckler, A., Pelletier, J., Housman, D., van Heyningen, V., Hastie, N. <strong>The candidate Wilms' tumour gene is involved in genitourinary development.</strong> Nature 346: 194-197, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2164159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2164159</a>] [<a href="https://doi.org/10.1038/346194a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2164159">Pritchard-Jones et al. (1990)</a> to study its role in normal development. This was done by in situ mRNA hybridization on sections of human embryos. The candidate Wilms tumor gene was expressed specifically in the condensed mesenchyme, renal vesicle, and glomerular epithelium of the developing kidney, in the related mesonephric glomeruli, and in cells approximating these structures in tumors. The other main sites of expression were the genital ridge, fetal gonad, and mesothelium. This was interpreted as indicating that the anomalies of the urinary tract and genitalia, which are frequent in both sporadic and syndrome-associated Wilms tumors, are a pleiotropic effect of the WT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2154335+2164159+2154702" 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>Both constitutional and somatic mutations disrupting the DNA-binding domain of WT1 result in a potentially dominant-negative phenotype. In generating inducible cell lines expressing wildtype isoforms of WT1 as well as WT1 mutants, <a href="#16" class="mim-tip-reference" title="Englert, C., Vidal, M., Maheswaran, S., Ge, Y., Ezzell, R. M., Isselbacher, K. J., Haber, D. A. <strong>Truncated WT1 mutants alter the subnuclear localization of the wild-type protein.</strong> Proc. Nat. Acad. Sci. 92: 11960-11964, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8618823/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8618823</a>] [<a href="https://doi.org/10.1073/pnas.92.26.11960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8618823">Englert et al. (1995)</a> observed dramatic differences in the subnuclear localization of the induced proteins. The WT1 isoform that binds with high affinity to a defined DNA target, WT1(-KTS), was diffusely localized throughout the nucleus. In contrast, expression of an alternative splicing variant with reduced DNA binding affinity, WT1(+KTS), or WT1 mutants with a disrupted zinc finger domain resulted in a speckled pattern of expression within the nucleus. Though similar in appearance, the localization of WT1 variants to subnuclear clusters was clearly distinct from that of the essential splicing factor SC35, suggesting that WT1 is not directly involved in pre-mRNA splicing. Localization to subnuclear clusters required the M terminus of WT1 and coexpression of a truncated WT1 mutant and wildtype WT1(-KTS) resulted in a physical association, the redistribution of WT1(-KTS) from a diffuse to a speckled pattern, and the inhibition of its transactivational activity. These observations suggested to the authors that different WT1 isoforms and WT1 mutants have distinct subnuclear compartments. Dominant-negative WT1 proteins physically associate with wildtype WT1 in vivo and may result in its sequestration within subnuclear structures. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8618823" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#73" class="mim-tip-reference" title="Scharnhorst, V., Dekker, P., van der Eb, A. J., Jochemsen, A. G. <strong>Internal translation initiation generates novel WT1 protein isoforms with distinct biological properties.</strong> J. Biol. Chem. 274: 23456-23462, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10438524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10438524</a>] [<a href="https://doi.org/10.1074/jbc.274.33.23456" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10438524">Scharnhorst et al. (1999)</a> described additional WT1 isoforms with distinct transcription-regulatory properties, indicating further the complexity of WT1 expression and activity. They stated that, including these novel forms, 32 WT1 protein forms had been described. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10438524" 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="#43" class="mim-tip-reference" title="Laity, J. H., Dyson, H. J., Wright, P. E. <strong>Molecular basis for modulation of biological function by alternate splicing of the Wilms' tumor suppressor protein.</strong> Proc. Nat. Acad. Sci. 97: 11932-11935, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11050227/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11050227</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11050227[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.97.22.11932" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11050227">Laity et al. (2000)</a> used NMR relaxation experiments to determine the molecular basis for the differing DNA recognition properties of the WT1(-KTS) and WT1(+KTS) isoforms. The results showed that the KTS insertion increases the flexibility of the linker between fingers 3 and 4 and abrogates binding of the fourth zinc finger to its cognate site in the DNA major groove. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11050227" 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 a series of site-directed mutations in both the genomic and cDNA context, <a href="#12" class="mim-tip-reference" title="Davies, R. C., Bratt, E., Hastie, N. D. <strong>Did nucleotides or amino acids drive evolutionary conservation of the WT1 +/- KTS alternative splice?</strong> Hum. Molec. Genet. 9: 1177-1183, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10767342/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10767342</a>] [<a href="https://doi.org/10.1093/hmg/9.8.1177" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10767342">Davies et al. (2000)</a> investigated the nucleotide-amino acid relationship of WT1 and the KTS tripeptide. Mutation analysis within the cDNA suggested that the precise amino acids inserted may not be critical, but rather the disruption of the zinc finger structure alone may be sufficient to generate proteins with different in vitro properties. However, analysis within the genomic context suggested that the precise structure of the splice junction is crucial in retaining the balance between +/- KTS splice isoforms. The authors hypothesized that this may account for the high nucleotide conservation of the gene structure from fish to mammals. Using nuclear magnetic resonance analysis, <a href="#42" class="mim-tip-reference" title="Laity, J. H., Chung, J., Dyson, H. J., Wright, P. E. <strong>Alternative splicing of Wilms' tumor suppressor protein modulates DNA binding activity through isoform-specific DNA-induced conformational changes.</strong> Biochemistry 39: 5341-5348, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10820004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10820004</a>] [<a href="https://doi.org/10.1021/bi9926678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10820004">Laity et al. (2000)</a> found that although the +/- KTS isoforms of WT1 are nearly identical in the absence of DNA, upon DNA binding the isoform lacking KTS forms a more stable complex because the KTS sequence disrupts interactions between the linker region and the adjacent zinc fingers. They found that the isoform lacking KTS appears to be involved in a C-terminal helix-capping, stabilizing interaction with the helix of the preceding finger. <a href="#42" class="mim-tip-reference" title="Laity, J. H., Chung, J., Dyson, H. J., Wright, P. E. <strong>Alternative splicing of Wilms' tumor suppressor protein modulates DNA binding activity through isoform-specific DNA-induced conformational changes.</strong> Biochemistry 39: 5341-5348, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10820004/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10820004</a>] [<a href="https://doi.org/10.1021/bi9926678" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10820004">Laity et al. (2000)</a> suggested that the presence of different isoforms of WT1 in different locations may allow it to act at both the transcriptional and posttranscriptional levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10767342+10820004" 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>Products of the steroidogenic factor-1 (SF1; <a href="/entry/184757">184757</a>) and WT1 genes are essential for mammalian gonadogenesis prior to sexual differentiation. In males, SF1 participates in sexual development by regulating expression of the polypeptide hormone mullerian inhibiting substance (MIS; <a href="/entry/600957">600957</a>). <a href="#56" class="mim-tip-reference" title="Nachtigal, M. W., Hirokawa, Y., Enyeart-VanHouten, D. L., Flanagan, J. N., Hammer, G. D., Ingraham, H. A. <strong>Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.</strong> Cell 93: 445-454, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590178</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590178">Nachtigal et al. (1998)</a> showed that WT1(-KTS) isoforms associate and synergize with SF1 to promote MIS expression. In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome (<a href="/entry/194080">194080</a>), fail to synergize with SF1. Additionally, the X-linked, candidate dosage-sensitive sex-reversal (DSS; <a href="/entry/300018">300018</a>) gene, DAX1 (NR0B1; <a href="/entry/300473">300473</a>), antagonizes synergy between SF1 and WT1, most likely through a direct interaction with SF1. <a href="#56" class="mim-tip-reference" title="Nachtigal, M. W., Hirokawa, Y., Enyeart-VanHouten, D. L., Flanagan, J. N., Hammer, G. D., Ingraham, H. A. <strong>Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.</strong> Cell 93: 445-454, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590178</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590178">Nachtigal et al. (1998)</a> proposed that WT1 and DAX1 functionally oppose each other in testis development by modulating SF1-mediated transactivation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9590178" 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>With use of reporter plasmids, gel shift assays, and transfection experiments, <a href="#29" class="mim-tip-reference" title="Hossain, A., Saunders, G. F. <strong>The human sex-determining gene SRY is a direct target of WT1.</strong> J. Biol. Chem. 276: 16817-16823, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11278460/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11278460</a>] [<a href="https://doi.org/10.1074/jbc.M009056200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11278460">Hossain and Saunders (2001)</a> determined that the WT1(-KTS) isoform is able to transactivate SRY (<a href="/entry/480000">480000</a>), a human sex-determining gene, by binding to its promoter region. They also found that WT1 with any of 4 common mutations causing Denys-Drash syndrome failed to activate the SRY promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11278460" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#45" class="mim-tip-reference" title="Little, M. H., Dunn, R., Byrne, J. A., Seawright, A., Smith, P. J., Pritchard-Jones, K., van Heyningen, V., Hastie, H. D. <strong>Equivalent expression of paternally and maternally inherited WT1 alleles in normal fetal tissue and Wilms' tumours.</strong> Oncogene 7: 635-641, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1314367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1314367</a>]" pmid="1314367">Little et al. (1992)</a> demonstrated that each parental allele of WT1 is equivalently expressed in normal fetal kidneys and Wilms tumors. On the other hand, <a href="#34" class="mim-tip-reference" title="Jinno, Y., Yun, K., Nishiwaki, K., Kubota, T., Ogawa, O., Reeve, A. E., Niikawa, N. <strong>Mosaic and polymorphic imprinting of the WT1 gene in humans.</strong> Nature Genet. 6: 305-309, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8012395/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8012395</a>] [<a href="https://doi.org/10.1038/ng0394-305" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8012395">Jinno et al. (1994)</a> identified imprinting of WT1, with maternal expression in about half of preterm placental villus and fetal brain tissue. Further extensive studies showed that maternal monoallelic expression was observed in 39% of the samples, while the expression in other samples was biallelic. <a href="#54" class="mim-tip-reference" title="Mitsuya, K., Sui, H., Meguro, M., Kugoh, H., Jinno, Y., Niikawa, N., Oshimura, M. <strong>Paternal expression of WT1 in human fibroblasts and lymphocytes.</strong> Hum. Molec. Genet. 6: 2243-2246, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9361029/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9361029</a>] [<a href="https://doi.org/10.1093/hmg/6.13.2243" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9361029">Mitsuya et al. (1997)</a> studied the allele-specific expression of WT1 as well as of IGF2 and H19 in fibroblasts and lymphocytes. The expression profiles of IGF2 and H19 were constant and consistent with those in other tissues. The unexpected finding was paternal or biallelic expression of WT1 in fibroblasts and lymphocytes. This, together with the previous findings of maternal or biallelic expression in placenta and brain, suggested that the allele-specific regulatory system of WT1 is unique and may be controlled by a putative tissue- and individual-specific modifier. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1314367+9361029+8012395" 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="#55" class="mim-tip-reference" title="Miyagawa, K., Kent, J., Moore, A., Charlieu, J.-P., Little, M. H., Williamson, K. A., Kelsey, A., Brown, K. W., Hassam, S., Briner, J., Hayashi, Y., Hirai, H., Yazaki, Y., van Heyningen, V., Hastie, N. D. <strong>Loss of WT1 function leads to ectopic myogenesis in Wilms' tumour. (Letter)</strong> Nature Genet. 18: 15-17, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9425891/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9425891</a>] [<a href="https://doi.org/10.1038/ng0198-15" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9425891">Miyagawa et al. (1998)</a> focused on the ectopic formation of skeletal muscle in Wilms tumors. They presented evidence supporting a negative regulatory role for WT1 in myogenesis. Their findings suggested that the metanephric-mesenchymal stem cells of the kidney may have the capacity to differentiate into skeletal muscle cells as well as epithelial cells. Normally, the expression of WT1 appears to prevent this ectopic differentiation program from being activated. In vitro studies suggested that WT1 may play a direct role in suppressing the formation of skeletal muscle. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9425891" 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="#50" class="mim-tip-reference" title="Little, N. A., Hastie, N. D., Davies, R. C. <strong>Identification of WTAP, a novel Wilms' tumour 1-associating protein.</strong> Hum. Molec. Genet. 9: 2231-2239, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11001926/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11001926</a>] [<a href="https://doi.org/10.1093/oxfordjournals.hmg.a018914" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11001926">Little et al. (2000)</a> used the yeast 2-hybrid system to identify a novel human WT1-associating protein, WTAP (<a href="/entry/605442">605442</a>). Both in vitro and in vivo assays demonstrated a specific interaction between WTAP and WT1, which occurred endogenously in cells. The mouse homolog of WTAP was isolated and found to be greater than 90% conserved at the nucleotide and protein levels. The human and mouse genes were mapped using fluorescence in situ hybridization to regions on chromosomes 6 (which is thought to harbor a tumor suppressor gene) and 17, respectively. WTAP appears to be a ubiquitously expressed nuclear protein, which, like WT1, localized throughout the nucleoplasm as well as in speckles and partially colocalized with splicing factors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11001926" 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 high titer retroviral infection, <a href="#15" class="mim-tip-reference" title="Ellisen, L. W., Carlesso, N., Cheng, T., Scadden, D. T., Haber, D. A. <strong>The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells.</strong> EMBO J. 20: 1897-1909, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11296223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11296223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11296223[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/20.8.1897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11296223">Ellisen et al. (2001)</a> examined the effect of the WT1(-KTS) and WT1(+KTS) isoforms on human hematopoietic progenitor cells and human leukemia-derived cells. WT1(-KTS) arrested both types of cells in G1 phase and reduced the number of cells in S phase. WT1(-KTS) also induced differentiation of both cell types, an effect that was enhanced by the presence of WT1(+KTS), while inducing quiescence in a primitive subset of precursors. <a href="#15" class="mim-tip-reference" title="Ellisen, L. W., Carlesso, N., Cheng, T., Scadden, D. T., Haber, D. A. <strong>The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells.</strong> EMBO J. 20: 1897-1909, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11296223/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11296223</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11296223[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/20.8.1897" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11296223">Ellisen et al. (2001)</a> noted that the effect of WT1 on hematopoietic precursors is stage-specific and that the variable expression of the protein is similar to that observed in the developing kidney. The functional role of WT1 in hematopoietic cells suggested that it may act as a tumor suppressor in leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11296223" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#79" class="mim-tip-reference" title="Wagner, K.-D., Wagner, N., Schley, G., Theres, H., Scholz, H. <strong>The Wilms' tumor suppressor Wt1 encodes a transcriptional activator of the class IV POU-domain factor Pou4f2 (Brn-3b).</strong> Gene 305: 217-223, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12609742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12609742</a>] [<a href="https://doi.org/10.1016/s0378-1119(02)01231-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12609742">Wagner et al. (2003)</a> found upregulation of POU4F2 (<a href="/entry/113725">113725</a>) at the transcript and protein levels in embryonic kidney and osteosarcoma cells stably transfected with WT1. WT1 expression activated a POU4F2 promoter-reporter construct about 4-fold. Stimulation of POU4F2 required the WT1 responsive element, WTE, which shows higher affinity for the -KTS isoform of WT1. Double immunofluorescence labeling revealed coexpression of Wt1 and Pou4f2 in glomerular podocytes of adult mouse kidney and in developing retinal ganglion cells of embryonic mice. Pou4F2 immunoreactivity was absent from the retinas of Wt1 null embryos. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12609742" 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="#58" class="mim-tip-reference" title="Niksic, M., Slight, J., Sanford, J. R., Caceres, J. F., Hastie, N. D. <strong>The Wilms' tumour protein (WT1) shuttles between nucleus and cytoplasm and is present in functional polysomes.</strong> Hum. Molec. Genet. 13: 463-471, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681305</a>] [<a href="https://doi.org/10.1093/hmg/ddh040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681305">Niksic et al. (2004)</a> found that WT1 protein is not restricted to the nucleus and shuttles continuously between the nucleus and cytoplasm. Western blot analysis showed that 10 to 50% of total cellular WT1 could be detected in the cytoplasm depending on the cell type. A significant proportion of cytoplasmic WT1 was associated with ribonucleoprotein particles (RNPs) and actively translating polysomes, supporting its role in RNA metabolism and suggesting its involvement in regulation of translation. Despite spatial and functional differences between WT1 (+/- KTS) isoforms within the nucleus, <a href="#58" class="mim-tip-reference" title="Niksic, M., Slight, J., Sanford, J. R., Caceres, J. F., Hastie, N. D. <strong>The Wilms' tumour protein (WT1) shuttles between nucleus and cytoplasm and is present in functional polysomes.</strong> Hum. Molec. Genet. 13: 463-471, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681305/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681305</a>] [<a href="https://doi.org/10.1093/hmg/ddh040" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681305">Niksic et al. (2004)</a> showed that both isoforms shared the shuttling property and were found in translating polysomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14681305" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Burwell, E. A., McCarty, G. P., Simpson, L. A., Thompson, K. A., Loeb, D. M. <strong>Isoforms of Wilms' tumor suppressor gene (WT1) have distinct effects on mammary epithelial cells.</strong> Oncogene 26: 3423-3430, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160023</a>] [<a href="https://doi.org/10.1038/sj.onc.1210127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160023">Burwell et al. (2007)</a> found that expression of WT1(-KTS) in a human mammary epithelial cell line upregulated p21 (CDKN1A; <a href="/entry/116899">116899</a>) expression, slowed proliferation, and promoted G2-phase cell cycle arrest. In artificial basement membranes, WT1(-KTS) promoted organization of cells into distinct acinar cellular aggregates. In contrast, WT1(+KTS) had no effect on p21 expression or cell proliferation, but it caused an epithelial-mesenchymal transition and redistribution of E-cadherin (CDH1; <a href="/entry/192090">192090</a>) from the cell membrane to the cytoplasm. WT1(+KTS) also caused cellular aggregates growing in artificial basement membranes to appear significantly less organized than control cells. <a href="#7" class="mim-tip-reference" title="Burwell, E. A., McCarty, G. P., Simpson, L. A., Thompson, K. A., Loeb, D. M. <strong>Isoforms of Wilms' tumor suppressor gene (WT1) have distinct effects on mammary epithelial cells.</strong> Oncogene 26: 3423-3430, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160023</a>] [<a href="https://doi.org/10.1038/sj.onc.1210127" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17160023">Burwell et al. (2007)</a> concluded that WT1 can function to either promote or suppress the transformed phenotype depending on the ratio of WT1 isoforms expressed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17160023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#81" class="mim-tip-reference" title="Zhou, B., Ma, Q., Rajagopal, S., Wu, S. M., Domian, I., Rivera-Feliciano, J., Jiang, D., von Gise, A., Ikeda, S., Chien, K. R., Pu, W. T. <strong>Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart.</strong> Nature 454: 109-113, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18568026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18568026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18568026[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/nature07060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18568026">Zhou et al. (2008)</a> identified a novel cardiogenic precursor marked by expression of the transcription factor WT1 and located within the epicardium. During normal murine heart development, a subset of these Wt1-positive precursors differentiated into fully functional cardiomyocytes. Wt1-positive proepicardial cells arose from progenitors that expressed Nkx2.5 (<a href="/entry/600584">600584</a>) and Isl1 (<a href="/entry/600366">600366</a>), suggesting that they share a developmental origin with multipotent Nkx2-5-positive and Isl1-positive progenitors. <a href="#81" class="mim-tip-reference" title="Zhou, B., Ma, Q., Rajagopal, S., Wu, S. M., Domian, I., Rivera-Feliciano, J., Jiang, D., von Gise, A., Ikeda, S., Chien, K. R., Pu, W. T. <strong>Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart.</strong> Nature 454: 109-113, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18568026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18568026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18568026[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/nature07060" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18568026">Zhou et al. (2008)</a> concluded that their results identified WT1-positive epicardial cells as previously unrecognized cardiomyocyte progenitors, and laid the foundation for future efforts to harness the cardiogenic potential of these progenitors for cardiac regeneration and repair. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18568026" 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="#44" class="mim-tip-reference" title="Lee, T. H., Lwu, S., Kim, J., Pelletier, J. <strong>Inhibition of Wilms tumor 1 transactivation by bone marrow zinc finger 2, a novel transcriptional repressor.</strong> J. Biol. Chem. 277: 44826-44837, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12239212/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12239212</a>] [<a href="https://doi.org/10.1074/jbc.M205667200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12239212">Lee et al. (2002)</a> demonstrated that the ZNF255 isoform of ZNF224 (<a href="/entry/194555">194555</a>) interacted with WT1 in vitro and in vivo. Mutation analysis showed that zinc fingers 6 to 10 of ZNF255 were required to interact with the zinc finger region of WT1. ZNF255 inhibited transcriptional activation by WT1, and the presence of a repressor domain within ZNF255 was confirmed in a reporter assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12239212" 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 coimmunoprecipitation analysis of human cell lines, <a href="#17" class="mim-tip-reference" title="Florio, F., Cesaro, E., Montano, G., Izzo, P., Miles, C., Costanzo, P. <strong>Biochemical and functional interaction between ZNF224 and ZNF255, two members of the Kruppel-like zinc-finger protein family and WT1 protein isoforms.</strong> Hum. Molec. Genet. 19: 3544-3556, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20591825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20591825</a>] [<a href="https://doi.org/10.1093/hmg/ddq270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20591825">Florio et al. (2010)</a> discovered that ZNF224 interacted specifically and exclusively with the -KTS isoform of WT1, whereas ZNF255 interacted with both the +KTS and -KTS isoforms of WT1. Using a reporter plasmid containing the promoter region of a WT1 target gene, VDR (<a href="/entry/601769">601769</a>), <a href="#17" class="mim-tip-reference" title="Florio, F., Cesaro, E., Montano, G., Izzo, P., Miles, C., Costanzo, P. <strong>Biochemical and functional interaction between ZNF224 and ZNF255, two members of the Kruppel-like zinc-finger protein family and WT1 protein isoforms.</strong> Hum. Molec. Genet. 19: 3544-3556, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20591825/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20591825</a>] [<a href="https://doi.org/10.1093/hmg/ddq270" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20591825">Florio et al. (2010)</a> showed that cotransfection of ZNF224 caused a dose-dependent enhancement of WT1(-KTS)-mediated VDR expression, while ZNF255 had no effect. Chromatin immunoprecipitation analysis showed that ZNF224 was recruited with WT1 to the VDR promoter. Knockdown of ZNF224 reduced VDR mRNA and protein. In contrast, ZNF255, but not ZNF224, colocalized with WT1(+KTS) in the polysome fraction of HEK293 cells and copurified with poly(A) ribonuclear particles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20591825" 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>WT1 Therapy</em></strong></p><p>
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The WT1 gene is overexpressed in leukemias and various types of solid tumors, and the WT1 protein was demonstrated to be an attractive target antigen for immunotherapy against these malignancies. <a href="#59" class="mim-tip-reference" title="Oka, Y., Tsuboi, A., Taguchi, T., Osaki, T., Kyo, T., Nakajima, H., Elisseeva, O. A., Oji, Y., Kawakami, M., Ikegame, K., Hosen, N., Yoshihara, S., and 14 others. <strong>Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression.</strong> Proc. Nat. Acad. Sci. 101: 13885-13890, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15365188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15365188</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=15365188[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0405884101" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15365188">Oka et al. (2004)</a> reported the outcome of a phase I clinical study of WT1 peptide-based immunotherapy for patients with breast or lung cancer, myelodysplastic syndrome, or acute myeloid leukemia. In 26 patients, one or more WT1 vaccinations were performed, consisting of intradermal injections of natural or modified 9-mer WT1 peptide, and 18 of 26 patients completed WT1 vaccination protocol with 3 or more injections. Toxicity consisted only of local erythema at the WT1 vaccine injection site in patients with breast or lung cancer or acute myeloid leukemia with adequate normal hematopoiesis, whereas severe leukocytopenia occurred in patients with myelodysplastic syndrome with abnormal hematopoiesis derived from WT1-expressing, transformed hematopoietic stem cells. Twelve of 20 patients for whom the efficacy of WT1 vaccination could be assessed showed clinical responses such as reduction in leukemic blast cells or tumor sizes and/or tumor markers. A clear correlation was observed between an increase in the frequencies of WT1-specific cytotoxic T lymphocytes after WT1 vaccination and clinical responses. It was thus demonstrated that WT1 vaccination could induce WT1-specific cytotoxic T lymphocytes and result in cancer regression without damage to normal tissues. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15365188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In mice, <a href="#76" class="mim-tip-reference" title="Smart, N., Bollini, S., Dube, K. N., Vieira, J. M., Zhou, B., Davidson, S., Yellon, D., Riegler, J., Price, A. N., Lythgoe, M. F., Pu, W. T., Riley, P. R. <strong>De novo cardiomyocytes from within the activated adult heart after injury.</strong> Nature 474: 640-644, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21654746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21654746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21654746[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/nature10188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21654746">Smart et al. (2011)</a> demonstrated that the adult heart contains a resident stem or progenitor cell population, which has the potential to contribute bona fide terminally differentiated cardiomyocytes after myocardial infarction. <a href="#76" class="mim-tip-reference" title="Smart, N., Bollini, S., Dube, K. N., Vieira, J. M., Zhou, B., Davidson, S., Yellon, D., Riegler, J., Price, A. N., Lythgoe, M. F., Pu, W. T., Riley, P. R. <strong>De novo cardiomyocytes from within the activated adult heart after injury.</strong> Nature 474: 640-644, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21654746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21654746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21654746[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/nature10188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21654746">Smart et al. (2011)</a> revealed a novel genetic label of the activated adult progenitors via reexpression of a key embryonic epicardial gene, Wt1, through priming by thymosin beta-4 (<a href="/entry/300159">300159</a>), a peptide shown to restore vascular potential to adult epicardium-derived progenitor cells with injury. Cumulative evidence indicated an epicardial origin of the progenitor population, and embryonic reprogramming resulted in the mobilization of this population and concomitant differentiation to give rise to de novo cardiomyocytes. Cell transplantation confirmed a progenitor source and chromosome painting of labeled donor cells revealed transdifferentiation to a myocyte fate in the absence of cell fusion. <a href="#76" class="mim-tip-reference" title="Smart, N., Bollini, S., Dube, K. N., Vieira, J. M., Zhou, B., Davidson, S., Yellon, D., Riegler, J., Price, A. N., Lythgoe, M. F., Pu, W. T., Riley, P. R. <strong>De novo cardiomyocytes from within the activated adult heart after injury.</strong> Nature 474: 640-644, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21654746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21654746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21654746[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/nature10188" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21654746">Smart et al. (2011)</a> showed that derived cardiomyocytes are able to structurally and functionally integrate with resident muscle; as such, stimulation of this adult progenitor pool represented a significant step towards resident cell-based therapy in human ischemic heart disease. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21654746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Huang, G. N., Thatcher, J. E., McAnally, J., Kong, Y., Qi, X., Tan, W., DiMaio, J. M., Amatruda, J. F., Gerard, R. D., Hill, J. A., Bassel-Duby, R., Olson, E. N. <strong>C/EBP transcription factors mediate epicardial activation during heart development and injury.</strong> Science 338: 1599-1603, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160954</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23160954[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.1229765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160954">Huang et al. (2012)</a> found that conserved regions CR2 in Raldh2 (<a href="/entry/603687">603687</a>) and CR14 in Wt1 are robust epicardial enhancers that respond to CCAAT/enhancer-binding protein (CEBP; <a href="/entry/116897">116897</a>). <a href="#31" class="mim-tip-reference" title="Huang, G. N., Thatcher, J. E., McAnally, J., Kong, Y., Qi, X., Tan, W., DiMaio, J. M., Amatruda, J. F., Gerard, R. D., Hill, J. A., Bassel-Duby, R., Olson, E. N. <strong>C/EBP transcription factors mediate epicardial activation during heart development and injury.</strong> Science 338: 1599-1603, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160954</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23160954[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.1229765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160954">Huang et al. (2012)</a> established a mouse embryonic heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered on CEBP transcription factors. Disruption of C/EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function. <a href="#31" class="mim-tip-reference" title="Huang, G. N., Thatcher, J. E., McAnally, J., Kong, Y., Qi, X., Tan, W., DiMaio, J. M., Amatruda, J. F., Gerard, R. D., Hill, J. A., Bassel-Duby, R., Olson, E. N. <strong>C/EBP transcription factors mediate epicardial activation during heart development and injury.</strong> Science 338: 1599-1603, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23160954/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23160954</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23160954[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.1229765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23160954">Huang et al. (2012)</a> concluded that their findings revealed a transcriptional basis for epicardial activation and heart injury. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23160954" 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="#21" class="mim-tip-reference" title="Gessler, M., Konig, A., Bruns, G. A. P. <strong>The genomic organization and expression of the WT1 gene.</strong> Genomics 12: 807-813, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1572653/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1572653</a>] [<a href="https://doi.org/10.1016/0888-7543(92)90313-h" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1572653">Gessler et al. (1992)</a> established the genomic organization of the WT1 gene and determined the sequence of all 10 exons and the flanking intron DNA. The pattern of alternative splicing in 2 regions was characterized in detail. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1572653" 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="#30" class="mim-tip-reference" title="Huang, A., Campbell, C. E., Bonetta, L., McAndrews-Hill, M. S., Chilton-MacNeill, S., Coppes, M. J., Law, D. J., Feinberg, A. P., Yeger, H., Williams, B. R. G. <strong>Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor.</strong> Science 250: 991-994, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2173145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2173145</a>] [<a href="https://doi.org/10.1126/science.2173145" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2173145">Huang et al. (1990)</a> determined that the WT1 and WIT1 genes are separated by about 0.6 kb and are transcribed in opposite directions from a single CpG island. The intervening sequence may function as a bidirectional promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2173145" 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 reporter plasmids containing both orientations of the intervening sequence between the WIT1 and WT1 genes, <a href="#9" class="mim-tip-reference" title="Campbell, C. E., Huang, A., Gurney, A. L., Kessler, P. M., Hewitt, J. A., Williams, B. R. G. <strong>Antisense transcripts and protein binding motifs within the Wilms tumour (WT1) locus.</strong> Oncogene 9: 583-595, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8290269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8290269</a>]" pmid="8290269">Campbell et al. (1994)</a> confirmed the bidirectionality of the reporter region in several transfected human and mouse cell lines. By DNase footprinting, they determined that the +KTS form of WT1 can bind at least 4 elements within the promoter region. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8290269" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#28" class="mim-tip-reference" title="Hofmann, W., Royer, H.-D., Drechsler, M., Schneider, S., Royer-Pokora, B. <strong>Characterization of the transcriptional regulatory region of the human WT1 gene.</strong> Oncogene 8: 3123-3132, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8414514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8414514</a>]" pmid="8414514">Hofmann et al. (1993)</a> determined that the WT1 promoter region is TATA-less and GC-rich and contains several SP1 (<a href="/entry/189906">189906</a>)-binding sites. Functional analysis confirmed that the promoter is responsive to SP1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8414514" 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="#69" class="mim-tip-reference" title="Rose, E. A., Glaser, T., Jones, C., Smith, C. L., Lewis, W. H., Call, K. M., Minden, M., Champagne, E., Bonetta, L., Yeger, H., Housman, D. E. <strong>Complete physical map of the WAGR region of 11p13 localizes a candidate Wilms' tumor gene.</strong> Cell 60: 495-508, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2154334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2154334</a>] [<a href="https://doi.org/10.1016/0092-8674(90)90600-j" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2154334">Rose et al. (1990)</a> mapped the WT1 gene to chromosome 11p13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2154334" 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="Gerald, W. L., Rosai, J., Ladanyi, M. <strong>Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor.</strong> Proc. Nat. Acad. Sci. 92: 1028-1032, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7862627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7862627</a>] [<a href="https://doi.org/10.1073/pnas.92.4.1028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7862627">Gerald et al. (1995)</a> reported the first example of a specific tumor associated with consistent translocation involving WT1. Desmoplastic small round cell tumor (DSRCT) is associated with a recurrent chromosomal translocation, t(11;22)(p13;q12). DSRCT is characterized by a predilection for young males, abdominal serosal involvement, poor prognosis, and a primitive histologic appearance. <a href="#20" class="mim-tip-reference" title="Gerald, W. L., Rosai, J., Ladanyi, M. <strong>Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor.</strong> Proc. Nat. Acad. Sci. 92: 1028-1032, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7862627/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7862627</a>] [<a href="https://doi.org/10.1073/pnas.92.4.1028" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7862627">Gerald et al. (1995)</a> found that the chromosome translocation breakpoints involved the intron between WT1 exons 7 and 8 and the intron between EWS (<a href="/entry/133450">133450</a>) exons 7 and 8. Chimeric transcripts corresponding to the fusion gene were detected in 4 of 6 cases of DSRCT. Analyses of these transcripts showed an in-frame fusion of RNA encoding the amino-terminal domain of EWS to both alternatively spliced forms of the last 3 zinc fingers of the DNA-binding domain of WT1. The chimeric products were predicted to modulate transcription at WT1 target sites and contribute to development of this unique tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7862627" 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>Mutations in the WT1 gene have been identified in patients with Wilms tumor (<a href="/entry/194070">194070</a>), WAGR syndrome (<a href="/entry/194072">194072</a>), Denys-Drash syndrome (DDS; <a href="/entry/194080">194080</a>), Frasier syndrome (<a href="/entry/136680">136680</a>), isolated diffuse mesangial sclerosis, referred to here as nephrotic syndrome type 4 (NPHS4; <a href="/entry/256370">256370</a>), and Meacham syndrome (<a href="/entry/608978">608978</a>).</p><p><a href="#32" class="mim-tip-reference" title="Huff, V., Miwa, H., Haber, D. A., Call, K. M., Housman, D., Strong, L. C., Saunders, G. F. <strong>Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT.</strong> Am. J. Hum. Genet. 48: 997-1003, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673293</a>]" pmid="1673293">Huff et al. (1991)</a> made observations that appeared to differentiate between WT33 and LK15, 2 similar candidate Wilms tumor cDNA clones that were identified on the basis of their expression in fetal kidney and their location within the smallest region of overlap of somatic with differences due to alternative splicing at 2 exons. <a href="#32" class="mim-tip-reference" title="Huff, V., Miwa, H., Haber, D. A., Call, K. M., Housman, D., Strong, L. C., Saunders, G. F. <strong>Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT.</strong> Am. J. Hum. Genet. 48: 997-1003, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1673293/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1673293</a>]" pmid="1673293">Huff et al. (1991)</a> reported a patient with bilateral Wilms tumor who was heterozygous for a small germinal mutation within the WT1 gene (as identified by the WT33 clone). DNA from both tumors was homozygous for this intragenic deletion, which was predicted to encode a protein truncated by 180 amino acids. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1673293" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#27" class="mim-tip-reference" title="Hastie, N. D. <strong>Dominant negative mutations in the Wilms tumour (WT1) gene cause Denys-Drash syndrome--proof that a tumour-suppressor gene plays a crucial role in normal genitourinary development.</strong> Hum. Molec. Genet. 1: 293-295, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1338905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1338905</a>] [<a href="https://doi.org/10.1093/hmg/1.5.293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1338905">Hastie (1992)</a> reviewed the evidence showing that mutations in the WT1 gene behave as dominant negatives, specifically in relation to causation of the Denys-Drash syndrome (DDS; <a href="/entry/194080">194080</a>). This is proof that a tumor suppressor gene plays a crucial role in normal genitourinary development. Remarkably, 12 of 25 patients from a total of 4 studies had the arg394-to-trp mutation (R394W; <a href="#0003">607102.0003</a>) in heterozygous form as the cause of the Denys-Drash syndrome. One reason for the preponderance of this mutation is that it represents a C-to-T transition at a CpG dimer. The same can be said for the arg366-to-his change (<a href="#0004">607102.0004</a>). This, however, appeared to be only part of the story since there are other equally vulnerable sites; <a href="#27" class="mim-tip-reference" title="Hastie, N. D. <strong>Dominant negative mutations in the Wilms tumour (WT1) gene cause Denys-Drash syndrome--proof that a tumour-suppressor gene plays a crucial role in normal genitourinary development.</strong> Hum. Molec. Genet. 1: 293-295, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1338905/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1338905</a>] [<a href="https://doi.org/10.1093/hmg/1.5.293" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1338905">Hastie (1992)</a> suggested that the zinc fingers carrying these 2 mutations may play a particularly important role in establishing stable binding. Mutations causing the Denys-Drash syndrome are clustered in the zinc finger-encoding exons, particularly the exons encoding Zf2 and Zf3. <a href="#47" class="mim-tip-reference" title="Little, M. H., Williamson, K. A., Mannens, M., Kelsey, A., Gosden, C., Hastie, N. D., van Heyningen, V. <strong>Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion.</strong> Hum. Molec. Genet. 2: 259-264, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388765</a>] [<a href="https://doi.org/10.1093/hmg/2.3.259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8388765">Little et al. (1993)</a> concluded that WT mutations resulting in the Denys-Drash syndrome may operate in a dominant-negative fashion; they observed an arg362-to-ter mutation predicted to result in a protein product lacking zinc fingers 2, 3 and 4, and therefore presumably incapable of binding DNA. <a href="#48" class="mim-tip-reference" title="Little, M., Holmes, G., Bickmore, W., van Heyningen, V., Hastie, N., Wainwright, B. <strong>DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations.</strong> Hum. Molec. Genet. 4: 351-358, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795587</a>] [<a href="https://doi.org/10.1093/hmg/4.3.351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7795587">Little et al. (1995)</a> found WT1 fusion constructs containing the different classes of DDS-causing mutations. They demonstrated that the DDS mutations, indeed, disrupt DNA binding. They interpreted this as compatible with a dominant-negative mode of action, perhaps through dimerization between different WT1 isoforms. <a href="#48" class="mim-tip-reference" title="Little, M., Holmes, G., Bickmore, W., van Heyningen, V., Hastie, N., Wainwright, B. <strong>DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations.</strong> Hum. Molec. Genet. 4: 351-358, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7795587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7795587</a>] [<a href="https://doi.org/10.1093/hmg/4.3.351" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7795587">Little et al. (1995)</a> noted that another mechanism by which the loss of DNA-binding could elicit the DDS phenotype would be a disturbed isoform dosage balance. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7795587+1338905+8388765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#49" class="mim-tip-reference" title="Little, M., Wells, C. <strong>A clinical overview of WT1 gene mutations.</strong> Hum. Mutat. 9: 209-225, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9090524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9090524</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1997)9:3<209::AID-HUMU2>3.0.CO;2-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9090524">Little and Wells (1997)</a> pointed out that only 5% of sporadic Wilms tumors have intragenic WT1 mutations, but more than 90% of patients with Denys-Drash syndrome, which includes Wilms tumor, carry constitutional intragenic WT1 mutations. WT mutations have also been reported in juvenile granulosa-cell tumor, non-asbestos-related mesothelioma (<a href="#61" class="mim-tip-reference" title="Park, S., Schalling, M., Bernard, A., Maheswaran, S., Shipley, G. C., Roberts, D., Fletcher, J., Shipman, R., Rheinwald, J., Demetri, G., Griffin, J., Minden, M., Housman, D. E., Haber, D. A. <strong>The Wilms tumour gene WT1 is expressed in murine mesoderm-derived tissues and mutated in a human mesothelioma.</strong> Nature Genet. 4: 415-420, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8401592/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8401592</a>] [<a href="https://doi.org/10.1038/ng0893-415" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8401592">Park et al., 1993</a>), desmoplastic small round cell tumor, and acute myeloid leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8401592+9090524" 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="#33" class="mim-tip-reference" title="Jeanpierre, C., Denamur, E., Henry, I., Cabanis, M.-O., Luce, S., Cecille, A., Elion, J., Peuchmaur, M., Loirat, C., Niaudet, P., Gubler, M.-C., Junien, C. <strong>Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.</strong> Am. J. Hum. Genet. 62: 824-833, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529364</a>] [<a href="https://doi.org/10.1086/301806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529364">Jeanpierre et al. (1998)</a> identified WT1 mutations in patients with nephrotic syndrome (NPHS4), i.e., patients without pseudohermaphroditism and/or Wilms tumor, which represent the other features of the Denys-Drash syndrome. In 4 of 10 patients, they found heterozygous mutations in the WT1 gene. Two of the mutations (<a href="#0006">607102.0006</a> and <a href="#0012">607102.0012</a>) had previously been identified in patients with DDS, one (<a href="#0018">607102.0018</a>) had previously been identified in a patient with Frasier syndrome, and one (<a href="#0028">607102.0028</a>) was novel. An analysis of genotype/phenotype correlation, on the basis of a WT1 mutation database of 84 germline mutations, demonstrated an association between mutations in exons 8 and 9 and nephrotic syndrome; among patients with nephrotic syndrome, a higher frequency of exon 8 mutations among 46,XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#40" class="mim-tip-reference" title="Koziell, A. B., Grundy, R., Barratt, T. M., Scambler, P. <strong>Evidence for the genetic heterogeneity of nephropathic phenotypes associated with Denys-Drash and Frasier syndrome. (Letter)</strong> Am. J. Hum. Genet. 64: 1778-1781, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330366</a>] [<a href="https://doi.org/10.1086/302409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330366">Koziell et al. (1999)</a> tested the hypothesis that WT1 gene mutations occur in cases of diffuse mesangial sclerosis (DMS; see <a href="/entry/256370">256370</a>) and in congenital/early-onset focal segmental glomerular sclerosis (FSGS; <a href="/entry/603278">603278</a>) without other features of Denys-Drash syndrome or Frasier syndrome, respectively. To determine how common mutations of the WT1 gene were in this population of cases and to begin establishing the boundaries of the DDS/Frasier syndrome spectrum of disease, they screened a series of 30 patients, 22 with DMS (2 of whom also had DDS) and 8 with FSGS (7 confirmed), for WT1 mutations. No WT1 mutations were detected in either the 20 patients with isolated DMS or the 7 patients with isolated FSGS. <a href="#40" class="mim-tip-reference" title="Koziell, A. B., Grundy, R., Barratt, T. M., Scambler, P. <strong>Evidence for the genetic heterogeneity of nephropathic phenotypes associated with Denys-Drash and Frasier syndrome. (Letter)</strong> Am. J. Hum. Genet. 64: 1778-1781, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330366</a>] [<a href="https://doi.org/10.1086/302409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330366">Koziell et al. (1999)</a> concluded that when a larger, more generalized population of cases is examined, mutations of the WT1 gene are less frequent in IDMS than initial data suggested, and are absent in isolated FSGS. This confirmed the genetic heterogeneity of IDMS and FSGS, despite the uniform renal histologic findings seen throughout this group of conditions. <a href="#40" class="mim-tip-reference" title="Koziell, A. B., Grundy, R., Barratt, T. M., Scambler, P. <strong>Evidence for the genetic heterogeneity of nephropathic phenotypes associated with Denys-Drash and Frasier syndrome. (Letter)</strong> Am. J. Hum. Genet. 64: 1778-1781, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330366</a>] [<a href="https://doi.org/10.1086/302409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330366">Koziell et al. (1999)</a> suggested that IDMS and isolated FSGS may also result from abnormalities of other glomerular genes, perhaps downstream of WT1 and mimicking the effects of WT1 mutations seen in DDS and Frasier syndrome. <a href="#40" class="mim-tip-reference" title="Koziell, A. B., Grundy, R., Barratt, T. M., Scambler, P. <strong>Evidence for the genetic heterogeneity of nephropathic phenotypes associated with Denys-Drash and Frasier syndrome. (Letter)</strong> Am. J. Hum. Genet. 64: 1778-1781, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10330366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10330366</a>] [<a href="https://doi.org/10.1086/302409" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10330366">Koziell et al. (1999)</a> noted that <a href="#38" class="mim-tip-reference" title="Klamt, B., Koziell, A., Poulat, F., Wieacker, P., Scambler, P., Berta, P., Gessler, M. <strong>Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.</strong> Hum. Molec. Genet. 7: 709-714, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499425</a>] [<a href="https://doi.org/10.1093/hmg/7.4.709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499425">Klamt et al. (1998)</a> had observed WT1 mutations in intron 9 in individuals with a 46,XX karyotype who developed nephropathy but no obvious gonadal abnormality. This supported the less critical role of WT1 in female gonadal development, as had been suggested by experimental data (<a href="#56" class="mim-tip-reference" title="Nachtigal, M. W., Hirokawa, Y., Enyeart-VanHouten, D. L., Flanagan, J. N., Hammer, G. D., Ingraham, H. A. <strong>Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.</strong> Cell 93: 445-454, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9590178/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9590178</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81172-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9590178">Nachtigal et al., 1998</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9590178+9499425+10330366" 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="Barbaux, S., Niaudet, P., Gubler, M.-C., Grunfeld, J.-P., Jaubert, F., Kuttenn, F., Fekete, C. N., Souleyreau-Therville, N., Thibaud, E., Fellous, M., McElreavey, K. <strong>Donor splice-site mutations in WT1 are responsible for Frasier syndrome.</strong> Nature Genet. 17: 467-470, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398852</a>] [<a href="https://doi.org/10.1038/ng1297-467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398852">Barbaux et al. (1997)</a> and <a href="#38" class="mim-tip-reference" title="Klamt, B., Koziell, A., Poulat, F., Wieacker, P., Scambler, P., Berta, P., Gessler, M. <strong>Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.</strong> Hum. Molec. Genet. 7: 709-714, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499425</a>] [<a href="https://doi.org/10.1093/hmg/7.4.709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499425">Klamt et al. (1998)</a> had reported a donor splice site mutation in intron 9 (<a href="#0018">607102.0018</a>) of the WT1 gene in patients with Frasier syndrome and concluded that loss of the +KTS (lys-thr-ser) isoform of the WT1 gene was responsible for this syndrome by inducing defective alternative splicing. However, in 2 unrelated patients with Frasier syndrome, <a href="#39" class="mim-tip-reference" title="Kohsaka, T., Tagawa, M., Takekoshi, Y., Yanagisawa, H., Tadokoro, K., Yamada, M. <strong>Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome.</strong> Hum. Mutat. 14: 466-470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10571943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10571943</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(199912)14:6<466::AID-HUMU4>3.0.CO;2-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10571943">Kohsaka et al. (1999)</a> found mutations in the same exon of the WT1 gene as detected in Denys-Drash syndrome with no alteration of the ratio of +/- KTS splice isoforms (see <a href="#0024">607102.0024</a>-<a href="#0025">607102.0025</a>). They suggested that Denys-Drash and Frasier syndromes originate from the same WT1 gene abnormality. They concluded that from a molecular biologic point of view the 2 diseases are not separable and that Frasier syndrome should be considered an atypical form of DDS. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9398852+9499425+10571943" 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="#70" class="mim-tip-reference" title="Royer-Pokora, B., Beier, M., Henzler, M., Alam, R., Schumacher, V., Weirich, A., Huff, V. <strong>Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development.</strong> Am. J. Med. Genet. 127A: 249-257, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15150775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15150775</a>] [<a href="https://doi.org/10.1002/ajmg.a.30015" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15150775">Royer-Pokora et al. (2004)</a> reported 24 new Wilms tumor patients and summarized genotype/phenotype correlations in a total of 282 patients, including 117 with and 165 without WT1 germline mutations. The median age at tumor onset was 12.5 months for those with a mutation and 36 months for those without. The earliest onset was in patients with truncation mutations, followed by those with missense and deletion mutations, with medians of 12 months (66 patients), 18 months (30 patients) and 22 months (21 patients), respectively. Patients with the 2 most frequent nonsense mutations, R362X and R390X, or the Denys-Drash syndrome hotspot mutation, R394W/Q/L, all had very early onset at 9, 12, and 18 months, respectively. Bilateral tumors were most frequently associated with truncation mutations, especially with those occurring in the 5-prime half of the gene. Carriers of a WT1 germline mutation were found to be at risk not only for genital tract anomalies but also for early onset, tumor bilaterality, and early-onset nephrotic syndrome with diffuse mesangial sclerosis and stromal-predominant histology. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15150775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#11" class="mim-tip-reference" title="Dallosso, A. R., Hancock, A. L., Brown, K. W., Williams, A. C., Jackson, S., Malik, K. <strong>Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours.</strong> Hum. Molec. Genet. 13: 405-415, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681303</a>] [<a href="https://doi.org/10.1093/hmg/ddh038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681303">Dallosso et al. (2004)</a> showed that both WT1-AS and AWT1 were imprinted in normal kidney with expression confined to the paternal allele. Wilms tumor samples displayed biallelic AWT1 expression, indicating relaxation of imprinting of AWT1 in a subset of WTs. <a href="#11" class="mim-tip-reference" title="Dallosso, A. R., Hancock, A. L., Brown, K. W., Williams, A. C., Jackson, S., Malik, K. <strong>Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours.</strong> Hum. Molec. Genet. 13: 405-415, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14681303/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14681303</a>] [<a href="https://doi.org/10.1093/hmg/ddh038" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14681303">Dallosso et al. (2004)</a> concluded that human chromosome 11p13 is an imprinted locus, which may suggest a molecular basis for the strong bias of paternal allele mutations and incomplete penetrance observed in syndromes with inherited WT1 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14681303" 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="#68" class="mim-tip-reference" title="Regev, M., Kirk, R., Mashevich, M., Bistritzer, Z., Reish, O. <strong>Vertical transmission of a mutation in exon 1 of the WT1 gene: lessons for genetic counseling.</strong> Am. J. Med. Genet. 146A: 2332-2336, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18688870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18688870</a>] [<a href="https://doi.org/10.1002/ajmg.a.32330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18688870">Regev et al. (2008)</a> reported maternal transmission of a nonsense mutation in the WT1 gene (<a href="#0027">607102.0027</a>). The mother had Wilms tumor in infancy and decreased fertility in adulthood, and her son displayed genitourinary abnormalities, including glanular hypospadias with chordee and bilateral undescended testes, gonadal dysgenesis with gonadoblastoma foci, and intraabdominal Mullerian derivatives. No Wilms tumor was detected in the son up to 6 years of age. The boy also carried 2 additional exon 1 polymorphisms, 17G-T and 390C-T (N130N), presumably transmitted from the paternal allele. <a href="#68" class="mim-tip-reference" title="Regev, M., Kirk, R., Mashevich, M., Bistritzer, Z., Reish, O. <strong>Vertical transmission of a mutation in exon 1 of the WT1 gene: lessons for genetic counseling.</strong> Am. J. Med. Genet. 146A: 2332-2336, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18688870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18688870</a>] [<a href="https://doi.org/10.1002/ajmg.a.32330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18688870">Regev et al. (2008)</a> stated that the nonsense mutation demonstrates the lack of correlation between genotype/phenotype and mutation position in the WT1 gene, the presence of intrafamilial variability, and the effect of gender on severity of genitourinary anomalies. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18688870" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Royer-Pokora, B., Busch, M., Beier, M., Duhme, C., de Torres, C., Mora, J., Brandt, A., Royer, H.-D. <strong>Wilms tumor cells with WT1 mutations have characteristic features of mesenchymal stem cells and express molecular markers of paraxial mesoderm.</strong> Hum. Molec. Genet. 19: 1651-1668, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20106868/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20106868</a>] [<a href="https://doi.org/10.1093/hmg/ddq042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20106868">Royer-Pokora et al. (2010)</a> described the establishment and characterization of long-term cell cultures derived from 5 individual WTs with WT1 mutations. Three of these tumor cell lines also had CTNNB1 (<a href="/entry/116806">116806</a>) mutations and an activated canonic Wnt (<a href="/entry/164820">164820</a>) signaling pathway as measured by beta-catenin/T cell-specific transcription factor transcriptional activity. Four lines showed loss of heterozygosity of chromosome 11p due to mitotic recombination in 11p11. Gene expression profiling revealed that the WT cell lines were highly similar to human mesenchymal stem cells (MSCs), and FACS analysis demonstrated the expression of MSC-specific surface proteins CD105 (ENG; <a href="/entry/131195">131195</a>), CD90 (THY1; <a href="/entry/188230">188230</a>), and CD73 (NT5E; <a href="/entry/129190">129190</a>). The stem cell-like nature of the WT cells was further supported by their adipogenic, chondrogenic, osteogenic, and myogenic differentiation potentials. By generating multipotent mesenchymal precursors from paraxial mesoderm in tissue culture using embryonal stem cells, gene expression profiles of paraxial mesoderm and MSCs were described. Using these published gene sets, the authors found coexpression of a large number of genes in WT cell lines, paraxial mesoderm, and MSCs. Lineage plasticity was indicated by the simultaneous expression of genes from the mesendodermal and neuroectodermal lineages. The authors concluded that WTs with WT1 mutations have specific traits of paraxial mesoderm, which is the source of kidney stromal cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20106868" 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="#35" class="mim-tip-reference" title="Jorgenson, E., Makki, N., Shen, L., Chen, D. C., Tian, C., Eckalbar, W. L., Hinds, D., Ahituv, N., Avins, A. <strong>A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia.</strong> Nature Commun. 6: 10130, 2015. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26686553/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26686553</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26686553[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/ncomms10130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26686553">Jorgenson et al. (2015)</a> showed that WT1 maps to a significant signal in a genomewide association study of susceptibility loci for inguinal hernia. The study included 5,295 cases and 67,510 controls with top associations confirmed in an independent cohort of 9,701 cases and 82,743 controls. The authors showed that WT1 is expressed in mouse connective tissue and, by network analysis, that it is likely to be involved in connective tissue maintenance and homeostasis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26686553" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Alexander, T. B., Gu, Z., Iacobucci, I., Dickerson, K., Choi, J. K., Xu, B., Payne-Turner, D., Yoshihara, H., Loh, M. L., Horan, J., Buldini, B., Basso, G., and 50 others. <strong>The genetic basis and cell of origin of mixed phenotype acute leukaemia.</strong> Nature 562: 373-379, 2018.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30209392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30209392</a>] [<a href="https://doi.org/10.1038/s41586-018-0436-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30209392">Alexander et al. (2018)</a> showed that biallelic WT1 alterations are common in the T-cell/myeloid form of mixed phenotype acute leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30209392" 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 gene targeting in embryonic stem cells, <a href="#41" class="mim-tip-reference" title="Kreidberg, J. A., Sariola, H., Loring, J. M., Maeda, M., Pelletier, J., Housman, D., Jaenisch, R. <strong>WT-1 is required for early kidney development.</strong> Cell 74: 679-691, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8395349/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8395349</a>] [<a href="https://doi.org/10.1016/0092-8674(93)90515-r" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8395349">Kreidberg et al. (1993)</a> introduced a mutation into the murine WT1 tumor suppressor gene. The mutation resulted in embryonic lethality in homozygotes, and examination of mutant embryos demonstrated a failure of kidney and gonad development. Specifically, at day 11 of gestation, the cells of the metanephric blastema underwent apoptosis, the ureteric bud failed to grow out from the wolffian duct, and the inductive events that lead to formation of the metanephric kidney did not occur. In addition, the mutation caused abnormal development of the mesothelium, heart, and lungs. The results established a crucial role for WT1 in early urogenital development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8395349" 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="#63" class="mim-tip-reference" title="Patek, C. E., Little, M. H., Fleming, S., Miles, C., Charlieu, J.-P., Clarke, A. R., Miyagawa, K., Christie, S., Doig, J., Harrison, D. J., Porteous, D. J., Brookes, A. J., Hooper, M. L., Hastie, N. D. <strong>A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome.</strong> Proc. Nat. Acad. Sci. 96: 2931-2936, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077614</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10077614[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.6.2931" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10077614">Patek et al. (1999)</a> reported that heterozygosity for a targeted murine Wt1 allele, which truncates zinc finger-3 at codon 396, induced mesangial sclerosis characteristic of Denys-Drash syndrome in adult heterozygous and chimeric mice. Male genital defects were also evident, and there was a single case of Wilms tumor in which the transcript of the nontargeted allele showed an exon 9 skipping event, implying a causal link between Wt1 dysfunction and Wilms tumorigenesis in mice. However, the mutant protein with the truncation at codon 396 accounted for only 5% of Wt1 protein in both heterozygous embryonic stem cells and the Wilms tumor. This has implications regarding the mechanism by which the mutant allele exerts its effect. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10077614" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Hammes, A., Guo, J.-K., Lutsch, G., Leheste, J.-R., Landrock, D., Ziegler, U., Gubler, M.-C., Schedl, A. <strong>Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation.</strong> Cell 106: 319-329, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11509181/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11509181</a>] [<a href="https://doi.org/10.1016/s0092-8674(01)00453-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11509181">Hammes et al. (2001)</a> generated mouse strains in which specific isoforms of Wt1 had been removed. Heterozygous mice with a reduction of +KTS levels developed glomerulosclerosis and represented a model for Frasier syndrome. Homozygous mutants of both strains died after birth due to kidney defects. Mice lacking +KTS isoforms showed a complete XY sex reversal due to a dramatic reduction of Sry expression levels. These data demonstrated distinct functions for the KTS splice variants and placed the +KTS variants as important regulators for SRY in the sex determination pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11509181" 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="#57" class="mim-tip-reference" title="Natoli, T. A., McDonald, A., Alberta, J. A., Taglienti, M. E., Housman, D. E., Kreidberg, J. A. <strong>A mammal-specific exon of WT1 is not required for development or fertility.</strong> Molec. Cell. Biol. 22: 4433-4438, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12024052/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12024052</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12024052[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.22.12.4433-4438.2002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12024052">Natoli et al. (2002)</a> noted that inclusion of a 17-amino acid stretch encoded by exon 5 of WT1 is found only in placental mammals. By gene targeting, they specifically eliminated this exon in mice and found that the homozygous mice are viable and develop normally. All of the mice are fertile and females are capable of lactation. No defects were found in the kidneys, testes, ovaries, oviducts, or uteri. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12024052" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#78" class="mim-tip-reference" title="Wagner, K. D., Wagner, N., Vidal, V. P. I., Schley, G., Wilhelm, D., Schedl, A., Englert, C., Scholz, H. <strong>The Wilms' tumor gene Wt1 is required for normal development of the retina.</strong> EMBO J. 21: 1398-1405, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11889045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11889045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11889045[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/21.6.1398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11889045">Wagner et al. (2002)</a> found expression of WT1 in the presumptive retinal ganglion cell layer of an autopsied human embryo at 19 weeks of gestation. In mice, they found evidence that disruption of WT1 can lead to retinal abnormalities. In normal mice, Wt1 was distributed throughout the neural retina and in the developing lens vesicle of 12-day embryos (E12). Expression became restricted to the presumptive retinal ganglion cell layer and was absent from adult retinas. <a href="#78" class="mim-tip-reference" title="Wagner, K. D., Wagner, N., Vidal, V. P. I., Schley, G., Wilhelm, D., Schedl, A., Englert, C., Scholz, H. <strong>The Wilms' tumor gene Wt1 is required for normal development of the retina.</strong> EMBO J. 21: 1398-1405, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11889045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11889045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11889045[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/21.6.1398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11889045">Wagner et al. (2002)</a> developed Wt1-null mice in a strain that allows embryo survival; at E12, these embryos showed markedly thinner neural retinas and significantly fewer cells, and at E18, their eyes were notably reduced in size and ganglion cells were lost by apoptosis. <a href="#78" class="mim-tip-reference" title="Wagner, K. D., Wagner, N., Vidal, V. P. I., Schley, G., Wilhelm, D., Schedl, A., Englert, C., Scholz, H. <strong>The Wilms' tumor gene Wt1 is required for normal development of the retina.</strong> EMBO J. 21: 1398-1405, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11889045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11889045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11889045[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/21.6.1398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11889045">Wagner et al. (2002)</a> found that Wt1 specifically activates the expression of Pou4f2 (<a href="/entry/113725">113725</a>) and not that of other POU-domain members. Pou4f2 immunoreactivity was detected in the developing ganglion cell layer of normal E18 mice, but not in the retina of Wt1-null mice. <a href="#78" class="mim-tip-reference" title="Wagner, K. D., Wagner, N., Vidal, V. P. I., Schley, G., Wilhelm, D., Schedl, A., Englert, C., Scholz, H. <strong>The Wilms' tumor gene Wt1 is required for normal development of the retina.</strong> EMBO J. 21: 1398-1405, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11889045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11889045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11889045[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/emboj/21.6.1398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11889045">Wagner et al. (2002)</a> verified direct and specific activation of Pou4f2 by Wt1 in transfection studies. Expression of the -KTS, but not the +KTS, isoform of Wt1 in human embryonic kidney cells caused an 8-fold increase in Pou4f2 mRNA levels. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11889045" 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 transgenic mice, <a href="#80" class="mim-tip-reference" title="Wilhelm, D., Englert, C. <strong>The Wilms tumor suppressor WT1 regulates early gonadal development by activation of Sf1.</strong> Genes Dev. 16: 1839-1851, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12130543[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/10.1101/gad.220102" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12130543">Wilhelm and Englert (2002)</a> showed that Wt1(-KTS) binds to 4 promoter sequences of the Sf1 gene (<a href="/entry/184757">184757</a>) and that Wt1(-KTS) and Lhx9 (<a href="/entry/606066">606066</a>) have an additive effect in activating the Sf1 promoter. Wt1 was also shown to regulate Dax1 (<a href="/entry/300200">300200</a>) activity in vivo. Gonad development and Dax1 and Sf1 expression were absent in Wt1 mutant mouse embryos. Thus, Wt1 regulates multiple genes involved in urogenital development and may act as a repressor or an activator. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12130543" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By combining Wt1-knockout and inducible yeast artificial chromosome transgenic mouse models, <a href="#23" class="mim-tip-reference" title="Guo, J.-K., Menke, A. L., Gubler, M.-C., Clarke, A. R., Harrison, D., Hammes, A., Hastie, N. D., Schedl, A. <strong>WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis.</strong> Hum. Molec. Genet. 11: 651-659, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11912180/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11912180</a>] [<a href="https://doi.org/10.1093/hmg/11.6.651" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11912180">Guo et al. (2002)</a> demonstrated that reduced expression levels of WT1 resulted in either crescentic glomerulonephritis or mesangial sclerosis, depending on the gene dosage. The 2 podocyte-specific genes, nephrin (<a href="/entry/602716">602716</a>) and podocalyxin (see <a href="/entry/602632">602632</a>), were downregulated in mice with decreased levels of Wt1, suggesting that these 2 genes may act downstream of Wt1. The authors hypothesized that reduced levels of Wt1 may be responsible for the pathogenesis of 2 distinct renal diseases, and may explain the increased occurrence of glomerulosclerosis in patients with WAGR syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11912180" 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="#63" class="mim-tip-reference" title="Patek, C. E., Little, M. H., Fleming, S., Miles, C., Charlieu, J.-P., Clarke, A. R., Miyagawa, K., Christie, S., Doig, J., Harrison, D. J., Porteous, D. J., Brookes, A. J., Hooper, M. L., Hastie, N. D. <strong>A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome.</strong> Proc. Nat. Acad. Sci. 96: 2931-2936, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10077614/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10077614</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10077614[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.96.6.2931" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10077614">Patek et al. (1999)</a> reported that heterozygosity for the Wt1(tmT396) mutation induced Denys-Drash syndrome in heterozygous and chimeric mice. <a href="#62" class="mim-tip-reference" title="Patek, C. E., Fleming, S., Miles, C. G., Bellamy, C. O., Ladomery, M., Spraggon, L., Mullins, J., Hastie, N. D., Hooper, M. L. <strong>Murine Denys-Drash syndrome: evidence of podocyte de-differentiation and systemic mediation of glomerulosclerosis.</strong> Hum. Molec. Genet. 12: 2379-2394, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12915483/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12915483</a>] [<a href="https://doi.org/10.1093/hmg/ddg240" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12915483">Patek et al. (2003)</a> further showed that Wt1 mutant cells colonized glomeruli efficiently, including podocytes, but some sclerotic glomeruli contained no detectable Wt1 mutant cells. The development of glomerulosclerosis was preceded by widespread loss of Zo1 (<a href="/entry/601009">601009</a>) signal in podocytes, increased intrarenal renin (<a href="/entry/179820">179820</a>) expression, and de novo podocyte TGF-beta-1 (<a href="/entry/190180">190180</a>) expression, but not podocyte Pax2 expression or loss of Wt1, synaptopodin (<a href="/entry/608155">608155</a>), alpha-actinin-4 (<a href="/entry/604638">604638</a>), or nephrin expression. However, podocytes in partially sclerotic glomeruli that still expressed WT1 at high levels showed reduced vimentin (<a href="/entry/193060">193060</a>) expression, cell cycle reentry, and reexpressed desmin (<a href="/entry/125660">125660</a>), cytokeratin (<a href="/entry/139350">139350</a>), and Pax2. The authors suggested that: (i) glomerulosclerosis may not be due to loss of WT1 expression by podocytes; (ii) podocyte PAX2 expression may reflect reexpression rather than persistent expression, and may be the consequence of glomerulosclerosis; (iii) glomerulosclerosis may be mediated systemically and the mechanism may involve activation of the renin-angiotensin system; and (iv) podocytes may undergo typical maturational changes but subsequently dedifferentiate and revert to an immature phenotype during disease progression. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10077614+12915483" 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="Gao, F., Maiti, S., Alam, N., Zhang, Z., Deng, J. M., Behringer, R. R., Lecureuil, C., Guillou, F., Huff, V. <strong>The Wilms tumor gene, Wt1, is required for Sox9 expression and maintenance of tubular architecture in the developing testis.</strong> Proc. Nat. Acad. Sci. 103: 11987-11992, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16877546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16877546</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16877546[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600994103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16877546">Gao et al. (2006)</a> created a mouse strain carrying a Wt1 conditional knockout allele that ablated Wt1 function specifically in Sertoli cells by embryonic day 14.5, several days after testis determination. Wt1 knockout disrupted development of seminiferous tubules, and there was progressive loss of Sertoli cells and germ cells, resulting in severe hypoplasia. The expression of Sox9 (<a href="/entry/608160">608160</a>) in mutant Sertoli cells was turned off at embryonic day 14.5 after Wt1 ablation. <a href="#19" class="mim-tip-reference" title="Gao, F., Maiti, S., Alam, N., Zhang, Z., Deng, J. M., Behringer, R. R., Lecureuil, C., Guillou, F., Huff, V. <strong>The Wilms tumor gene, Wt1, is required for Sox9 expression and maintenance of tubular architecture in the developing testis.</strong> Proc. Nat. Acad. Sci. 103: 11987-11992, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16877546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16877546</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16877546[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.0600994103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16877546">Gao et al. (2006)</a> concluded that Wt1 is essential at multiple steps in testicular development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16877546" 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>Defects in WT1 are thought to modify the crosstalk between podocytes and other glomerular cells and ultimately lead to glomerular sclerosis, as observed in diffuse mesangial sclerosis (DMS). To identify podocyte WT1 targets, <a href="#67" class="mim-tip-reference" title="Ratelade, J., Arrondel, C., Hamard, G., Garbay, S., Harvey, S., Biebuyck, N., Schulz, H., Hastie, N., Pontoglio, M., Gubler, M.-C., Antignac, C., Heidet, L. <strong>A murine model of Denys-Drash syndrome reveals novel transcriptional targets of WT1 in podocytes.</strong> Hum. Molec. Genet. 19: 1-15, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19797313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19797313</a>] [<a href="https://doi.org/10.1093/hmg/ddp462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19797313">Ratelade et al. (2010)</a> generated a novel DMS mouse line, performed gene expression profiling in isolated glomeruli, and identified candidates that may modify podocyte differentiation and growth factor signaling in glomeruli. Sciellin (SCEL; <a href="/entry/604112">604112</a>) and Sulf1 (<a href="/entry/610012">610012</a>), which encodes a 6-O-endosulfatase, were expressed in wildtype podocytes and strongly downregulated in mutants. Coexpression of Wt1, Scel, and Sulf1 was found in a mesonephric cell line, and siRNA-mediated knockdown of WT1 decreased Scel and Sulf1 mRNAs and proteins. ChIP assay showed that Scel and Sulf1 were direct WT1 targets. Cyp26a1 (<a href="/entry/602239">602239</a>), encoding an enzyme involved in the degradation of retinoic acid, was upregulated in mutant podocytes. <a href="#67" class="mim-tip-reference" title="Ratelade, J., Arrondel, C., Hamard, G., Garbay, S., Harvey, S., Biebuyck, N., Schulz, H., Hastie, N., Pontoglio, M., Gubler, M.-C., Antignac, C., Heidet, L. <strong>A murine model of Denys-Drash syndrome reveals novel transcriptional targets of WT1 in podocytes.</strong> Hum. Molec. Genet. 19: 1-15, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19797313/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19797313</a>] [<a href="https://doi.org/10.1093/hmg/ddp462" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19797313">Ratelade et al. (2010)</a> noted that CYP26A1 may play a role in the development of glomerular lesions but does not seem to be regulated by WT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19797313" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#51" class="mim-tip-reference" title="Martinez-Estrada, O. M., Lettice, L. A., Essafi, A., Guadix, J. A., Slight, J., Velecela, V., Hall, E., Reichmann, J., Devenney, P. S., Hohenstein, P., Hosen, N., Hill, R. E., Munoz-Chapuli, R., Hastie, N. D. <strong>Wt1 is required for cardiovascular progenitor cell formation through transcriptional control of Snail and E-cadherin.</strong> Nature Genet. 42: 89-93, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20023660/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20023660</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20023660[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.494" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20023660">Martinez-Estrada et al. (2010)</a> found that epicardial-specific knockout of Wt1 in mice led to embryonic lethality due to cardiovascular failure. Mutant hearts showed reduced numbers of mesenchymal progenitor cells and their derivatives. This effect was due to derepression of the epithelial phenotype in epicardial cells and during embryonic stem cell differentiation. Mutant hearts showed reduced expression of the epithelial-mesenchymal transition regulator Snai1 (<a href="/entry/604238">604238</a>) and upregulation of the epithelial marker Cdh1 (<a href="/entry/192090">192090</a>). Some mesodermal lineages did not form in Wt1-null embryoid bodies, but this effect was rescued by expression of Snai1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20023660" 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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<p>In a patient with bilateral Wilms tumor (<a href="/entry/194070">194070</a>), hypospadias, and undescended left testis, <a href="#65" class="mim-tip-reference" title="Pelletier, J., Bruening, W., Li, F. P., Haber, D. A., Glaser, T., Housman, D. E. <strong>WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour.</strong> Nature 353: 431-434, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1654525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1654525</a>] [<a href="https://doi.org/10.1038/353431a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1654525">Pelletier et al. (1991)</a> identified heterozygosity for a 17-bp deletion in exon 4 of the WT1 gene. The deletion occurred between 2 copies of the pentanucleotide sequence TGACA. The mutation appeared to be the consequence of either polymerase skipping during DNA replication or an unequal crossover event. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1654525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776574 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776574;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=rs587776574" 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=rs587776574" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#65" class="mim-tip-reference" title="Pelletier, J., Bruening, W., Li, F. P., Haber, D. A., Glaser, T., Housman, D. E. <strong>WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour.</strong> Nature 353: 431-434, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1654525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1654525</a>] [<a href="https://doi.org/10.1038/353431a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1654525">Pelletier et al. (1991)</a> reported a father and son with Wilms tumor (<a href="/entry/194070">194070</a>) who were found by single-strand conformation polymorphism (SCCP) analysis to have a single nucleotide deletion, a guanosine, in exon 6 of the WT1 gene, predicted to cause a frameshift and early termination of translation. The son was born with hypospadias and bilateral cryptorchidism and developed Wilms tumor at age 3 years. The father had been treated successfully for Wilms tumor. This was probably the first documentation of a transmitted WT1 mutation in familial Wilms tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1654525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003656 OR RCV000003657 OR RCV000003658 OR RCV000467701 OR RCV000484426 OR RCV001003819 OR RCV001290016 OR RCV002293973 OR RCV004739285 OR RCV005003322" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003656, RCV000003657, RCV000003658, RCV000467701, RCV000484426, RCV001003819, RCV001290016, RCV002293973, RCV004739285, RCV005003322" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003656...</a>
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<p>In 7 unrelated patients with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), <a href="#64" class="mim-tip-reference" title="Pelletier, J., Bruening, W., Kashtan, C. E., Mauer, S. M., Manivel, J. C., Striegel, J. E., Houghton, D. C., Junien, C., Habib, R., Fouser, L., Fine, R. N., Silverman, B. L., Haber, D. A., Housman, D. <strong>Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.</strong> Cell 67: 437-447, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1655284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1655284</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90194-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1655284">Pelletier et al. (1991)</a> identified a 1180C-T transition in exon 9 of the WT1 gene, resulting in an arg394-to-trp (R394W) substitution in zinc finger-3. Most had the classic triad of pseudohermaphroditism, Wilms tumor, and nephrotic syndrome. Wilms tumors from 3 individuals and 1 juvenile granulosa cell tumor demonstrated reduction to homozygosity for the mutated WT1 allele. In vitro functional expression studies showed that the mutant WT1 protein was unable to bind DNA sequences. The findings indicated a dominant-negative mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1655284" 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="Bruening, W., Bardeesy, N., Silverman, B. L., Cohn, R. A., Machin, G. A., Aronson, A. J., Housman, D., Pelletier, J. <strong>Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development.</strong> Nature Genet. 1: 144-148, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302008</a>] [<a href="https://doi.org/10.1038/ng0592-144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302008">Bruening et al. (1992)</a> identified the R394W mutation in a 46,XY individual with Drash syndrome reported by <a href="#52" class="mim-tip-reference" title="McCoy, F. E., Jr., Franklin, W. A., Aronson, A. J., Spargo, B. H. <strong>Glomerulonephritis associated with male pseudohermaphroditism and nephroblastoma.</strong> Am. J. Surg. Path. 7: 387-395, 1983.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/6307071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">6307071</a>] [<a href="https://doi.org/10.1097/00000478-198306000-00011" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="6307071">McCoy et al. (1983)</a>. The patient had ambiguous genitalia, rudimentary uterus, fimbriated fallopian tubes, and streak gonads. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1302008+6307071" 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="Baird, P. N., Santos, A., Groves, N., Jadresic, L., Cowell, J. K. <strong>Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome.</strong> Hum. Molec. Genet. 1: 301-305, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1338906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1338906</a>] [<a href="https://doi.org/10.1093/hmg/1.5.301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1338906">Baird et al. (1992)</a> found the R394W mutation in 3 of 8 patients with Denys-Drash syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1338906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Coppes, M. J., Liefers, G. J., Higuchi, M., Zinn, A. B., Balfe, J. W., Williams, B. R. G. <strong>Inherited WT1 mutation in Denys-Drash syndrome.</strong> Cancer Res. 52: 6125-6128, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1327525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1327525</a>]" pmid="1327525">Coppes et al. (1992)</a> identified the R394W mutation in 2 of 3 patients with Denys-Drash syndrome. Unlike patients in previous reports, 1 of the patients inherited the mutant allele from his phenotypically unaffected father. The father had no abnormalities and, in particular, he had bilaterally descended testes of normal volume and a normal penis without hypospadias. He had donated his kidney for transplantation to his son with Denys-Drash syndrome. <a href="#47" class="mim-tip-reference" title="Little, M. H., Williamson, K. A., Mannens, M., Kelsey, A., Gosden, C., Hastie, N. D., van Heyningen, V. <strong>Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion.</strong> Hum. Molec. Genet. 2: 259-264, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388765</a>] [<a href="https://doi.org/10.1093/hmg/2.3.259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8388765">Little et al. (1993)</a> reported the same mutation in Denys-Drash syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1327525+8388765" 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="#74" class="mim-tip-reference" title="Schumacher, V., Scharer, K., Wuhl, E., Altrogge, H., Bonzel, K.-E., Guschmann, M., Neuhaus, T. J., Pollastro, R. M., Kuwertz-Broking, E., Bulla, M., Tondera, A.-M., Mundel, P., Helmchen, U., Waldherr, R., Weirich, A., Royer-Pokora, B. <strong>Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations.</strong> Kidney Int. 53: 1594-1600, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9607189/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9607189</a>] [<a href="https://doi.org/10.1046/j.1523-1755.1998.00948.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9607189">Schumacher et al. (1998)</a> identified the R394W mutation in 4 unrelated patients with early-onset nephrotic syndrome. Two of the patients had complete Denys-Drash syndrome, 1 had incomplete Denys-Drash syndrome without urogenital anomalies but with Wilms tumor, and the fourth had nephrotic syndrome type 4 (NPHS4; <a href="/entry/256370">256370</a>) without urogenital anomalies or Wilms tumor. Renal biopsies showed diffuse mesangial sclerosis in 3 patients and focal segmental glomerulosclerosis in 1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9607189" 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="#77" class="mim-tip-reference" title="Suri, M., Kelehan, P., O'Neill, D., Vadeyar, S., Grant, J., Ahmed, S. F., Tolmie, J., McCann, E., Lam, W., Smith, S., FitzPatrick, D., Hastie, N. D., Reardon, W. <strong>WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations.</strong> Am. J. Med. Genet. 143A: 2312-2320, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17853480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17853480</a>] [<a href="https://doi.org/10.1002/ajmg.a.31924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17853480">Suri et al. (2007)</a> identified a hemizygous R394W mutation in a patient with Meacham syndrome (<a href="/entry/608978">608978</a>). This 46,XY infant was born with ambiguous external genitalia, a single testis, and congenital diaphragmatic hernia. He showed unusually long survival, with death at age 3 years. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17853480" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907901 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907901;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=rs121907901" 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=rs121907901" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), <a href="#64" class="mim-tip-reference" title="Pelletier, J., Bruening, W., Kashtan, C. E., Mauer, S. M., Manivel, J. C., Striegel, J. E., Houghton, D. C., Junien, C., Habib, R., Fouser, L., Fine, R. N., Silverman, B. L., Haber, D. A., Housman, D. <strong>Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.</strong> Cell 67: 437-447, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1655284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1655284</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90194-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1655284">Pelletier et al. (1991)</a> identified a G-to-A transition in exon 8 of the WT1 gene, resulting in an arg366-to-his (R366H) substitution in the second zinc finger domain. The same mutation was observed by <a href="#3" class="mim-tip-reference" title="Baird, P. N., Santos, A., Groves, N., Jadresic, L., Cowell, J. K. <strong>Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome.</strong> Hum. Molec. Genet. 1: 301-305, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1338906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1338906</a>] [<a href="https://doi.org/10.1093/hmg/1.5.301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1338906">Baird et al. (1992)</a> in a patient with Denys-Drash syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1655284+1338906" 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="Antonius, T., van Bon, B., Eggink, A., van der Burgt, I., Noordam, K., van Heijst, A. <strong>Denys-Drash syndrome and congenital diaphragmatic hernia: another case with the 1097G-A (arg366his) mutation.</strong> Am. J. Med. Genet. 146A: 496-499, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18203154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18203154</a>] [<a href="https://doi.org/10.1002/ajmg.a.32168" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18203154">Antonius et al. (2008)</a> reported another patient with Denys-Drash syndrome and a heterozygous R366H substitution. The authors stated that 10 DDS patients had been reported with this specific mutation, and noted that their patient was the third reported patient with DDS and congenital diaphragmatic hernia associated with the R366H mutation. A mutation in this same codon (R366C; <a href="#0026">607102.0026</a>) has been identified in a patient with Meacham syndrome (<a href="/entry/608978">608978</a>) and diaphragmatic hernia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18203154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907902 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907902;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=rs121907902" 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=rs121907902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a patient with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), <a href="#64" class="mim-tip-reference" title="Pelletier, J., Bruening, W., Kashtan, C. E., Mauer, S. M., Manivel, J. C., Striegel, J. E., Houghton, D. C., Junien, C., Habib, R., Fouser, L., Fine, R. N., Silverman, B. L., Haber, D. A., Housman, D. <strong>Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.</strong> Cell 67: 437-447, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1655284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1655284</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90194-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1655284">Pelletier et al. (1991)</a> identified a mutation in the WT1 gene, resulting in an asp396-to-gly (D396G) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1655284" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28941778 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28941778;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/rs28941778?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=rs28941778" 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=rs28941778" 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=RCV000003661 OR RCV000003662 OR RCV003322746" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003661, RCV000003662, RCV003322746" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003661...</a>
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<p>In a patient with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), <a href="#64" class="mim-tip-reference" title="Pelletier, J., Bruening, W., Kashtan, C. E., Mauer, S. M., Manivel, J. C., Striegel, J. E., Houghton, D. C., Junien, C., Habib, R., Fouser, L., Fine, R. N., Silverman, B. L., Haber, D. A., Housman, D. <strong>Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.</strong> Cell 67: 437-447, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1655284/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1655284</a>] [<a href="https://doi.org/10.1016/0092-8674(91)90194-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1655284">Pelletier et al. (1991)</a> identified a 1186G-A transition in the WT1 gene, resulting in an asp396-to-asn (D396N) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1655284" 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="Baird, P. N., Santos, A., Groves, N., Jadresic, L., Cowell, J. K. <strong>Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome.</strong> Hum. Molec. Genet. 1: 301-305, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1338906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1338906</a>] [<a href="https://doi.org/10.1093/hmg/1.5.301" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1338906">Baird et al. (1992)</a> and <a href="#47" class="mim-tip-reference" title="Little, M. H., Williamson, K. A., Mannens, M., Kelsey, A., Gosden, C., Hastie, N. D., van Heyningen, V. <strong>Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion.</strong> Hum. Molec. Genet. 2: 259-264, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388765</a>] [<a href="https://doi.org/10.1093/hmg/2.3.259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8388765">Little et al. (1993)</a> identified the D396N mutation in patients with Denys-Drash syndrome. Wilms tumor tissue derived from the patient reported by <a href="#47" class="mim-tip-reference" title="Little, M. H., Williamson, K. A., Mannens, M., Kelsey, A., Gosden, C., Hastie, N. D., van Heyningen, V. <strong>Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion.</strong> Hum. Molec. Genet. 2: 259-264, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388765</a>] [<a href="https://doi.org/10.1093/hmg/2.3.259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8388765">Little et al. (1993)</a> showed complete loss of WT1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1338906+8388765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 46,XX female with normal external genitalia and nephrotic syndrome (NPHS4; <a href="/entry/256370">256370</a>), <a href="#33" class="mim-tip-reference" title="Jeanpierre, C., Denamur, E., Henry, I., Cabanis, M.-O., Luce, S., Cecille, A., Elion, J., Peuchmaur, M., Loirat, C., Niaudet, P., Gubler, M.-C., Junien, C. <strong>Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.</strong> Am. J. Hum. Genet. 62: 824-833, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529364</a>] [<a href="https://doi.org/10.1086/301806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529364">Jeanpierre et al. (1998)</a> identified heterozygosity for the 1186G-A transition in exon 9 of the WT1 gene, leading to the D396N substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907903 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907903;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=rs121907903" 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=rs121907903" 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=RCV000003663 OR RCV004547456" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003663, RCV004547456" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003663...</a>
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<p>In a patient with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), <a href="#6" class="mim-tip-reference" title="Bruening, W., Bardeesy, N., Silverman, B. L., Cohn, R. A., Machin, G. A., Aronson, A. J., Housman, D., Pelletier, J. <strong>Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development.</strong> Nature Genet. 1: 144-148, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302008</a>] [<a href="https://doi.org/10.1038/ng0592-144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302008">Bruening et al. (1992)</a> identified a G-to-C transversion in exon 9 of the WT1 gene, resulting in an arg394-to-pro (R394P) substitution. Although genomic DNA from this patient was available only from a Wilms tumor specimen embedded in paraffin, <a href="#6" class="mim-tip-reference" title="Bruening, W., Bardeesy, N., Silverman, B. L., Cohn, R. A., Machin, G. A., Aronson, A. J., Housman, D., Pelletier, J. <strong>Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development.</strong> Nature Genet. 1: 144-148, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302008</a>] [<a href="https://doi.org/10.1038/ng0592-144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302008">Bruening et al. (1992)</a> suspected that the patient was germline hemizygous for this mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907904 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907904;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=rs121907904" 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=rs121907904" 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=RCV000003664" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003664" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003664</a>
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<p>In a patient with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), <a href="#6" class="mim-tip-reference" title="Bruening, W., Bardeesy, N., Silverman, B. L., Cohn, R. A., Machin, G. A., Aronson, A. J., Housman, D., Pelletier, J. <strong>Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development.</strong> Nature Genet. 1: 144-148, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302008</a>] [<a href="https://doi.org/10.1038/ng0592-144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302008">Bruening et al. (1992)</a> identified a point mutation in exon 7 of the WT1 gene, resulting in a cys330-to-tyr (C330Y) substitution in zinc finger-1. The patient had a 46,XX karyotype and mild clitoromegaly. Nephropathy was present and both kidneys showed extensive intralobar persistent renal blastema but no overt Wilms tumor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302008" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776576 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776576;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=rs587776576" 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=rs587776576" 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=RCV000003665 OR RCV000030876 OR RCV000208283 OR RCV000589623 OR RCV000705142 OR RCV001288155 OR RCV001290018 OR RCV004547457 OR RCV005003323" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003665, RCV000030876, RCV000208283, RCV000589623, RCV000705142, RCV001288155, RCV001290018, RCV004547457, RCV005003323" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003665...</a>
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<p>In a patient with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), with renal failure due to glomerular sclerosis associated with female external genitalia and a 46,XY karyotype, <a href="#6" class="mim-tip-reference" title="Bruening, W., Bardeesy, N., Silverman, B. L., Cohn, R. A., Machin, G. A., Aronson, A. J., Housman, D., Pelletier, J. <strong>Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development.</strong> Nature Genet. 1: 144-148, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302008</a>] [<a href="https://doi.org/10.1038/ng0592-144" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1302008">Bruening et al. (1992)</a> identified a G-to-A transition at position +5 of the splice donor site within intron 9. It appeared that the mutation affected the alternative splice site selection at exon 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302008" 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>.0010 WILMS TUMOR 1</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">rs121907909 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907909;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=rs121907909" 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=rs121907909" 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=RCV000003666 OR RCV000030877 OR RCV000471023 OR RCV000521800 OR RCV002293974 OR RCV005003324" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003666, RCV000030877, RCV000471023, RCV000521800, RCV002293974, RCV005003324" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003666...</a>
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<p>In an infant who presented with simultaneous bilateral Wilms tumor (<a href="/entry/194070">194070</a>) at the age of 11 months, <a href="#46" class="mim-tip-reference" title="Little, M. H., Prosser, J., Condie, A., Smith, P. J., Van Heyningen, V., Hastie, N. D. <strong>Zinc finger point mutations within the WT1 gene in Wilms tumor patients.</strong> Proc. Nat. Acad. Sci. 89: 4791-4795, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1317572/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1317572</a>] [<a href="https://doi.org/10.1073/pnas.89.11.4791" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1317572">Little et al. (1992)</a> found a point mutation at a CpG dinucleotide in zinc finger-3, changing a C to a T and resulting in an arginine becoming a stop codon. The mutation was detected constitutionally in both tumors of the patient. It was present in heterozygous state in 1 tumor and in somatic cells, whereas due to hemizygosity, the other tumor carried only the mutant allele. Neither parent carried the mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1317572" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a patient with Wilms tumor, <a href="#75" class="mim-tip-reference" title="Schumacher, V., Schneider, S., Figge, A., Wildhardt, G., Harms, D., Schmidt, D., Weirich, A., Ludwig, R., Royer-Pokora, B. <strong>Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant history.</strong> Proc. Nat. Acad. Sci. 94: 3972-3977, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9108089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9108089</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9108089[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.8.3972" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9108089">Schumacher et al. (1997)</a> identified a 1546C-T transition in the WT1 gene, resulting in an arg390-to-ter (R390X) substitution. They stated that this mutation had previously been identified by <a href="#45" class="mim-tip-reference" title="Little, M. H., Dunn, R., Byrne, J. A., Seawright, A., Smith, P. J., Pritchard-Jones, K., van Heyningen, V., Hastie, H. D. <strong>Equivalent expression of paternally and maternally inherited WT1 alleles in normal fetal tissue and Wilms' tumours.</strong> Oncogene 7: 635-641, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1314367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1314367</a>]" pmid="1314367">Little et al. (1992)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1314367+9108089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), <a href="#10" class="mim-tip-reference" title="Coppes, M. J., Liefers, G. J., Higuchi, M., Zinn, A. B., Balfe, J. W., Williams, B. R. G. <strong>Inherited WT1 mutation in Denys-Drash syndrome.</strong> Cancer Res. 52: 6125-6128, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1327525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1327525</a>]" pmid="1327525">Coppes et al. (1992)</a> found a 1129C-T transition in exon 8 of the WT1 gene, resulting in a his377-to-tyr (H377Y) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1327525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 46,XX female with normal external genitalia and normal puberty associated with nephrotic syndrome (NPHS4; <a href="/entry/256370">256370</a>), <a href="#33" class="mim-tip-reference" title="Jeanpierre, C., Denamur, E., Henry, I., Cabanis, M.-O., Luce, S., Cecille, A., Elion, J., Peuchmaur, M., Loirat, C., Niaudet, P., Gubler, M.-C., Junien, C. <strong>Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.</strong> Am. J. Hum. Genet. 62: 824-833, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529364</a>] [<a href="https://doi.org/10.1086/301806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529364">Jeanpierre et al. (1998)</a> identified heterozygosity for the H377Y mutation in the WT1 gene. The first symptoms occurred at the age of 6 months; end-stage renal failure was present by age 3 years and 10 months. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a patient with unilateral Wilms tumor and nephropathy consistent with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), <a href="#47" class="mim-tip-reference" title="Little, M. H., Williamson, K. A., Mannens, M., Kelsey, A., Gosden, C., Hastie, N. D., van Heyningen, V. <strong>Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion.</strong> Hum. Molec. Genet. 2: 259-264, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388765</a>] [<a href="https://doi.org/10.1093/hmg/2.3.259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8388765">Little et al. (1993)</a> identified a T-to-G transversion in the WT1 gene, resulting in a cys360-to-gly (C360G) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8388765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In a 46,XY patient with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), <a href="#47" class="mim-tip-reference" title="Little, M. H., Williamson, K. A., Mannens, M., Kelsey, A., Gosden, C., Hastie, N. D., van Heyningen, V. <strong>Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion.</strong> Hum. Molec. Genet. 2: 259-264, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388765</a>] [<a href="https://doi.org/10.1093/hmg/2.3.259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8388765">Little et al. (1993)</a> identified a C-to-T transition in the WT1 gene, resulting in an arg362-to-ter (R362X) substitution. It was present in heterozygous state in the germline and homozygous state in the tumors. Since the mutation affected zinc finger-2, resulting in a truncated protein interfering with DNA binding, <a href="#47" class="mim-tip-reference" title="Little, M. H., Williamson, K. A., Mannens, M., Kelsey, A., Gosden, C., Hastie, N. D., van Heyningen, V. <strong>Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion.</strong> Hum. Molec. Genet. 2: 259-264, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388765</a>] [<a href="https://doi.org/10.1093/hmg/2.3.259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8388765">Little et al. (1993)</a> suggested that missense mutations in this region operate by a dominant-negative mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8388765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Kaplinsky, C., Ghahremani, M., Frishberg, Y., Rechavi, G., Pelletier, J. <strong>Familial Wilms' tumor associated with a WT1 zinc finger mutation.</strong> Genomics 38: 451-453, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8975729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8975729</a>] [<a href="https://doi.org/10.1006/geno.1996.0655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8975729">Kaplinsky et al. (1996)</a> identified a nonsense mutation in the WT1 gene in the Wilms tumor (<a href="/entry/194070">194070</a>) of 3 sisters who had the same father but 2 different mothers: a C-to-T transition at nucleotide 1084 (relative to the A of the ATG initiation codon) resulted in an arg362-to-ter substitution within zinc finger-2. The mutation was predicted to result in the production of a truncated WT1 polypeptide unable to bind DNA. Two other sibs, both male, were unaffected. Two of the sisters had unilateral Wilms tumor, 1 had bilateral disease. The father, although a carrier, had never developed WT. <a href="#36" class="mim-tip-reference" title="Kaplinsky, C., Ghahremani, M., Frishberg, Y., Rechavi, G., Pelletier, J. <strong>Familial Wilms' tumor associated with a WT1 zinc finger mutation.</strong> Genomics 38: 451-453, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8975729/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8975729</a>] [<a href="https://doi.org/10.1006/geno.1996.0655" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8975729">Kaplinsky et al. (1996)</a> commented that this may be due to incomplete penetrance, which is not gender related. Alternatively, the father could be mosaic for the WT1 mutation, such that mutant cells had not substantially contributed to development of the urogenital system. A third possibility is that genomic imprinting of the mutated WT1 allele is responsible for masking its expression in the male carrier. In the proband, analysis of DNA from a Wilms tumor revealed loss of heterozygosity with retention of 1 set of conformers present in the proband and the father. This pattern is classical for tumor suppressor gene analysis and suggested the unmasking of a recessive mutation by loss of the wildtype allele. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8975729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003672" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003672" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003672</a>
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<p>In a 46,XY patient with hypospadias and nephropathy consistent with Denys-Drash syndrome (<a href="/entry/194080">194080</a>), <a href="#47" class="mim-tip-reference" title="Little, M. H., Williamson, K. A., Mannens, M., Kelsey, A., Gosden, C., Hastie, N. D., van Heyningen, V. <strong>Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion.</strong> Hum. Molec. Genet. 2: 259-264, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388765/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388765</a>] [<a href="https://doi.org/10.1093/hmg/2.3.259" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8388765">Little et al. (1993)</a> identified a C-to-G transversion in the WT1 gene, resulting in a his373-to-gln (H373Q) substitution in zinc finger-2. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8388765" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907908 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907908;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=rs121907908" 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=rs121907908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#60" class="mim-tip-reference" title="Park, S., Bernard, A., Bove, K. E., Sens, D. A., Hazen-Martin, D. J., Garvin, A. J., Haber, D. A. <strong>Inactivation of WT1 in nephrogenic rests, genetic precursors to Wilms' tumour.</strong> Nature Genet. 5: 363-367, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8298644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8298644</a>] [<a href="https://doi.org/10.1038/ng1293-363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8298644">Park et al. (1993)</a> showed that the WT1 gene, in addition to being expressed in tissues of the genitourinary system, is also expressed at high levels in many supportive structures of mesodermal origin in the mouse. Furthermore, they described a case of adult human mesothelioma (<a href="/entry/156240">156240</a>) that contained a homozygous A-to-G transition resulting in a serine to glycine substitution at codon 273 (S273G). Normal tissue from the patient showed no evidence of this mutation, indicating that it was absent from the germline and arose as a somatic mutation within the tumor. Mesothelioma is a tumor derived from the peritoneal lining. The particular tumor studied was of the rare multicystic type which is not metastatic and has been classified as a hamartoma or a developmental abnormality of borderline malignancy (<a href="#72" class="mim-tip-reference" title="Salazar, H., Kanbour, A., Burgess, F. <strong>Ultrastructure and observations on the histogenesis of mesotheliomas 'adenomatoid tumors' of the female genital tract.</strong> Cancer 29: 141-152, 1972.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/4332312/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">4332312</a>] [<a href="https://doi.org/10.1002/1097-0142(197201)29:1<141::aid-cncr2820290122>3.0.co;2-p" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="4332312">Salazar et al., 1972</a>). Unlike most mesotheliomas, multicystic tumors are not associated with a history of asbestos exposure. <a href="#60" class="mim-tip-reference" title="Park, S., Bernard, A., Bove, K. E., Sens, D. A., Hazen-Martin, D. J., Garvin, A. J., Haber, D. A. <strong>Inactivation of WT1 in nephrogenic rests, genetic precursors to Wilms' tumour.</strong> Nature Genet. 5: 363-367, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8298644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8298644</a>] [<a href="https://doi.org/10.1038/ng1293-363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8298644">Park et al. (1993)</a> screened 32 specimens of asbestos-related mesothelioma and found no WT1 mutations. The ser273-to-gly mutation was the first reported outside the zinc finger domain that leads to an amino acid substitution rather than a termination codon. Codon 273 is highly conserved across species. Whereas wildtype WT1 represses transcription from the early growth response-1 (EGR1; <a href="/entry/128990">128990</a>) promoter, following cotransfection into NIH 3T3 cells, <a href="#60" class="mim-tip-reference" title="Park, S., Bernard, A., Bove, K. E., Sens, D. A., Hazen-Martin, D. J., Garvin, A. J., Haber, D. A. <strong>Inactivation of WT1 in nephrogenic rests, genetic precursors to Wilms' tumour.</strong> Nature Genet. 5: 363-367, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8298644/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8298644</a>] [<a href="https://doi.org/10.1038/ng1293-363" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8298644">Park et al. (1993)</a> found that insertion of the ser273-to-gly mutation resulted in a WT1 protein that activated transcription from the EGR1 promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=4332312+8298644" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776577 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776577;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=rs587776577" 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=rs587776577" 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=RCV000003674 OR RCV000003675 OR RCV000157584 OR RCV000489749 OR RCV001003818 OR RCV001216104 OR RCV001290017 OR RCV004547458 OR RCV005049315" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003674, RCV000003675, RCV000157584, RCV000489749, RCV001003818, RCV001216104, RCV001290017, RCV004547458, RCV005049315" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003674...</a>
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<p>Alternative splicing of WT1 generates 4 isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows the addition of 3 amino acids (lys-thr-ser, or KTS) between the third and fourth zinc fingers of the WT1 protein (<a href="#24" class="mim-tip-reference" title="Haber, D. A., Sohn, R. L., Buckler, A. J., Pelletier, J., Call, K. M., Housman, D. E. <strong>Alternative splicing and genomic structure of the Wilms tumor gene WT1.</strong> Proc. Nat. Acad. Sci. 88: 9618-9622, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1658787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1658787</a>] [<a href="https://doi.org/10.1073/pnas.88.21.9618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1658787">Haber et al., 1991</a>). In 3 unrelated patients with Frasier syndrome (<a href="/entry/136680">136680</a>), <a href="#4" class="mim-tip-reference" title="Barbaux, S., Niaudet, P., Gubler, M.-C., Grunfeld, J.-P., Jaubert, F., Kuttenn, F., Fekete, C. N., Souleyreau-Therville, N., Thibaud, E., Fellous, M., McElreavey, K. <strong>Donor splice-site mutations in WT1 are responsible for Frasier syndrome.</strong> Nature Genet. 17: 467-470, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398852</a>] [<a href="https://doi.org/10.1038/ng1297-467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398852">Barbaux et al. (1997)</a> identified a mutation in the donor splice site in intron 9 of WT1, with the predicted loss of the so-called +KTS isoform. Examination of WT1 transcripts showed a diminution of the +KTS/-KTS isoform ratio in patients with Frasier syndrome. Two of 3 patients were found to carry a C-to-T transition at position +4 of intron 9 in 1 allele (IVSDS+4C-T). This nucleotide substitution was not detected in the DNA from either parent, indicating a de novo mutation. A third patient was found to have a mutation in intron 9 at position +6, substituting a thymidine for an adenine (IVS9DS+6A-T; <a href="#0019">607102.0019</a>). A screen of the SRY gene (<a href="/entry/480000">480000</a>) had failed to detect mutations in any of the 3 patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9398852+1658787" 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="#38" class="mim-tip-reference" title="Klamt, B., Koziell, A., Poulat, F., Wieacker, P., Scambler, P., Berta, P., Gessler, M. <strong>Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.</strong> Hum. Molec. Genet. 7: 709-714, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499425</a>] [<a href="https://doi.org/10.1093/hmg/7.4.709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499425">Klamt et al. (1998)</a> reported 3 cases of Frasier syndrome and the IVS9DS+4C-T mutation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9499425" 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="Barbosa, A. S., Hadjiathanasiou, C. G., Theodoridis, C., Papathanasiou, A., Tar, A., Merksz, M., Gyorvari, B., Sultan, C., Dumas, R., Jaubert, F., Niaudet, P., Moreira-Filho, C. A., Cotinot, C., Fellous, M. <strong>The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms' tumor.</strong> Hum. Mutat. 13: 146-153, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10094551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10094551</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:2<146::AID-HUMU7>3.0.CO;2-I" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10094551">Barbosa et al. (1999)</a> stated that 18 patients with Frasier syndrome had been described, all with heterozygous point mutations affecting the donor splice site of intron 9 of WT1; none had presented with Wilms tumor. They described 2 patients with Frasier syndrome and the IVS9DS+4C-T mutation; one of these patients also had Wilms tumor. The mutation was detected in both peripheral blood and in tumor-derived DNA of the patient with Frasier syndrome and Wilms tumor. The congenital anomalies in these 2 patients were the same as in other cases of Frasier syndrome: female external genitalia, in spite of a 46,XY karyotype, and streak gonads. The nephroblastoma in the patient with Wilms tumor had been diagnosed at the age of 3 years. The possibility that the patient actually represented a case of Denys-Drash syndrome was rejected because of normal histology of the kidney removed at age 3; the late onset of proteinuria; the slow progression of nephropathy, once developed; and the presence of a complete female phenotype with dysgenetic gonads, typical of Frasier syndrome. Thus this is the only one of 20 patients carrying mutations within splice site 2 of exon 9 of the WT1 gene who developed Wilms tumor in association with the features of Frasier syndrome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10094551" 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="#53" class="mim-tip-reference" title="Melo, K. F. S., Martin, R. M., Costa, E. M. F., Carvalho, F. M., Jorge, A. A., Arnhold, I. J. P., Mendonca, B. B. <strong>An unusual phenotype of Frasier syndrome due to IVS9+4C-T mutation in the WT1 gene: predominantly male ambiguous genitalia and absence of gonadal dysgenesis.</strong> J. Clin. Endocr. Metab. 87: 2500-2505, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12050205/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12050205</a>] [<a href="https://doi.org/10.1210/jcem.87.6.8521" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12050205">Melo et al. (2002)</a> reported a 19-year-old male with Frasier syndrome who had the IVS9+4C-T mutation, which predicts a change in splice site utilization. He had an unusual phenotype. WT1 transcript analysis showed reversal of the normal positive/negative KTS isoform ratio, confirming the diagnosis of FS. The authors concluded that this patient had the external genitalia characteristic of Denys-Drash syndrome, suggesting that these 2 syndromes are not distinct diseases but may represent 2 ends of a spectrum of disorders caused by alterations in the WT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12050205" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a 46,XX female with nephrotic syndrome (NPHS4; <a href="/entry/256370">256370</a>), <a href="#33" class="mim-tip-reference" title="Jeanpierre, C., Denamur, E., Henry, I., Cabanis, M.-O., Luce, S., Cecille, A., Elion, J., Peuchmaur, M., Loirat, C., Niaudet, P., Gubler, M.-C., Junien, C. <strong>Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.</strong> Am. J. Hum. Genet. 62: 824-833, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529364</a>] [<a href="https://doi.org/10.1086/301806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529364">Jeanpierre et al. (1998)</a> identified the IVS9+4C-T mutation in the WT1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs587776575 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs587776575;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=rs587776575" 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=rs587776575" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>See <a href="#0018">607102.0018</a> and <a href="#4" class="mim-tip-reference" title="Barbaux, S., Niaudet, P., Gubler, M.-C., Grunfeld, J.-P., Jaubert, F., Kuttenn, F., Fekete, C. N., Souleyreau-Therville, N., Thibaud, E., Fellous, M., McElreavey, K. <strong>Donor splice-site mutations in WT1 are responsible for Frasier syndrome.</strong> Nature Genet. 17: 467-470, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398852</a>] [<a href="https://doi.org/10.1038/ng1297-467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9398852">Barbaux et al. (1997)</a>. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398852" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000003665 OR RCV000030876 OR RCV000208283 OR RCV000589623 OR RCV000705142 OR RCV001288155 OR RCV001290018 OR RCV004547457 OR RCV005003323" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003665, RCV000030876, RCV000208283, RCV000589623, RCV000705142, RCV001288155, RCV001290018, RCV004547457, RCV005003323" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003665...</a>
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<p><a href="#38" class="mim-tip-reference" title="Klamt, B., Koziell, A., Poulat, F., Wieacker, P., Scambler, P., Berta, P., Gessler, M. <strong>Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.</strong> Hum. Molec. Genet. 7: 709-714, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499425</a>] [<a href="https://doi.org/10.1093/hmg/7.4.709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499425">Klamt et al. (1998)</a> described 6 cases of an IVS9DS+5G-A mutation in the WT1 gene in patients with Frasier syndrome (<a href="/entry/136680">136680</a>). Merging of mutational data from 18 cases demonstrated a striking bias: 15 of the 18 cases showed either the +4C-T (<a href="#0018">607102.0018</a>) or the +5G-A mutations. This mutation hotspot probably results from the potential to deaminate 5-methylcytosine at the +4/+5 CpG dinucleotide. <a href="#38" class="mim-tip-reference" title="Klamt, B., Koziell, A., Poulat, F., Wieacker, P., Scambler, P., Berta, P., Gessler, M. <strong>Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.</strong> Hum. Molec. Genet. 7: 709-714, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9499425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9499425</a>] [<a href="https://doi.org/10.1093/hmg/7.4.709" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9499425">Klamt et al. (1998)</a> showed that disruption of alternative splicing at the exon 9 donor splice site prevents synthesis of the usually more abundant WT1(+KTS) isoform from the mutant allele. In contrast to Denys-Drash syndrome (<a href="/entry/194080">194080</a>), no mutant protein is produced. The splice mutation leads to an imbalance of WT1 isoforms in vivo, as detected by RT-PCR on streak gonadal tissue. Thus, WT1 isoforms must have different functions, and the pathology of Frasier syndrome suggests that gonadal development may be particularly sensitive to imbalance or relative underrepresentation of the WT1 +KTS isoform. (The +KTS isoform has 3 additional amino acids, lys-thr-ser, between the third and fourth zinc fingers of the WT1 protein (<a href="#24" class="mim-tip-reference" title="Haber, D. A., Sohn, R. L., Buckler, A. J., Pelletier, J., Call, K. M., Housman, D. E. <strong>Alternative splicing and genomic structure of the Wilms tumor gene WT1.</strong> Proc. Nat. Acad. Sci. 88: 9618-9622, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1658787/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1658787</a>] [<a href="https://doi.org/10.1073/pnas.88.21.9618" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1658787">Haber et al., 1991</a>).) <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9499425+1658787" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs28941777 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28941777;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=rs28941777" 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=rs28941777" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a male patient with normal external genitalia and normal puberty associated with nephrotic syndrome (NPHS4; <a href="/entry/256370">256370</a>), <a href="#33" class="mim-tip-reference" title="Jeanpierre, C., Denamur, E., Henry, I., Cabanis, M.-O., Luce, S., Cecille, A., Elion, J., Peuchmaur, M., Loirat, C., Niaudet, P., Gubler, M.-C., Junien, C. <strong>Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.</strong> Am. J. Hum. Genet. 62: 824-833, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9529364/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9529364</a>] [<a href="https://doi.org/10.1086/301806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9529364">Jeanpierre et al. (1998)</a> identified heterozygosity for an 1147T-C transition in exon 9, leading to an phe383-to-leu (F383L) amino acid substitution in the WT1 protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9529364" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907909 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907909;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=rs121907909" 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=rs121907909" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p><a href="#39" class="mim-tip-reference" title="Kohsaka, T., Tagawa, M., Takekoshi, Y., Yanagisawa, H., Tadokoro, K., Yamada, M. <strong>Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome.</strong> Hum. Mutat. 14: 466-470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10571943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10571943</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(199912)14:6<466::AID-HUMU4>3.0.CO;2-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10571943">Kohsaka et al. (1999)</a> described 2 patients with Frasier syndrome (<a href="/entry/136680">136680</a>) who had novel mutations in exon 9 of the WT1 gene; 1 patient had a nonsense mutation (arg390 to ter) and the other had a missense mutation (phe392 to leu; <a href="#0025">607102.0025</a>). There was no alteration in the ratio of +/- KTS splice isoforms in these 2 patients. The patient with the R390X mutation, which was caused by an 1168C-T transition, was a 25-year-old 46,XY male who at birth was diagnosed with pseudohermaphroditism with retentio testis, penoscrotal hypospadias, and cryptorchidism. Proteinuria was detected on school mass screening at the age of 8, but no other abnormalities were detected in renal function. At the age of 16, renal biopsy showed global glomerulosclerosis. Renal insufficiency requiring hemodialysis developed at the age of 19. At bilateral surgical gonadectomy, a premature uterus and dysgenic gonad were noted. Gonadoblastoma in situ was observed. Many translucent cells were observed among increased Leydig cells and spermatogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10571943" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs28941779 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs28941779;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/rs28941779?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=rs28941779" 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=rs28941779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>The patient with Frasier syndrome (<a href="/entry/136680">136680</a>) reported by <a href="#39" class="mim-tip-reference" title="Kohsaka, T., Tagawa, M., Takekoshi, Y., Yanagisawa, H., Tadokoro, K., Yamada, M. <strong>Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome.</strong> Hum. Mutat. 14: 466-470, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10571943/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10571943</a>] [<a href="https://doi.org/10.1002/(SICI)1098-1004(199912)14:6<466::AID-HUMU4>3.0.CO;2-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10571943">Kohsaka et al. (1999)</a> who was found to have a phe392-to-leu mutation, caused by an 1174T-C transition in exon 9 of the WT1 gene, had no changes in the KTS splice isoforms. The patient was a 19-year-old male with a 46,XY karyotype. Hypospadias and cryptorchidism were detected at birth. Proteinuria was noted at 5 years of age at which time renal biopsy showed minimal change. At the age of 13, mild hypertension developed and renal biopsy showed a progressive stage of glomerulosclerosis. Hemodialysis was started at age 13. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10571943" 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>.0026 MEACHAM SYNDROME</strong>
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WT1, ARG366CYS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907910 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907910;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=rs121907910" 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=rs121907910" 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=RCV000003680 OR RCV001288153" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003680, RCV001288153" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003680...</a>
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<p>In a patient with Meacham syndrome (<a href="/entry/608978">608978</a>), <a href="#77" class="mim-tip-reference" title="Suri, M., Kelehan, P., O'Neill, D., Vadeyar, S., Grant, J., Ahmed, S. F., Tolmie, J., McCann, E., Lam, W., Smith, S., FitzPatrick, D., Hastie, N. D., Reardon, W. <strong>WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations.</strong> Am. J. Med. Genet. 143A: 2312-2320, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17853480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17853480</a>] [<a href="https://doi.org/10.1002/ajmg.a.31924" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17853480">Suri et al. (2007)</a> identified a hemizygous mutation in exon 8 of the WT1 gene, resulting in an arg366-to-cys (R366C) substitution. This 46,XY infant had female external genitalia, septate uterus, double vagina, 2 ovaries, left diaphragmatic hernia, and left pulmonary hypoplasia. Death occurred at age 1 day. The unrelated parents had had 2 prior miscarriages. A mutation in this same codon (R366H; <a href="#0004">607102.0004</a>) has been identified in patients with Denys-Drash syndrome (<a href="/entry/194080">194080</a>) and diaphragmatic hernia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17853480" 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>.0027 WILMS TUMOR 1</strong>
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WT1, TYR109TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121907911 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121907911;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=rs121907911" 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=rs121907911" 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=RCV000003681" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000003681" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000003681</a>
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<p>In a 34-year-old woman who had Wilms tumor (<a href="/entry/194070">194070</a>) removed at age 16 months and had decreased fertility in adulthood, <a href="#68" class="mim-tip-reference" title="Regev, M., Kirk, R., Mashevich, M., Bistritzer, Z., Reish, O. <strong>Vertical transmission of a mutation in exon 1 of the WT1 gene: lessons for genetic counseling.</strong> Am. J. Med. Genet. 146A: 2332-2336, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18688870/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18688870</a>] [<a href="https://doi.org/10.1002/ajmg.a.32330" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18688870">Regev et al. (2008)</a> identified heterozygosity for a 327C-A transversion in exon 1 of the WT1 gene, resulting in a tyr109-to-ter (Y109X) substitution. Her son, who had genitourinary abnormalities, including glanular hypospadias with chordee and bilateral undescended testes, gonadal dysgenesis with gonadoblastoma foci, and intraabdominal Mullerian derivatives, was also heterozygous for the Y109X mutation. He also had ventricular septal defect by echocardiography; no Wilms tumor was detected up to 6 years of age. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18688870" 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="seeAlso" class="mim-anchor"></a>
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<h4 href="#mimSeeAlsoFold" id="mimSeeAlsoToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span class="mim-font">
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<span id="mimSeeAlsoToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>See Also:</strong>
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</span>
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</h4>
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<div id="mimSeeAlsoFold" class="collapse in mimTextToggleFold">
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<span class="mim-text-font">
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<a href="#Denys1967" class="mim-tip-reference" title="Denys, P., Malvaux, P., van den Berghe, H., Tanghe, W., Proesmans, W. <strong>Association d'un syndrome anatomo-pathologique de pseudohermaphrodisme masculin, d'une tumeur de Wilms, d'une nephropathie parenchymateuse et d'un mosaicisme XX/XY.</strong> Arch. Franc. Pediat. 24: 729-739, 1967.">Denys et al. (1967)</a>; <a href="#Frasier1964" class="mim-tip-reference" title="Frasier, S. D., Bashore, R. A., Mosier, H. D. <strong>Gonadoblastoma associated with pure gonadal dysgenesis in monozygotic twins.</strong> J. Pediat. 64: 740-745, 1964.">Frasier et al. (1964)</a>; <a href="#Haning1985" class="mim-tip-reference" title="Haning, R. V., Jr., Chesney, R. W., Moorthy, A. V., Gilbert, E. F. <strong>A syndrome of chronic renal failure and XY gonadal dysgenesis in young phenotypic females without genital ambiguity.</strong> Am. J. Kidney Dis. 6: 40-48, 1985.">Haning et al. (1985)</a>; <a href="#Kinberg1987" class="mim-tip-reference" title="Kinberg, J. A., Angle, C. R., Wilson, R. B. <strong>Nephropathy-gonadal dysgenesis, type 2: renal failure in three siblings with XY dysgenesis in one.</strong> Am. J. Kidney Dis. 9: 507-510, 1987.">Kinberg et al. (1987)</a>
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<a id="references"class="mim-anchor"></a>
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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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</span>
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<div id="mimReferencesFold" class="collapse in mimTextToggleFold">
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<a id="1" class="mim-anchor"></a>
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<a id="Alexander2018" class="mim-anchor"></a>
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Alexander, T. B., Gu, Z., Iacobucci, I., Dickerson, K., Choi, J. K., Xu, B., Payne-Turner, D., Yoshihara, H., Loh, M. L., Horan, J., Buldini, B., Basso, G., and 50 others.
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<strong>The genetic basis and cell of origin of mixed phenotype acute leukaemia.</strong>
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Nature 562: 373-379, 2018.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30209392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30209392</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30209392" 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/s41586-018-0436-0" target="_blank">Full Text</a>]
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<a id="2" class="mim-anchor"></a>
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<a id="Antonius2008" class="mim-anchor"></a>
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Antonius, T., van Bon, B., Eggink, A., van der Burgt, I., Noordam, K., van Heijst, A.
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<strong>Denys-Drash syndrome and congenital diaphragmatic hernia: another case with the 1097G-A (arg366his) mutation.</strong>
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Am. J. Med. Genet. 146A: 496-499, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18203154/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18203154</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18203154" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/ajmg.a.32168" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Baird1992" class="mim-anchor"></a>
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<p class="mim-text-font">
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Baird, P. N., Santos, A., Groves, N., Jadresic, L., Cowell, J. K.
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<strong>Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome.</strong>
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Hum. Molec. Genet. 1: 301-305, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1338906/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1338906</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1338906" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1093/hmg/1.5.301" target="_blank">Full Text</a>]
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<a id="Barbaux1997" class="mim-anchor"></a>
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<div class="">
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Barbaux, S., Niaudet, P., Gubler, M.-C., Grunfeld, J.-P., Jaubert, F., Kuttenn, F., Fekete, C. N., Souleyreau-Therville, N., Thibaud, E., Fellous, M., McElreavey, K.
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<strong>Donor splice-site mutations in WT1 are responsible for Frasier syndrome.</strong>
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Nature Genet. 17: 467-470, 1997.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9398852/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9398852</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9398852" 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/ng1297-467" target="_blank">Full Text</a>]
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<a id="Barbosa1999" class="mim-anchor"></a>
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Barbosa, A. S., Hadjiathanasiou, C. G., Theodoridis, C., Papathanasiou, A., Tar, A., Merksz, M., Gyorvari, B., Sultan, C., Dumas, R., Jaubert, F., Niaudet, P., Moreira-Filho, C. A., Cotinot, C., Fellous, M.
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<strong>The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms' tumor.</strong>
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Hum. Mutat. 13: 146-153, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10094551/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10094551</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10094551" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/(SICI)1098-1004(1999)13:2<146::AID-HUMU7>3.0.CO;2-I" target="_blank">Full Text</a>]
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<a id="6" class="mim-anchor"></a>
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<a id="Bruening1992" class="mim-anchor"></a>
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Bruening, W., Bardeesy, N., Silverman, B. L., Cohn, R. A., Machin, G. A., Aronson, A. J., Housman, D., Pelletier, J.
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<strong>Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development.</strong>
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Nature Genet. 1: 144-148, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1302008/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1302008</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1302008" 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/ng0592-144" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Burwell2007" class="mim-anchor"></a>
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Burwell, E. A., McCarty, G. P., Simpson, L. A., Thompson, K. A., Loeb, D. M.
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<strong>Isoforms of Wilms' tumor suppressor gene (WT1) have distinct effects on mammary epithelial cells.</strong>
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Oncogene 26: 3423-3430, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17160023/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17160023</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17160023" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1210127" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Call1990" class="mim-anchor"></a>
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Call, K. M., Glaser, T., Ito, C. Y., Buckler, A. J., Pelletier, J., Haber, D. A., Rose, E. A., Kral, A., Yeger, H., Lewis, W. H., Jones, C., Housman, D. E.
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<strong>Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.</strong>
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Cell 60: 509-520, 1990.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2154335/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2154335</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=2154335" 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/10.1016/0092-8674(90)90601-a" target="_blank">Full Text</a>]
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<a id="Campbell1994" class="mim-anchor"></a>
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Campbell, C. E., Huang, A., Gurney, A. L., Kessler, P. M., Hewitt, J. A., Williams, B. R. G.
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[<a href="https://doi.org/10.1016/s0272-6386(85)80036-6" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/1.5.293" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9108089/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9108089</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9108089[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=9108089" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
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|
|
[<a href="https://doi.org/10.1073/pnas.94.8.3972" target="_blank">Full Text</a>]
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|
</p>
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|
</div>
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|
</li>
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<li>
|
|
<a id="76" class="mim-anchor"></a>
|
|
<a id="Smart2011" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Smart, N., Bollini, S., Dube, K. N., Vieira, J. M., Zhou, B., Davidson, S., Yellon, D., Riegler, J., Price, A. N., Lythgoe, M. F., Pu, W. T., Riley, P. R.
|
|
<strong>De novo cardiomyocytes from within the activated adult heart after injury.</strong>
|
|
Nature 474: 640-644, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21654746/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21654746</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21654746[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=21654746" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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|
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[<a href="https://doi.org/10.1038/nature10188" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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|
<a id="77" class="mim-anchor"></a>
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|
<a id="Suri2007" class="mim-anchor"></a>
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|
<div class="">
|
|
<p class="mim-text-font">
|
|
Suri, M., Kelehan, P., O'Neill, D., Vadeyar, S., Grant, J., Ahmed, S. F., Tolmie, J., McCann, E., Lam, W., Smith, S., FitzPatrick, D., Hastie, N. D., Reardon, W.
|
|
<strong>WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations.</strong>
|
|
Am. J. Med. Genet. 143A: 2312-2320, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17853480/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17853480</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17853480" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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|
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[<a href="https://doi.org/10.1002/ajmg.a.31924" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="78" class="mim-anchor"></a>
|
|
<a id="Wagner2002" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wagner, K. D., Wagner, N., Vidal, V. P. I., Schley, G., Wilhelm, D., Schedl, A., Englert, C., Scholz, H.
|
|
<strong>The Wilms' tumor gene Wt1 is required for normal development of the retina.</strong>
|
|
EMBO J. 21: 1398-1405, 2002.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11889045/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11889045</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11889045[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=11889045" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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|
|
[<a href="https://doi.org/10.1093/emboj/21.6.1398" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="79" class="mim-anchor"></a>
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<a id="Wagner2003" class="mim-anchor"></a>
|
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<div class="">
|
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<p class="mim-text-font">
|
|
Wagner, K.-D., Wagner, N., Schley, G., Theres, H., Scholz, H.
|
|
<strong>The Wilms' tumor suppressor Wt1 encodes a transcriptional activator of the class IV POU-domain factor Pou4f2 (Brn-3b).</strong>
|
|
Gene 305: 217-223, 2003.
|
|
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|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12609742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12609742</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12609742" 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/s0378-1119(02)01231-3" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="80" class="mim-anchor"></a>
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<a id="Wilhelm2002" class="mim-anchor"></a>
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|
<div class="">
|
|
<p class="mim-text-font">
|
|
Wilhelm, D., Englert, C.
|
|
<strong>The Wilms tumor suppressor WT1 regulates early gonadal development by activation of Sf1.</strong>
|
|
Genes Dev. 16: 1839-1851, 2002.
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|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12130543/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12130543</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12130543[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=12130543" 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/10.1101/gad.220102" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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|
<a id="81" class="mim-anchor"></a>
|
|
<a id="Zhou2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zhou, B., Ma, Q., Rajagopal, S., Wu, S. M., Domian, I., Rivera-Feliciano, J., Jiang, D., von Gise, A., Ikeda, S., Chien, K. R., Pu, W. T.
|
|
<strong>Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart.</strong>
|
|
Nature 454: 109-113, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18568026/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18568026</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18568026[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=18568026" 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/nature07060" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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</ol>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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<a id="contributors" class="mim-anchor"></a>
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
|
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
|
|
</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Ada Hamosh - updated : 02/28/2019
|
|
</span>
|
|
</div>
|
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</div>
|
|
<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">
|
|
<span class="mim-text-font">
|
|
Alan F. Scott - updated : 1/13/2016<br>Ada Hamosh - updated : 1/23/2013<br>Patricia A. Hartz - updated : 4/26/2012<br>George E. Tiller - updated : 12/2/2011<br>Ada Hamosh - updated : 8/24/2011<br>George E. Tiller - updated : 11/12/2010<br>Patricia A. Hartz - updated : 2/1/2010<br>Marla J. F. O'Neill - updated : 4/1/2009<br>Ada Hamosh - updated : 8/29/2008<br>Patricia A. Hartz - updated : 5/1/2008<br>Cassandra L. Kniffin - updated : 2/26/2008<br>George E. Tiller - updated : 12/4/2006<br>Patricia A. Hartz - updated : 9/15/2006<br>George E. Tiller - updated : 9/9/2005<br>Victor A. McKusick - updated : 11/24/2004<br>Natalie E. Krasikov - updated : 10/1/2004<br>Patricia A. Hartz - updated : 6/19/2003<br>John A. Phillips, III - updated : 2/4/2003<br>George E. Tiller - updated : 10/10/2002<br>Cassandra L. Kniffin - updated : 9/10/2002
|
|
</span>
|
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</div>
|
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</div>
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</div>
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<div>
|
|
<a id="creationDate" class="mim-anchor"></a>
|
|
<div class="row">
|
|
<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
|
<span class="text-nowrap mim-text-font">
|
|
Creation Date:
|
|
</span>
|
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</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
Cassandra L. Kniffin : 7/9/2002
|
|
</span>
|
|
</div>
|
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</div>
|
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</div>
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<div>
|
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<a id="editHistory" class="mim-anchor"></a>
|
|
|
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<div class="row">
|
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
|
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<span class="text-nowrap mim-text-font">
|
|
<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
|
|
</span>
|
|
</div>
|
|
<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 09/30/2019
|
|
</span>
|
|
</div>
|
|
</div>
|
|
<div class="row collapse" id="mimCollapseEditHistory">
|
|
<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
|
|
<span class="mim-text-font">
|
|
carol : 09/27/2019<br>carol : 06/17/2019<br>alopez : 06/14/2019<br>alopez : 02/28/2019<br>alopez : 11/07/2018<br>carol : 03/19/2018<br>carol : 10/18/2016<br>carol : 01/13/2016<br>carol : 8/11/2014<br>carol : 3/28/2014<br>carol : 9/17/2013<br>alopez : 1/28/2013<br>terry : 1/23/2013<br>mgross : 5/1/2012<br>terry : 4/26/2012<br>alopez : 12/2/2011<br>terry : 12/2/2011<br>alopez : 8/26/2011<br>alopez : 8/26/2011<br>terry : 8/24/2011<br>ckniffin : 8/8/2011<br>carol : 6/1/2011<br>wwang : 11/18/2010<br>terry : 11/12/2010<br>carol : 10/25/2010<br>ckniffin : 10/21/2010<br>ckniffin : 10/21/2010<br>carol : 10/21/2010<br>ckniffin : 10/8/2010<br>carol : 2/2/2010<br>alopez : 2/1/2010<br>carol : 1/29/2010<br>carol : 7/22/2009<br>carol : 7/21/2009<br>carol : 7/21/2009<br>wwang : 4/15/2009<br>terry : 4/1/2009<br>terry : 9/26/2008<br>alopez : 9/11/2008<br>terry : 8/29/2008<br>carol : 8/5/2008<br>mgross : 5/1/2008<br>carol : 3/11/2008<br>ckniffin : 2/26/2008<br>carol : 1/19/2007<br>wwang : 12/5/2006<br>terry : 12/4/2006<br>wwang : 9/21/2006<br>terry : 9/15/2006<br>alopez : 10/19/2005<br>terry : 9/9/2005<br>terry : 8/3/2005<br>alopez : 12/7/2004<br>terry : 11/24/2004<br>carol : 10/1/2004<br>carol : 2/23/2004<br>tkritzer : 2/6/2004<br>mgross : 6/19/2003<br>cwells : 2/4/2003<br>cwells : 10/10/2002<br>ckniffin : 9/11/2002<br>carol : 9/10/2002<br>ckniffin : 8/30/2002<br>carol : 8/22/2002<br>carol : 8/22/2002<br>ckniffin : 8/19/2002<br>ckniffin : 7/11/2002<br>ckniffin : 7/10/2002
|
|
</span>
|
|
</div>
|
|
</div>
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</div>
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</div>
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</div>
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|
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</div>
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|
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|
|
<div class="container visible-print-block">
|
|
|
|
<div class="row">
|
|
|
|
|
|
|
|
<div class="col-md-8 col-md-offset-1">
|
|
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|
<div>
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
<strong>*</strong> 607102
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
|
|
<div>
|
|
<h3>
|
|
<span class="mim-font">
|
|
|
|
WT1 TRANSCRIPTION FACTOR; WT1
|
|
|
|
</span>
|
|
</h3>
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<div>
|
|
<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
WT1/EWS FUSION GENE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</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>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: WT1</em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
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<div>
|
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<p>
|
|
<span class="mim-text-font">
|
|
|
|
<strong>SNOMEDCT:</strong> 236385009, 25081006, 302849000, 445431000, 722461004;
|
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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 />
|
|
</div>
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<div>
|
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<p>
|
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<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: 11p13
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : 11:32,387,775-32,435,539 </span>
|
|
</em>
|
|
</strong>
|
|
<span class="small">(from NCBI)</span>
|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
|
<br />
|
|
</div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="6">
|
|
<span class="mim-font">
|
|
11p13
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Denys-Drash syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
194080
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Somatic mutation
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
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</tr>
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<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
Frasier syndrome
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
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136680
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Somatic mutation
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Meacham syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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608978
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Mesothelioma, somatic
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</span>
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</td>
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<td>
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<span class="mim-font">
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156240
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</span>
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</td>
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<td>
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<span class="mim-font">
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Nephrotic syndrome, type 4
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</span>
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</td>
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<td>
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<span class="mim-font">
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256370
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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<tr>
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<td>
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<span class="mim-font">
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Wilms tumor, type 1
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</span>
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</td>
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<td>
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<span class="mim-font">
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194070
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant; Somatic mutation
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The WT1 gene encodes a zinc finger DNA-binding protein that acts as a transcriptional activator or repressor depending on the cellular or chromosomal context (summary by Hossain and Saunders, 2001). WT1 is required for normal formation of the genitourinary system and mesothelial tissues (summary by Wagner et al., 2003). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>To localize a candidate gene for Wilms tumor (194070), Rose et al. (1990) developed a physical map of the 11p13 region, deleted in individuals with Wilms tumor, by a combination of pulsed field gel electrophoresis and irradiation-reduced somatic cell hybrids of the Goss-Harris type. Restriction fragments contained in 11p13 were visualized directly using interspersed repeated DNA sequences as hybridization probes. The Wilms tumor locus was narrowed down to a region of less than 345 kb, and a transcript was identified with many of the characteristics expected for the Wilms tumor gene: a GC-rich region mapped to the 5-prime end of a transcription unit encoding a zinc finger protein. Call et al. (1990) reported further on these characteristics. The 429-amino acid polypeptide had features suggesting a role in transcriptional regulation: the presence of 4 zinc finger domains and a region rich in proline and glutamine. The amino acid sequence of the predicted polypeptide showed significant homology to EGR1 (128990) and EGR2 (129010). The mRNA was expressed predominantly in the kidney and a subset of hematopoietic cells. Gessler et al. (1990) likewise isolated a cDNA clone derived from an RNA highly expressed in fetal kidney which is predicted to encode a Kruppel-like zinc finger protein that is probably a transcription factor. </p><p>Huang et al. (1990) independently cloned WT1, which they designated WIT2, from a chromosomal region homozygously deleted in a Wilms tumor cell line. Northern blot analysis of fetal tissues detected a major 3.5-kb WT1 transcript expressed predominantly in kidney and spleen. Expression was much lower in 5-year-old and adult kidney. Huang et al. (1990) determined that expression of WIT1 (607899), which is located on chromosome 11p13 and is transcribed in the opposite direction of WT1, mirrors expression of WT1 in normal and Wilms tumor tissues, but at lower abundance. </p><p>Dallosso et al. (2004) identified a novel alternative WT1 transcript (AWT1) that retains exons 2 to 10 of WT1 but utilizes an alternative exon 1a located in intron 1 of WT1, replacing 147 amino acids of exon 1 with 4 amino acids of exon 1a. AWT1 encodes proteins of approximately 33 kD, comprising all exon 5 and exon 9 splicing variants previously characterized for WT1. AWT1 was coexpressed with WT1 in renal and hematopoietic cells. </p><p>Florio et al. (2010) stated that at least 24 different WT1 isoforms are produced by alternative splicing and the use of alternate translation initiation sites. </p><p><strong><em>WT1-Antisense/WIT1 Fusion Transcript</em></strong></p><p>
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Eccles et al. (1994) and Campbell et al. (1994) identified a cDNA clone transcribed in the opposite direction of WT1 that includes sequences from WIT1 and WT1 and may include WT1 intronic sequences. By Northern blot analysis and RNase protection analyses, Eccles et al. (1994) detected this transcript expressed at 7 to 10 kb in fetal kidney. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>WT1 is a zinc finger DNA-binding protein that acts as a transcriptional activator or repressor depending on the cellular or chromosomal context. It has 4 major isoforms, due to the insertion of 3 amino acids (KTS) between zinc fingers 3 and 4, and the insertion of an alternatively spliced 17-amino acid segment encoded by exon 5 in the middle of the protein (Hossain and Saunders, 2001). The conservation in structure and relative levels of the 4 WT1 mRNA species suggests that each encoded polypeptide makes a significant contribution to normal gene function. The control of cellular proliferation and differentiation exerted by the WT1 gene products may involve interactions between the 4 polypeptides with distinct targets and functions (Haber et al., 1991). </p><p>The WT1 protein that was isolated by Call et al. (1990) and Gessler et al. (1990) as the likely 'cause' of Wilms tumor was used by Pritchard-Jones et al. (1990) to study its role in normal development. This was done by in situ mRNA hybridization on sections of human embryos. The candidate Wilms tumor gene was expressed specifically in the condensed mesenchyme, renal vesicle, and glomerular epithelium of the developing kidney, in the related mesonephric glomeruli, and in cells approximating these structures in tumors. The other main sites of expression were the genital ridge, fetal gonad, and mesothelium. This was interpreted as indicating that the anomalies of the urinary tract and genitalia, which are frequent in both sporadic and syndrome-associated Wilms tumors, are a pleiotropic effect of the WT1 gene. </p><p>Both constitutional and somatic mutations disrupting the DNA-binding domain of WT1 result in a potentially dominant-negative phenotype. In generating inducible cell lines expressing wildtype isoforms of WT1 as well as WT1 mutants, Englert et al. (1995) observed dramatic differences in the subnuclear localization of the induced proteins. The WT1 isoform that binds with high affinity to a defined DNA target, WT1(-KTS), was diffusely localized throughout the nucleus. In contrast, expression of an alternative splicing variant with reduced DNA binding affinity, WT1(+KTS), or WT1 mutants with a disrupted zinc finger domain resulted in a speckled pattern of expression within the nucleus. Though similar in appearance, the localization of WT1 variants to subnuclear clusters was clearly distinct from that of the essential splicing factor SC35, suggesting that WT1 is not directly involved in pre-mRNA splicing. Localization to subnuclear clusters required the M terminus of WT1 and coexpression of a truncated WT1 mutant and wildtype WT1(-KTS) resulted in a physical association, the redistribution of WT1(-KTS) from a diffuse to a speckled pattern, and the inhibition of its transactivational activity. These observations suggested to the authors that different WT1 isoforms and WT1 mutants have distinct subnuclear compartments. Dominant-negative WT1 proteins physically associate with wildtype WT1 in vivo and may result in its sequestration within subnuclear structures. </p><p>Scharnhorst et al. (1999) described additional WT1 isoforms with distinct transcription-regulatory properties, indicating further the complexity of WT1 expression and activity. They stated that, including these novel forms, 32 WT1 protein forms had been described. </p><p>Laity et al. (2000) used NMR relaxation experiments to determine the molecular basis for the differing DNA recognition properties of the WT1(-KTS) and WT1(+KTS) isoforms. The results showed that the KTS insertion increases the flexibility of the linker between fingers 3 and 4 and abrogates binding of the fourth zinc finger to its cognate site in the DNA major groove. </p><p>Using a series of site-directed mutations in both the genomic and cDNA context, Davies et al. (2000) investigated the nucleotide-amino acid relationship of WT1 and the KTS tripeptide. Mutation analysis within the cDNA suggested that the precise amino acids inserted may not be critical, but rather the disruption of the zinc finger structure alone may be sufficient to generate proteins with different in vitro properties. However, analysis within the genomic context suggested that the precise structure of the splice junction is crucial in retaining the balance between +/- KTS splice isoforms. The authors hypothesized that this may account for the high nucleotide conservation of the gene structure from fish to mammals. Using nuclear magnetic resonance analysis, Laity et al. (2000) found that although the +/- KTS isoforms of WT1 are nearly identical in the absence of DNA, upon DNA binding the isoform lacking KTS forms a more stable complex because the KTS sequence disrupts interactions between the linker region and the adjacent zinc fingers. They found that the isoform lacking KTS appears to be involved in a C-terminal helix-capping, stabilizing interaction with the helix of the preceding finger. Laity et al. (2000) suggested that the presence of different isoforms of WT1 in different locations may allow it to act at both the transcriptional and posttranscriptional levels. </p><p>Products of the steroidogenic factor-1 (SF1; 184757) and WT1 genes are essential for mammalian gonadogenesis prior to sexual differentiation. In males, SF1 participates in sexual development by regulating expression of the polypeptide hormone mullerian inhibiting substance (MIS; 600957). Nachtigal et al. (1998) showed that WT1(-KTS) isoforms associate and synergize with SF1 to promote MIS expression. In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome (194080), fail to synergize with SF1. Additionally, the X-linked, candidate dosage-sensitive sex-reversal (DSS; 300018) gene, DAX1 (NR0B1; 300473), antagonizes synergy between SF1 and WT1, most likely through a direct interaction with SF1. Nachtigal et al. (1998) proposed that WT1 and DAX1 functionally oppose each other in testis development by modulating SF1-mediated transactivation. </p><p>With use of reporter plasmids, gel shift assays, and transfection experiments, Hossain and Saunders (2001) determined that the WT1(-KTS) isoform is able to transactivate SRY (480000), a human sex-determining gene, by binding to its promoter region. They also found that WT1 with any of 4 common mutations causing Denys-Drash syndrome failed to activate the SRY promoter. </p><p>Little et al. (1992) demonstrated that each parental allele of WT1 is equivalently expressed in normal fetal kidneys and Wilms tumors. On the other hand, Jinno et al. (1994) identified imprinting of WT1, with maternal expression in about half of preterm placental villus and fetal brain tissue. Further extensive studies showed that maternal monoallelic expression was observed in 39% of the samples, while the expression in other samples was biallelic. Mitsuya et al. (1997) studied the allele-specific expression of WT1 as well as of IGF2 and H19 in fibroblasts and lymphocytes. The expression profiles of IGF2 and H19 were constant and consistent with those in other tissues. The unexpected finding was paternal or biallelic expression of WT1 in fibroblasts and lymphocytes. This, together with the previous findings of maternal or biallelic expression in placenta and brain, suggested that the allele-specific regulatory system of WT1 is unique and may be controlled by a putative tissue- and individual-specific modifier. </p><p>Miyagawa et al. (1998) focused on the ectopic formation of skeletal muscle in Wilms tumors. They presented evidence supporting a negative regulatory role for WT1 in myogenesis. Their findings suggested that the metanephric-mesenchymal stem cells of the kidney may have the capacity to differentiate into skeletal muscle cells as well as epithelial cells. Normally, the expression of WT1 appears to prevent this ectopic differentiation program from being activated. In vitro studies suggested that WT1 may play a direct role in suppressing the formation of skeletal muscle. </p><p>Little et al. (2000) used the yeast 2-hybrid system to identify a novel human WT1-associating protein, WTAP (605442). Both in vitro and in vivo assays demonstrated a specific interaction between WTAP and WT1, which occurred endogenously in cells. The mouse homolog of WTAP was isolated and found to be greater than 90% conserved at the nucleotide and protein levels. The human and mouse genes were mapped using fluorescence in situ hybridization to regions on chromosomes 6 (which is thought to harbor a tumor suppressor gene) and 17, respectively. WTAP appears to be a ubiquitously expressed nuclear protein, which, like WT1, localized throughout the nucleoplasm as well as in speckles and partially colocalized with splicing factors. </p><p>Using high titer retroviral infection, Ellisen et al. (2001) examined the effect of the WT1(-KTS) and WT1(+KTS) isoforms on human hematopoietic progenitor cells and human leukemia-derived cells. WT1(-KTS) arrested both types of cells in G1 phase and reduced the number of cells in S phase. WT1(-KTS) also induced differentiation of both cell types, an effect that was enhanced by the presence of WT1(+KTS), while inducing quiescence in a primitive subset of precursors. Ellisen et al. (2001) noted that the effect of WT1 on hematopoietic precursors is stage-specific and that the variable expression of the protein is similar to that observed in the developing kidney. The functional role of WT1 in hematopoietic cells suggested that it may act as a tumor suppressor in leukemia. </p><p>Wagner et al. (2003) found upregulation of POU4F2 (113725) at the transcript and protein levels in embryonic kidney and osteosarcoma cells stably transfected with WT1. WT1 expression activated a POU4F2 promoter-reporter construct about 4-fold. Stimulation of POU4F2 required the WT1 responsive element, WTE, which shows higher affinity for the -KTS isoform of WT1. Double immunofluorescence labeling revealed coexpression of Wt1 and Pou4f2 in glomerular podocytes of adult mouse kidney and in developing retinal ganglion cells of embryonic mice. Pou4F2 immunoreactivity was absent from the retinas of Wt1 null embryos. </p><p>Niksic et al. (2004) found that WT1 protein is not restricted to the nucleus and shuttles continuously between the nucleus and cytoplasm. Western blot analysis showed that 10 to 50% of total cellular WT1 could be detected in the cytoplasm depending on the cell type. A significant proportion of cytoplasmic WT1 was associated with ribonucleoprotein particles (RNPs) and actively translating polysomes, supporting its role in RNA metabolism and suggesting its involvement in regulation of translation. Despite spatial and functional differences between WT1 (+/- KTS) isoforms within the nucleus, Niksic et al. (2004) showed that both isoforms shared the shuttling property and were found in translating polysomes. </p><p>Burwell et al. (2007) found that expression of WT1(-KTS) in a human mammary epithelial cell line upregulated p21 (CDKN1A; 116899) expression, slowed proliferation, and promoted G2-phase cell cycle arrest. In artificial basement membranes, WT1(-KTS) promoted organization of cells into distinct acinar cellular aggregates. In contrast, WT1(+KTS) had no effect on p21 expression or cell proliferation, but it caused an epithelial-mesenchymal transition and redistribution of E-cadherin (CDH1; 192090) from the cell membrane to the cytoplasm. WT1(+KTS) also caused cellular aggregates growing in artificial basement membranes to appear significantly less organized than control cells. Burwell et al. (2007) concluded that WT1 can function to either promote or suppress the transformed phenotype depending on the ratio of WT1 isoforms expressed. </p><p>Zhou et al. (2008) identified a novel cardiogenic precursor marked by expression of the transcription factor WT1 and located within the epicardium. During normal murine heart development, a subset of these Wt1-positive precursors differentiated into fully functional cardiomyocytes. Wt1-positive proepicardial cells arose from progenitors that expressed Nkx2.5 (600584) and Isl1 (600366), suggesting that they share a developmental origin with multipotent Nkx2-5-positive and Isl1-positive progenitors. Zhou et al. (2008) concluded that their results identified WT1-positive epicardial cells as previously unrecognized cardiomyocyte progenitors, and laid the foundation for future efforts to harness the cardiogenic potential of these progenitors for cardiac regeneration and repair. </p><p>Lee et al. (2002) demonstrated that the ZNF255 isoform of ZNF224 (194555) interacted with WT1 in vitro and in vivo. Mutation analysis showed that zinc fingers 6 to 10 of ZNF255 were required to interact with the zinc finger region of WT1. ZNF255 inhibited transcriptional activation by WT1, and the presence of a repressor domain within ZNF255 was confirmed in a reporter assay. </p><p>By coimmunoprecipitation analysis of human cell lines, Florio et al. (2010) discovered that ZNF224 interacted specifically and exclusively with the -KTS isoform of WT1, whereas ZNF255 interacted with both the +KTS and -KTS isoforms of WT1. Using a reporter plasmid containing the promoter region of a WT1 target gene, VDR (601769), Florio et al. (2010) showed that cotransfection of ZNF224 caused a dose-dependent enhancement of WT1(-KTS)-mediated VDR expression, while ZNF255 had no effect. Chromatin immunoprecipitation analysis showed that ZNF224 was recruited with WT1 to the VDR promoter. Knockdown of ZNF224 reduced VDR mRNA and protein. In contrast, ZNF255, but not ZNF224, colocalized with WT1(+KTS) in the polysome fraction of HEK293 cells and copurified with poly(A) ribonuclear particles. </p><p><strong><em>WT1 Therapy</em></strong></p><p>
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|
The WT1 gene is overexpressed in leukemias and various types of solid tumors, and the WT1 protein was demonstrated to be an attractive target antigen for immunotherapy against these malignancies. Oka et al. (2004) reported the outcome of a phase I clinical study of WT1 peptide-based immunotherapy for patients with breast or lung cancer, myelodysplastic syndrome, or acute myeloid leukemia. In 26 patients, one or more WT1 vaccinations were performed, consisting of intradermal injections of natural or modified 9-mer WT1 peptide, and 18 of 26 patients completed WT1 vaccination protocol with 3 or more injections. Toxicity consisted only of local erythema at the WT1 vaccine injection site in patients with breast or lung cancer or acute myeloid leukemia with adequate normal hematopoiesis, whereas severe leukocytopenia occurred in patients with myelodysplastic syndrome with abnormal hematopoiesis derived from WT1-expressing, transformed hematopoietic stem cells. Twelve of 20 patients for whom the efficacy of WT1 vaccination could be assessed showed clinical responses such as reduction in leukemic blast cells or tumor sizes and/or tumor markers. A clear correlation was observed between an increase in the frequencies of WT1-specific cytotoxic T lymphocytes after WT1 vaccination and clinical responses. It was thus demonstrated that WT1 vaccination could induce WT1-specific cytotoxic T lymphocytes and result in cancer regression without damage to normal tissues. </p><p>In mice, Smart et al. (2011) demonstrated that the adult heart contains a resident stem or progenitor cell population, which has the potential to contribute bona fide terminally differentiated cardiomyocytes after myocardial infarction. Smart et al. (2011) revealed a novel genetic label of the activated adult progenitors via reexpression of a key embryonic epicardial gene, Wt1, through priming by thymosin beta-4 (300159), a peptide shown to restore vascular potential to adult epicardium-derived progenitor cells with injury. Cumulative evidence indicated an epicardial origin of the progenitor population, and embryonic reprogramming resulted in the mobilization of this population and concomitant differentiation to give rise to de novo cardiomyocytes. Cell transplantation confirmed a progenitor source and chromosome painting of labeled donor cells revealed transdifferentiation to a myocyte fate in the absence of cell fusion. Smart et al. (2011) showed that derived cardiomyocytes are able to structurally and functionally integrate with resident muscle; as such, stimulation of this adult progenitor pool represented a significant step towards resident cell-based therapy in human ischemic heart disease. </p><p>Huang et al. (2012) found that conserved regions CR2 in Raldh2 (603687) and CR14 in Wt1 are robust epicardial enhancers that respond to CCAAT/enhancer-binding protein (CEBP; 116897). Huang et al. (2012) established a mouse embryonic heart organ culture and gene expression system that facilitated the identification of epicardial enhancers activated during heart development and injury. Epicardial activation of these enhancers depends on a combinatorial transcriptional code centered on CEBP transcription factors. Disruption of C/EBP signaling in the adult epicardium reduced injury-induced neutrophil infiltration and improved cardiac function. Huang et al. (2012) concluded that their findings revealed a transcriptional basis for epicardial activation and heart injury. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
|
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gessler et al. (1992) established the genomic organization of the WT1 gene and determined the sequence of all 10 exons and the flanking intron DNA. The pattern of alternative splicing in 2 regions was characterized in detail. </p><p>Huang et al. (1990) determined that the WT1 and WIT1 genes are separated by about 0.6 kb and are transcribed in opposite directions from a single CpG island. The intervening sequence may function as a bidirectional promoter. </p><p>Using reporter plasmids containing both orientations of the intervening sequence between the WIT1 and WT1 genes, Campbell et al. (1994) confirmed the bidirectionality of the reporter region in several transfected human and mouse cell lines. By DNase footprinting, they determined that the +KTS form of WT1 can bind at least 4 elements within the promoter region. </p><p>Hofmann et al. (1993) determined that the WT1 promoter region is TATA-less and GC-rich and contains several SP1 (189906)-binding sites. Functional analysis confirmed that the promoter is responsive to SP1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Rose et al. (1990) mapped the WT1 gene to chromosome 11p13. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gerald et al. (1995) reported the first example of a specific tumor associated with consistent translocation involving WT1. Desmoplastic small round cell tumor (DSRCT) is associated with a recurrent chromosomal translocation, t(11;22)(p13;q12). DSRCT is characterized by a predilection for young males, abdominal serosal involvement, poor prognosis, and a primitive histologic appearance. Gerald et al. (1995) found that the chromosome translocation breakpoints involved the intron between WT1 exons 7 and 8 and the intron between EWS (133450) exons 7 and 8. Chimeric transcripts corresponding to the fusion gene were detected in 4 of 6 cases of DSRCT. Analyses of these transcripts showed an in-frame fusion of RNA encoding the amino-terminal domain of EWS to both alternatively spliced forms of the last 3 zinc fingers of the DNA-binding domain of WT1. The chimeric products were predicted to modulate transcription at WT1 target sites and contribute to development of this unique tumor. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Mutations in the WT1 gene have been identified in patients with Wilms tumor (194070), WAGR syndrome (194072), Denys-Drash syndrome (DDS; 194080), Frasier syndrome (136680), isolated diffuse mesangial sclerosis, referred to here as nephrotic syndrome type 4 (NPHS4; 256370), and Meacham syndrome (608978).</p><p>Huff et al. (1991) made observations that appeared to differentiate between WT33 and LK15, 2 similar candidate Wilms tumor cDNA clones that were identified on the basis of their expression in fetal kidney and their location within the smallest region of overlap of somatic with differences due to alternative splicing at 2 exons. Huff et al. (1991) reported a patient with bilateral Wilms tumor who was heterozygous for a small germinal mutation within the WT1 gene (as identified by the WT33 clone). DNA from both tumors was homozygous for this intragenic deletion, which was predicted to encode a protein truncated by 180 amino acids. </p><p>Hastie (1992) reviewed the evidence showing that mutations in the WT1 gene behave as dominant negatives, specifically in relation to causation of the Denys-Drash syndrome (DDS; 194080). This is proof that a tumor suppressor gene plays a crucial role in normal genitourinary development. Remarkably, 12 of 25 patients from a total of 4 studies had the arg394-to-trp mutation (R394W; 607102.0003) in heterozygous form as the cause of the Denys-Drash syndrome. One reason for the preponderance of this mutation is that it represents a C-to-T transition at a CpG dimer. The same can be said for the arg366-to-his change (607102.0004). This, however, appeared to be only part of the story since there are other equally vulnerable sites; Hastie (1992) suggested that the zinc fingers carrying these 2 mutations may play a particularly important role in establishing stable binding. Mutations causing the Denys-Drash syndrome are clustered in the zinc finger-encoding exons, particularly the exons encoding Zf2 and Zf3. Little et al. (1993) concluded that WT mutations resulting in the Denys-Drash syndrome may operate in a dominant-negative fashion; they observed an arg362-to-ter mutation predicted to result in a protein product lacking zinc fingers 2, 3 and 4, and therefore presumably incapable of binding DNA. Little et al. (1995) found WT1 fusion constructs containing the different classes of DDS-causing mutations. They demonstrated that the DDS mutations, indeed, disrupt DNA binding. They interpreted this as compatible with a dominant-negative mode of action, perhaps through dimerization between different WT1 isoforms. Little et al. (1995) noted that another mechanism by which the loss of DNA-binding could elicit the DDS phenotype would be a disturbed isoform dosage balance. </p><p>Little and Wells (1997) pointed out that only 5% of sporadic Wilms tumors have intragenic WT1 mutations, but more than 90% of patients with Denys-Drash syndrome, which includes Wilms tumor, carry constitutional intragenic WT1 mutations. WT mutations have also been reported in juvenile granulosa-cell tumor, non-asbestos-related mesothelioma (Park et al., 1993), desmoplastic small round cell tumor, and acute myeloid leukemia. </p><p>Jeanpierre et al. (1998) identified WT1 mutations in patients with nephrotic syndrome (NPHS4), i.e., patients without pseudohermaphroditism and/or Wilms tumor, which represent the other features of the Denys-Drash syndrome. In 4 of 10 patients, they found heterozygous mutations in the WT1 gene. Two of the mutations (607102.0006 and 607102.0012) had previously been identified in patients with DDS, one (607102.0018) had previously been identified in a patient with Frasier syndrome, and one (607102.0028) was novel. An analysis of genotype/phenotype correlation, on the basis of a WT1 mutation database of 84 germline mutations, demonstrated an association between mutations in exons 8 and 9 and nephrotic syndrome; among patients with nephrotic syndrome, a higher frequency of exon 8 mutations among 46,XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions. </p><p>Koziell et al. (1999) tested the hypothesis that WT1 gene mutations occur in cases of diffuse mesangial sclerosis (DMS; see 256370) and in congenital/early-onset focal segmental glomerular sclerosis (FSGS; 603278) without other features of Denys-Drash syndrome or Frasier syndrome, respectively. To determine how common mutations of the WT1 gene were in this population of cases and to begin establishing the boundaries of the DDS/Frasier syndrome spectrum of disease, they screened a series of 30 patients, 22 with DMS (2 of whom also had DDS) and 8 with FSGS (7 confirmed), for WT1 mutations. No WT1 mutations were detected in either the 20 patients with isolated DMS or the 7 patients with isolated FSGS. Koziell et al. (1999) concluded that when a larger, more generalized population of cases is examined, mutations of the WT1 gene are less frequent in IDMS than initial data suggested, and are absent in isolated FSGS. This confirmed the genetic heterogeneity of IDMS and FSGS, despite the uniform renal histologic findings seen throughout this group of conditions. Koziell et al. (1999) suggested that IDMS and isolated FSGS may also result from abnormalities of other glomerular genes, perhaps downstream of WT1 and mimicking the effects of WT1 mutations seen in DDS and Frasier syndrome. Koziell et al. (1999) noted that Klamt et al. (1998) had observed WT1 mutations in intron 9 in individuals with a 46,XX karyotype who developed nephropathy but no obvious gonadal abnormality. This supported the less critical role of WT1 in female gonadal development, as had been suggested by experimental data (Nachtigal et al., 1998). </p><p>Barbaux et al. (1997) and Klamt et al. (1998) had reported a donor splice site mutation in intron 9 (607102.0018) of the WT1 gene in patients with Frasier syndrome and concluded that loss of the +KTS (lys-thr-ser) isoform of the WT1 gene was responsible for this syndrome by inducing defective alternative splicing. However, in 2 unrelated patients with Frasier syndrome, Kohsaka et al. (1999) found mutations in the same exon of the WT1 gene as detected in Denys-Drash syndrome with no alteration of the ratio of +/- KTS splice isoforms (see 607102.0024-607102.0025). They suggested that Denys-Drash and Frasier syndromes originate from the same WT1 gene abnormality. They concluded that from a molecular biologic point of view the 2 diseases are not separable and that Frasier syndrome should be considered an atypical form of DDS. </p><p>Royer-Pokora et al. (2004) reported 24 new Wilms tumor patients and summarized genotype/phenotype correlations in a total of 282 patients, including 117 with and 165 without WT1 germline mutations. The median age at tumor onset was 12.5 months for those with a mutation and 36 months for those without. The earliest onset was in patients with truncation mutations, followed by those with missense and deletion mutations, with medians of 12 months (66 patients), 18 months (30 patients) and 22 months (21 patients), respectively. Patients with the 2 most frequent nonsense mutations, R362X and R390X, or the Denys-Drash syndrome hotspot mutation, R394W/Q/L, all had very early onset at 9, 12, and 18 months, respectively. Bilateral tumors were most frequently associated with truncation mutations, especially with those occurring in the 5-prime half of the gene. Carriers of a WT1 germline mutation were found to be at risk not only for genital tract anomalies but also for early onset, tumor bilaterality, and early-onset nephrotic syndrome with diffuse mesangial sclerosis and stromal-predominant histology. </p><p>Dallosso et al. (2004) showed that both WT1-AS and AWT1 were imprinted in normal kidney with expression confined to the paternal allele. Wilms tumor samples displayed biallelic AWT1 expression, indicating relaxation of imprinting of AWT1 in a subset of WTs. Dallosso et al. (2004) concluded that human chromosome 11p13 is an imprinted locus, which may suggest a molecular basis for the strong bias of paternal allele mutations and incomplete penetrance observed in syndromes with inherited WT1 mutations. </p><p>Regev et al. (2008) reported maternal transmission of a nonsense mutation in the WT1 gene (607102.0027). The mother had Wilms tumor in infancy and decreased fertility in adulthood, and her son displayed genitourinary abnormalities, including glanular hypospadias with chordee and bilateral undescended testes, gonadal dysgenesis with gonadoblastoma foci, and intraabdominal Mullerian derivatives. No Wilms tumor was detected in the son up to 6 years of age. The boy also carried 2 additional exon 1 polymorphisms, 17G-T and 390C-T (N130N), presumably transmitted from the paternal allele. Regev et al. (2008) stated that the nonsense mutation demonstrates the lack of correlation between genotype/phenotype and mutation position in the WT1 gene, the presence of intrafamilial variability, and the effect of gender on severity of genitourinary anomalies. </p><p>Royer-Pokora et al. (2010) described the establishment and characterization of long-term cell cultures derived from 5 individual WTs with WT1 mutations. Three of these tumor cell lines also had CTNNB1 (116806) mutations and an activated canonic Wnt (164820) signaling pathway as measured by beta-catenin/T cell-specific transcription factor transcriptional activity. Four lines showed loss of heterozygosity of chromosome 11p due to mitotic recombination in 11p11. Gene expression profiling revealed that the WT cell lines were highly similar to human mesenchymal stem cells (MSCs), and FACS analysis demonstrated the expression of MSC-specific surface proteins CD105 (ENG; 131195), CD90 (THY1; 188230), and CD73 (NT5E; 129190). The stem cell-like nature of the WT cells was further supported by their adipogenic, chondrogenic, osteogenic, and myogenic differentiation potentials. By generating multipotent mesenchymal precursors from paraxial mesoderm in tissue culture using embryonal stem cells, gene expression profiles of paraxial mesoderm and MSCs were described. Using these published gene sets, the authors found coexpression of a large number of genes in WT cell lines, paraxial mesoderm, and MSCs. Lineage plasticity was indicated by the simultaneous expression of genes from the mesendodermal and neuroectodermal lineages. The authors concluded that WTs with WT1 mutations have specific traits of paraxial mesoderm, which is the source of kidney stromal cells. </p><p>Jorgenson et al. (2015) showed that WT1 maps to a significant signal in a genomewide association study of susceptibility loci for inguinal hernia. The study included 5,295 cases and 67,510 controls with top associations confirmed in an independent cohort of 9,701 cases and 82,743 controls. The authors showed that WT1 is expressed in mouse connective tissue and, by network analysis, that it is likely to be involved in connective tissue maintenance and homeostasis. </p><p>Alexander et al. (2018) showed that biallelic WT1 alterations are common in the T-cell/myeloid form of mixed phenotype acute leukemia. </p>
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<strong>Animal Model</strong>
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<p>By gene targeting in embryonic stem cells, Kreidberg et al. (1993) introduced a mutation into the murine WT1 tumor suppressor gene. The mutation resulted in embryonic lethality in homozygotes, and examination of mutant embryos demonstrated a failure of kidney and gonad development. Specifically, at day 11 of gestation, the cells of the metanephric blastema underwent apoptosis, the ureteric bud failed to grow out from the wolffian duct, and the inductive events that lead to formation of the metanephric kidney did not occur. In addition, the mutation caused abnormal development of the mesothelium, heart, and lungs. The results established a crucial role for WT1 in early urogenital development. </p><p>Patek et al. (1999) reported that heterozygosity for a targeted murine Wt1 allele, which truncates zinc finger-3 at codon 396, induced mesangial sclerosis characteristic of Denys-Drash syndrome in adult heterozygous and chimeric mice. Male genital defects were also evident, and there was a single case of Wilms tumor in which the transcript of the nontargeted allele showed an exon 9 skipping event, implying a causal link between Wt1 dysfunction and Wilms tumorigenesis in mice. However, the mutant protein with the truncation at codon 396 accounted for only 5% of Wt1 protein in both heterozygous embryonic stem cells and the Wilms tumor. This has implications regarding the mechanism by which the mutant allele exerts its effect. </p><p>Hammes et al. (2001) generated mouse strains in which specific isoforms of Wt1 had been removed. Heterozygous mice with a reduction of +KTS levels developed glomerulosclerosis and represented a model for Frasier syndrome. Homozygous mutants of both strains died after birth due to kidney defects. Mice lacking +KTS isoforms showed a complete XY sex reversal due to a dramatic reduction of Sry expression levels. These data demonstrated distinct functions for the KTS splice variants and placed the +KTS variants as important regulators for SRY in the sex determination pathway. </p><p>Natoli et al. (2002) noted that inclusion of a 17-amino acid stretch encoded by exon 5 of WT1 is found only in placental mammals. By gene targeting, they specifically eliminated this exon in mice and found that the homozygous mice are viable and develop normally. All of the mice are fertile and females are capable of lactation. No defects were found in the kidneys, testes, ovaries, oviducts, or uteri. </p><p>Wagner et al. (2002) found expression of WT1 in the presumptive retinal ganglion cell layer of an autopsied human embryo at 19 weeks of gestation. In mice, they found evidence that disruption of WT1 can lead to retinal abnormalities. In normal mice, Wt1 was distributed throughout the neural retina and in the developing lens vesicle of 12-day embryos (E12). Expression became restricted to the presumptive retinal ganglion cell layer and was absent from adult retinas. Wagner et al. (2002) developed Wt1-null mice in a strain that allows embryo survival; at E12, these embryos showed markedly thinner neural retinas and significantly fewer cells, and at E18, their eyes were notably reduced in size and ganglion cells were lost by apoptosis. Wagner et al. (2002) found that Wt1 specifically activates the expression of Pou4f2 (113725) and not that of other POU-domain members. Pou4f2 immunoreactivity was detected in the developing ganglion cell layer of normal E18 mice, but not in the retina of Wt1-null mice. Wagner et al. (2002) verified direct and specific activation of Pou4f2 by Wt1 in transfection studies. Expression of the -KTS, but not the +KTS, isoform of Wt1 in human embryonic kidney cells caused an 8-fold increase in Pou4f2 mRNA levels. </p><p>Using transgenic mice, Wilhelm and Englert (2002) showed that Wt1(-KTS) binds to 4 promoter sequences of the Sf1 gene (184757) and that Wt1(-KTS) and Lhx9 (606066) have an additive effect in activating the Sf1 promoter. Wt1 was also shown to regulate Dax1 (300200) activity in vivo. Gonad development and Dax1 and Sf1 expression were absent in Wt1 mutant mouse embryos. Thus, Wt1 regulates multiple genes involved in urogenital development and may act as a repressor or an activator. </p><p>By combining Wt1-knockout and inducible yeast artificial chromosome transgenic mouse models, Guo et al. (2002) demonstrated that reduced expression levels of WT1 resulted in either crescentic glomerulonephritis or mesangial sclerosis, depending on the gene dosage. The 2 podocyte-specific genes, nephrin (602716) and podocalyxin (see 602632), were downregulated in mice with decreased levels of Wt1, suggesting that these 2 genes may act downstream of Wt1. The authors hypothesized that reduced levels of Wt1 may be responsible for the pathogenesis of 2 distinct renal diseases, and may explain the increased occurrence of glomerulosclerosis in patients with WAGR syndrome. </p><p>Patek et al. (1999) reported that heterozygosity for the Wt1(tmT396) mutation induced Denys-Drash syndrome in heterozygous and chimeric mice. Patek et al. (2003) further showed that Wt1 mutant cells colonized glomeruli efficiently, including podocytes, but some sclerotic glomeruli contained no detectable Wt1 mutant cells. The development of glomerulosclerosis was preceded by widespread loss of Zo1 (601009) signal in podocytes, increased intrarenal renin (179820) expression, and de novo podocyte TGF-beta-1 (190180) expression, but not podocyte Pax2 expression or loss of Wt1, synaptopodin (608155), alpha-actinin-4 (604638), or nephrin expression. However, podocytes in partially sclerotic glomeruli that still expressed WT1 at high levels showed reduced vimentin (193060) expression, cell cycle reentry, and reexpressed desmin (125660), cytokeratin (139350), and Pax2. The authors suggested that: (i) glomerulosclerosis may not be due to loss of WT1 expression by podocytes; (ii) podocyte PAX2 expression may reflect reexpression rather than persistent expression, and may be the consequence of glomerulosclerosis; (iii) glomerulosclerosis may be mediated systemically and the mechanism may involve activation of the renin-angiotensin system; and (iv) podocytes may undergo typical maturational changes but subsequently dedifferentiate and revert to an immature phenotype during disease progression. </p><p>Gao et al. (2006) created a mouse strain carrying a Wt1 conditional knockout allele that ablated Wt1 function specifically in Sertoli cells by embryonic day 14.5, several days after testis determination. Wt1 knockout disrupted development of seminiferous tubules, and there was progressive loss of Sertoli cells and germ cells, resulting in severe hypoplasia. The expression of Sox9 (608160) in mutant Sertoli cells was turned off at embryonic day 14.5 after Wt1 ablation. Gao et al. (2006) concluded that Wt1 is essential at multiple steps in testicular development. </p><p>Defects in WT1 are thought to modify the crosstalk between podocytes and other glomerular cells and ultimately lead to glomerular sclerosis, as observed in diffuse mesangial sclerosis (DMS). To identify podocyte WT1 targets, Ratelade et al. (2010) generated a novel DMS mouse line, performed gene expression profiling in isolated glomeruli, and identified candidates that may modify podocyte differentiation and growth factor signaling in glomeruli. Sciellin (SCEL; 604112) and Sulf1 (610012), which encodes a 6-O-endosulfatase, were expressed in wildtype podocytes and strongly downregulated in mutants. Coexpression of Wt1, Scel, and Sulf1 was found in a mesonephric cell line, and siRNA-mediated knockdown of WT1 decreased Scel and Sulf1 mRNAs and proteins. ChIP assay showed that Scel and Sulf1 were direct WT1 targets. Cyp26a1 (602239), encoding an enzyme involved in the degradation of retinoic acid, was upregulated in mutant podocytes. Ratelade et al. (2010) noted that CYP26A1 may play a role in the development of glomerular lesions but does not seem to be regulated by WT1. </p><p>Martinez-Estrada et al. (2010) found that epicardial-specific knockout of Wt1 in mice led to embryonic lethality due to cardiovascular failure. Mutant hearts showed reduced numbers of mesenchymal progenitor cells and their derivatives. This effect was due to derepression of the epithelial phenotype in epicardial cells and during embryonic stem cell differentiation. Mutant hearts showed reduced expression of the epithelial-mesenchymal transition regulator Snai1 (604238) and upregulation of the epithelial marker Cdh1 (192090). Some mesodermal lineages did not form in Wt1-null embryoid bodies, but this effect was rescued by expression of Snai1. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>27 Selected Examples):</strong>
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<strong>.0001 WILMS TUMOR 1</strong>
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WT1, 17-BP DEL, EX4
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SNP: rs587776573,
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ClinVar: RCV000003653
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<p>In a patient with bilateral Wilms tumor (194070), hypospadias, and undescended left testis, Pelletier et al. (1991) identified heterozygosity for a 17-bp deletion in exon 4 of the WT1 gene. The deletion occurred between 2 copies of the pentanucleotide sequence TGACA. The mutation appeared to be the consequence of either polymerase skipping during DNA replication or an unequal crossover event. </p>
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<span class="mim-font">
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<strong>.0002 WILMS TUMOR 1</strong>
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WT1, 1-BP DEL, G, EX6
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SNP: rs587776574,
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ClinVar: RCV000003654
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<p>Pelletier et al. (1991) reported a father and son with Wilms tumor (194070) who were found by single-strand conformation polymorphism (SCCP) analysis to have a single nucleotide deletion, a guanosine, in exon 6 of the WT1 gene, predicted to cause a frameshift and early termination of translation. The son was born with hypospadias and bilateral cryptorchidism and developed Wilms tumor at age 3 years. The father had been treated successfully for Wilms tumor. This was probably the first documentation of a transmitted WT1 mutation in familial Wilms tumor. </p>
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<strong>.0003 DENYS-DRASH SYNDROME</strong>
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MEACHAM SYNDROME, INCLUDED<br />
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NEPHROTIC SYNDROME TYPE 4, INCLUDED
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WT1, ARG394TRP
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SNP: rs121907900,
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gnomAD: rs121907900,
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ClinVar: RCV000003656, RCV000003657, RCV000003658, RCV000467701, RCV000484426, RCV001003819, RCV001290016, RCV002293973, RCV004739285, RCV005003322
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<p>In 7 unrelated patients with Denys-Drash syndrome (194080), Pelletier et al. (1991) identified a 1180C-T transition in exon 9 of the WT1 gene, resulting in an arg394-to-trp (R394W) substitution in zinc finger-3. Most had the classic triad of pseudohermaphroditism, Wilms tumor, and nephrotic syndrome. Wilms tumors from 3 individuals and 1 juvenile granulosa cell tumor demonstrated reduction to homozygosity for the mutated WT1 allele. In vitro functional expression studies showed that the mutant WT1 protein was unable to bind DNA sequences. The findings indicated a dominant-negative mechanism. </p><p>Bruening et al. (1992) identified the R394W mutation in a 46,XY individual with Drash syndrome reported by McCoy et al. (1983). The patient had ambiguous genitalia, rudimentary uterus, fimbriated fallopian tubes, and streak gonads. </p><p>Baird et al. (1992) found the R394W mutation in 3 of 8 patients with Denys-Drash syndrome. </p><p>Coppes et al. (1992) identified the R394W mutation in 2 of 3 patients with Denys-Drash syndrome. Unlike patients in previous reports, 1 of the patients inherited the mutant allele from his phenotypically unaffected father. The father had no abnormalities and, in particular, he had bilaterally descended testes of normal volume and a normal penis without hypospadias. He had donated his kidney for transplantation to his son with Denys-Drash syndrome. Little et al. (1993) reported the same mutation in Denys-Drash syndrome. </p><p>Schumacher et al. (1998) identified the R394W mutation in 4 unrelated patients with early-onset nephrotic syndrome. Two of the patients had complete Denys-Drash syndrome, 1 had incomplete Denys-Drash syndrome without urogenital anomalies but with Wilms tumor, and the fourth had nephrotic syndrome type 4 (NPHS4; 256370) without urogenital anomalies or Wilms tumor. Renal biopsies showed diffuse mesangial sclerosis in 3 patients and focal segmental glomerulosclerosis in 1. </p><p>Suri et al. (2007) identified a hemizygous R394W mutation in a patient with Meacham syndrome (608978). This 46,XY infant was born with ambiguous external genitalia, a single testis, and congenital diaphragmatic hernia. He showed unusually long survival, with death at age 3 years. </p>
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<span class="mim-font">
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<strong>.0004 DENYS-DRASH SYNDROME</strong>
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WT1, ARG366HIS
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SNP: rs121907901,
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ClinVar: RCV000003659, RCV000484493, RCV001250546, RCV001851622, RCV002243617, RCV002496247, RCV003147274
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<p>In a patient with Denys-Drash syndrome (194080), Pelletier et al. (1991) identified a G-to-A transition in exon 8 of the WT1 gene, resulting in an arg366-to-his (R366H) substitution in the second zinc finger domain. The same mutation was observed by Baird et al. (1992) in a patient with Denys-Drash syndrome. </p><p>Antonius et al. (2008) reported another patient with Denys-Drash syndrome and a heterozygous R366H substitution. The authors stated that 10 DDS patients had been reported with this specific mutation, and noted that their patient was the third reported patient with DDS and congenital diaphragmatic hernia associated with the R366H mutation. A mutation in this same codon (R366C; 607102.0026) has been identified in a patient with Meacham syndrome (608978) and diaphragmatic hernia. </p>
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<span class="mim-font">
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<strong>.0005 DENYS-DRASH SYNDROME</strong>
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</span>
|
|
</h4>
|
|
</div>
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|
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|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
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|
WT1, ASP396GLY
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|
<br />
|
|
|
|
SNP: rs121907902,
|
|
|
|
|
|
|
|
ClinVar: RCV000003660, RCV001376854
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Denys-Drash syndrome (194080), Pelletier et al. (1991) identified a mutation in the WT1 gene, resulting in an asp396-to-gly (D396G) substitution. </p>
|
|
</span>
|
|
</div>
|
|
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|
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<div>
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|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 DENYS-DRASH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEPHROTIC SYNDROME, TYPE 4, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
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|
|
|
WT1, ASP396ASN
|
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|
|
|
<br />
|
|
|
|
SNP: rs28941778,
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|
|
|
|
|
gnomAD: rs28941778,
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|
|
|
|
|
ClinVar: RCV000003661, RCV000003662, RCV003322746
|
|
|
|
|
|
</span>
|
|
</div>
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|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Denys-Drash syndrome (194080), Pelletier et al. (1991) identified a 1186G-A transition in the WT1 gene, resulting in an asp396-to-asn (D396N) substitution. </p><p>Baird et al. (1992) and Little et al. (1993) identified the D396N mutation in patients with Denys-Drash syndrome. Wilms tumor tissue derived from the patient reported by Little et al. (1993) showed complete loss of WT1. </p><p>In a 46,XX female with normal external genitalia and nephrotic syndrome (NPHS4; 256370), Jeanpierre et al. (1998) identified heterozygosity for the 1186G-A transition in exon 9 of the WT1 gene, leading to the D396N substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 DENYS-DRASH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, ARG394PRO
|
|
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|
<br />
|
|
|
|
SNP: rs121907903,
|
|
|
|
|
|
|
|
ClinVar: RCV000003663, RCV004547456
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Denys-Drash syndrome (194080), Bruening et al. (1992) identified a G-to-C transversion in exon 9 of the WT1 gene, resulting in an arg394-to-pro (R394P) substitution. Although genomic DNA from this patient was available only from a Wilms tumor specimen embedded in paraffin, Bruening et al. (1992) suspected that the patient was germline hemizygous for this mutation. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 DENYS-DRASH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, CYS330TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907904,
|
|
|
|
|
|
|
|
ClinVar: RCV000003664
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Denys-Drash syndrome (194080), Bruening et al. (1992) identified a point mutation in exon 7 of the WT1 gene, resulting in a cys330-to-tyr (C330Y) substitution in zinc finger-1. The patient had a 46,XX karyotype and mild clitoromegaly. Nephropathy was present and both kidneys showed extensive intralobar persistent renal blastema but no overt Wilms tumor. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0009 DENYS-DRASH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, IVS9DS, G-A, +5
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776576,
|
|
|
|
|
|
|
|
ClinVar: RCV000003665, RCV000030876, RCV000208283, RCV000589623, RCV000705142, RCV001288155, RCV001290018, RCV004547457, RCV005003323
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Denys-Drash syndrome (194080), with renal failure due to glomerular sclerosis associated with female external genitalia and a 46,XY karyotype, Bruening et al. (1992) identified a G-to-A transition at position +5 of the splice donor site within intron 9. It appeared that the mutation affected the alternative splice site selection at exon 9. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0010 WILMS TUMOR 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, ARG390TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907909,
|
|
|
|
|
|
|
|
ClinVar: RCV000003666, RCV000030877, RCV000471023, RCV000521800, RCV002293974, RCV005003324
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In an infant who presented with simultaneous bilateral Wilms tumor (194070) at the age of 11 months, Little et al. (1992) found a point mutation at a CpG dinucleotide in zinc finger-3, changing a C to a T and resulting in an arginine becoming a stop codon. The mutation was detected constitutionally in both tumors of the patient. It was present in heterozygous state in 1 tumor and in somatic cells, whereas due to hemizygosity, the other tumor carried only the mutant allele. Neither parent carried the mutation. </p><p>In a patient with Wilms tumor, Schumacher et al. (1997) identified a 1546C-T transition in the WT1 gene, resulting in an arg390-to-ter (R390X) substitution. They stated that this mutation had previously been identified by Little et al. (1992). </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0011 REMOVED FROM DATABASE</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0012 DENYS-DRASH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEPHROTIC SYNDROME, TYPE 4, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, HIS377TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs28942089,
|
|
|
|
|
|
|
|
ClinVar: RCV000003667, RCV000003668, RCV002512715
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Denys-Drash syndrome (194080), Coppes et al. (1992) found a 1129C-T transition in exon 8 of the WT1 gene, resulting in a his377-to-tyr (H377Y) substitution. </p><p>In a 46,XX female with normal external genitalia and normal puberty associated with nephrotic syndrome (NPHS4; 256370), Jeanpierre et al. (1998) identified heterozygosity for the H377Y mutation in the WT1 gene. The first symptoms occurred at the age of 6 months; end-stage renal failure was present by age 3 years and 10 months. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0013 DENYS-DRASH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, CYS360GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907905,
|
|
|
|
|
|
|
|
ClinVar: RCV000003669, RCV002512716
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with unilateral Wilms tumor and nephropathy consistent with Denys-Drash syndrome (194080), Little et al. (1993) identified a T-to-G transversion in the WT1 gene, resulting in a cys360-to-gly (C360G) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0014 DENYS-DRASH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
WILMS TUMOR 1, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, ARG362TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907906,
|
|
|
|
|
|
|
|
ClinVar: RCV000003670, RCV000003671, RCV000685465, RCV000762840, RCV001565696, RCV004795369
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 46,XY patient with Denys-Drash syndrome (194080), Little et al. (1993) identified a C-to-T transition in the WT1 gene, resulting in an arg362-to-ter (R362X) substitution. It was present in heterozygous state in the germline and homozygous state in the tumors. Since the mutation affected zinc finger-2, resulting in a truncated protein interfering with DNA binding, Little et al. (1993) suggested that missense mutations in this region operate by a dominant-negative mechanism. </p><p>Kaplinsky et al. (1996) identified a nonsense mutation in the WT1 gene in the Wilms tumor (194070) of 3 sisters who had the same father but 2 different mothers: a C-to-T transition at nucleotide 1084 (relative to the A of the ATG initiation codon) resulted in an arg362-to-ter substitution within zinc finger-2. The mutation was predicted to result in the production of a truncated WT1 polypeptide unable to bind DNA. Two other sibs, both male, were unaffected. Two of the sisters had unilateral Wilms tumor, 1 had bilateral disease. The father, although a carrier, had never developed WT. Kaplinsky et al. (1996) commented that this may be due to incomplete penetrance, which is not gender related. Alternatively, the father could be mosaic for the WT1 mutation, such that mutant cells had not substantially contributed to development of the urogenital system. A third possibility is that genomic imprinting of the mutated WT1 allele is responsible for masking its expression in the male carrier. In the proband, analysis of DNA from a Wilms tumor revealed loss of heterozygosity with retention of 1 set of conformers present in the proband and the father. This pattern is classical for tumor suppressor gene analysis and suggested the unmasking of a recessive mutation by loss of the wildtype allele. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0015 DENYS-DRASH SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, HIS373GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907907,
|
|
|
|
|
|
gnomAD: rs121907907,
|
|
|
|
|
|
ClinVar: RCV000003672
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 46,XY patient with hypospadias and nephropathy consistent with Denys-Drash syndrome (194080), Little et al. (1993) identified a C-to-G transversion in the WT1 gene, resulting in a his373-to-gln (H373Q) substitution in zinc finger-2. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0016 MESOTHELIOMA, SOMATIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, SER273GLY
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121907908,
|
|
|
|
|
|
|
|
ClinVar: RCV000003673
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Park et al. (1993) showed that the WT1 gene, in addition to being expressed in tissues of the genitourinary system, is also expressed at high levels in many supportive structures of mesodermal origin in the mouse. Furthermore, they described a case of adult human mesothelioma (156240) that contained a homozygous A-to-G transition resulting in a serine to glycine substitution at codon 273 (S273G). Normal tissue from the patient showed no evidence of this mutation, indicating that it was absent from the germline and arose as a somatic mutation within the tumor. Mesothelioma is a tumor derived from the peritoneal lining. The particular tumor studied was of the rare multicystic type which is not metastatic and has been classified as a hamartoma or a developmental abnormality of borderline malignancy (Salazar et al., 1972). Unlike most mesotheliomas, multicystic tumors are not associated with a history of asbestos exposure. Park et al. (1993) screened 32 specimens of asbestos-related mesothelioma and found no WT1 mutations. The ser273-to-gly mutation was the first reported outside the zinc finger domain that leads to an amino acid substitution rather than a termination codon. Codon 273 is highly conserved across species. Whereas wildtype WT1 represses transcription from the early growth response-1 (EGR1; 128990) promoter, following cotransfection into NIH 3T3 cells, Park et al. (1993) found that insertion of the ser273-to-gly mutation resulted in a WT1 protein that activated transcription from the EGR1 promoter. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-text-font">
|
|
<strong>.0017 MOVED TO 607102.0014</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0018 FRASIER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
NEPHROTIC SYNDROME, TYPE 4, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, IVS9DS, C-T, +4
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs587776577,
|
|
|
|
|
|
|
|
ClinVar: RCV000003674, RCV000003675, RCV000157584, RCV000489749, RCV001003818, RCV001216104, RCV001290017, RCV004547458, RCV005049315
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>Alternative splicing of WT1 generates 4 isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows the addition of 3 amino acids (lys-thr-ser, or KTS) between the third and fourth zinc fingers of the WT1 protein (Haber et al., 1991). In 3 unrelated patients with Frasier syndrome (136680), Barbaux et al. (1997) identified a mutation in the donor splice site in intron 9 of WT1, with the predicted loss of the so-called +KTS isoform. Examination of WT1 transcripts showed a diminution of the +KTS/-KTS isoform ratio in patients with Frasier syndrome. Two of 3 patients were found to carry a C-to-T transition at position +4 of intron 9 in 1 allele (IVSDS+4C-T). This nucleotide substitution was not detected in the DNA from either parent, indicating a de novo mutation. A third patient was found to have a mutation in intron 9 at position +6, substituting a thymidine for an adenine (IVS9DS+6A-T; 607102.0019). A screen of the SRY gene (480000) had failed to detect mutations in any of the 3 patients. </p><p>Klamt et al. (1998) reported 3 cases of Frasier syndrome and the IVS9DS+4C-T mutation. </p><p>Barbosa et al. (1999) stated that 18 patients with Frasier syndrome had been described, all with heterozygous point mutations affecting the donor splice site of intron 9 of WT1; none had presented with Wilms tumor. They described 2 patients with Frasier syndrome and the IVS9DS+4C-T mutation; one of these patients also had Wilms tumor. The mutation was detected in both peripheral blood and in tumor-derived DNA of the patient with Frasier syndrome and Wilms tumor. The congenital anomalies in these 2 patients were the same as in other cases of Frasier syndrome: female external genitalia, in spite of a 46,XY karyotype, and streak gonads. The nephroblastoma in the patient with Wilms tumor had been diagnosed at the age of 3 years. The possibility that the patient actually represented a case of Denys-Drash syndrome was rejected because of normal histology of the kidney removed at age 3; the late onset of proteinuria; the slow progression of nephropathy, once developed; and the presence of a complete female phenotype with dysgenetic gonads, typical of Frasier syndrome. Thus this is the only one of 20 patients carrying mutations within splice site 2 of exon 9 of the WT1 gene who developed Wilms tumor in association with the features of Frasier syndrome. </p><p>Melo et al. (2002) reported a 19-year-old male with Frasier syndrome who had the IVS9+4C-T mutation, which predicts a change in splice site utilization. He had an unusual phenotype. WT1 transcript analysis showed reversal of the normal positive/negative KTS isoform ratio, confirming the diagnosis of FS. The authors concluded that this patient had the external genitalia characteristic of Denys-Drash syndrome, suggesting that these 2 syndromes are not distinct diseases but may represent 2 ends of a spectrum of disorders caused by alterations in the WT1 gene. </p><p>In a 46,XX female with nephrotic syndrome (NPHS4; 256370), Jeanpierre et al. (1998) identified the IVS9+4C-T mutation in the WT1 gene. </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>.0019 FRASIER SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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WT1, IVS9DS, A-T, +6
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<br />
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SNP: rs587776575,
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ClinVar: RCV000003655
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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>See 607102.0018 and Barbaux et al. (1997). </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>.0020 FRASIER SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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WT1, IVS9DS, G-A, +5
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<br />
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ClinVar: RCV000003665, RCV000030876, RCV000208283, RCV000589623, RCV000705142, RCV001288155, RCV001290018, RCV004547457, RCV005003323
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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>Klamt et al. (1998) described 6 cases of an IVS9DS+5G-A mutation in the WT1 gene in patients with Frasier syndrome (136680). Merging of mutational data from 18 cases demonstrated a striking bias: 15 of the 18 cases showed either the +4C-T (607102.0018) or the +5G-A mutations. This mutation hotspot probably results from the potential to deaminate 5-methylcytosine at the +4/+5 CpG dinucleotide. Klamt et al. (1998) showed that disruption of alternative splicing at the exon 9 donor splice site prevents synthesis of the usually more abundant WT1(+KTS) isoform from the mutant allele. In contrast to Denys-Drash syndrome (194080), no mutant protein is produced. The splice mutation leads to an imbalance of WT1 isoforms in vivo, as detected by RT-PCR on streak gonadal tissue. Thus, WT1 isoforms must have different functions, and the pathology of Frasier syndrome suggests that gonadal development may be particularly sensitive to imbalance or relative underrepresentation of the WT1 +KTS isoform. (The +KTS isoform has 3 additional amino acids, lys-thr-ser, between the third and fourth zinc fingers of the WT1 protein (Haber et al., 1991).) </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-text-font">
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<strong>.0021 MOVED TO 607102.0012</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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<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>.0022 NEPHROTIC SYNDROME, TYPE 4</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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WT1, PHE383LEU
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<br />
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SNP: rs28941777,
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ClinVar: RCV000003677
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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 male patient with normal external genitalia and normal puberty associated with nephrotic syndrome (NPHS4; 256370), Jeanpierre et al. (1998) identified heterozygosity for an 1147T-C transition in exon 9, leading to an phe383-to-leu (F383L) amino acid substitution in the WT1 protein. </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-text-font">
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<strong>.0023 MOVED TO 607102.0006</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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<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>.0024 FRASIER SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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WT1, ARG390TER
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<br />
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SNP: rs121907909,
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ClinVar: RCV000003666, RCV000030877, RCV000471023, RCV000521800, RCV002293974, RCV005003324
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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>Kohsaka et al. (1999) described 2 patients with Frasier syndrome (136680) who had novel mutations in exon 9 of the WT1 gene; 1 patient had a nonsense mutation (arg390 to ter) and the other had a missense mutation (phe392 to leu; 607102.0025). There was no alteration in the ratio of +/- KTS splice isoforms in these 2 patients. The patient with the R390X mutation, which was caused by an 1168C-T transition, was a 25-year-old 46,XY male who at birth was diagnosed with pseudohermaphroditism with retentio testis, penoscrotal hypospadias, and cryptorchidism. Proteinuria was detected on school mass screening at the age of 8, but no other abnormalities were detected in renal function. At the age of 16, renal biopsy showed global glomerulosclerosis. Renal insufficiency requiring hemodialysis developed at the age of 19. At bilateral surgical gonadectomy, a premature uterus and dysgenic gonad were noted. Gonadoblastoma in situ was observed. Many translucent cells were observed among increased Leydig cells and spermatogenesis. </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>.0025 FRASIER SYNDROME</strong>
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</span>
|
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
|
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WT1, PHE392LEU
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<br />
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SNP: rs28941779,
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|
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gnomAD: rs28941779,
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ClinVar: RCV000003679
|
|
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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>The patient with Frasier syndrome (136680) reported by Kohsaka et al. (1999) who was found to have a phe392-to-leu mutation, caused by an 1174T-C transition in exon 9 of the WT1 gene, had no changes in the KTS splice isoforms. The patient was a 19-year-old male with a 46,XY karyotype. Hypospadias and cryptorchidism were detected at birth. Proteinuria was noted at 5 years of age at which time renal biopsy showed minimal change. At the age of 13, mild hypertension developed and renal biopsy showed a progressive stage of glomerulosclerosis. Hemodialysis was started at age 13. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>.0026 MEACHAM SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
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<div>
|
|
<span class="mim-text-font">
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|
WT1, ARG366CYS
|
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<br />
|
|
|
|
SNP: rs121907910,
|
|
|
|
|
|
|
|
ClinVar: RCV000003680, RCV001288153
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with Meacham syndrome (608978), Suri et al. (2007) identified a hemizygous mutation in exon 8 of the WT1 gene, resulting in an arg366-to-cys (R366C) substitution. This 46,XY infant had female external genitalia, septate uterus, double vagina, 2 ovaries, left diaphragmatic hernia, and left pulmonary hypoplasia. Death occurred at age 1 day. The unrelated parents had had 2 prior miscarriages. A mutation in this same codon (R366H; 607102.0004) has been identified in patients with Denys-Drash syndrome (194080) and diaphragmatic hernia. </p>
|
|
</span>
|
|
</div>
|
|
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<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0027 WILMS TUMOR 1</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
WT1, TYR109TER
|
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|
|
|
<br />
|
|
|
|
SNP: rs121907911,
|
|
|
|
|
|
|
|
ClinVar: RCV000003681
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 34-year-old woman who had Wilms tumor (194070) removed at age 16 months and had decreased fertility in adulthood, Regev et al. (2008) identified heterozygosity for a 327C-A transversion in exon 1 of the WT1 gene, resulting in a tyr109-to-ter (Y109X) substitution. Her son, who had genitourinary abnormalities, including glanular hypospadias with chordee and bilateral undescended testes, gonadal dysgenesis with gonadoblastoma foci, and intraabdominal Mullerian derivatives, was also heterozygous for the Y109X mutation. He also had ventricular septal defect by echocardiography; no Wilms tumor was detected up to 6 years of age. </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>
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<h4>
|
|
<span class="mim-font">
|
|
<strong>See Also:</strong>
|
|
</span>
|
|
</h4>
|
|
<span class="mim-text-font">
|
|
Denys et al. (1967); Frasier et al. (1964); Haning et al. (1985);
|
|
Kinberg et al. (1987)
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
</div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
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<div>
|
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<p />
|
|
</div>
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<div>
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<ol>
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<li>
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<p class="mim-text-font">
|
|
Alexander, T. B., Gu, Z., Iacobucci, I., Dickerson, K., Choi, J. K., Xu, B., Payne-Turner, D., Yoshihara, H., Loh, M. L., Horan, J., Buldini, B., Basso, G., and 50 others.
|
|
<strong>The genetic basis and cell of origin of mixed phenotype acute leukaemia.</strong>
|
|
Nature 562: 373-379, 2018.
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[PubMed: 30209392]
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[Full Text: https://doi.org/10.1038/s41586-018-0436-0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Antonius, T., van Bon, B., Eggink, A., van der Burgt, I., Noordam, K., van Heijst, A.
|
|
<strong>Denys-Drash syndrome and congenital diaphragmatic hernia: another case with the 1097G-A (arg366his) mutation.</strong>
|
|
Am. J. Med. Genet. 146A: 496-499, 2008.
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[PubMed: 18203154]
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[Full Text: https://doi.org/10.1002/ajmg.a.32168]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Baird, P. N., Santos, A., Groves, N., Jadresic, L., Cowell, J. K.
|
|
<strong>Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome.</strong>
|
|
Hum. Molec. Genet. 1: 301-305, 1992.
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[PubMed: 1338906]
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[Full Text: https://doi.org/10.1093/hmg/1.5.301]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Barbaux, S., Niaudet, P., Gubler, M.-C., Grunfeld, J.-P., Jaubert, F., Kuttenn, F., Fekete, C. N., Souleyreau-Therville, N., Thibaud, E., Fellous, M., McElreavey, K.
|
|
<strong>Donor splice-site mutations in WT1 are responsible for Frasier syndrome.</strong>
|
|
Nature Genet. 17: 467-470, 1997.
|
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|
|
[PubMed: 9398852]
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[Full Text: https://doi.org/10.1038/ng1297-467]
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</p>
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</li>
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<li>
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|
<p class="mim-text-font">
|
|
Barbosa, A. S., Hadjiathanasiou, C. G., Theodoridis, C., Papathanasiou, A., Tar, A., Merksz, M., Gyorvari, B., Sultan, C., Dumas, R., Jaubert, F., Niaudet, P., Moreira-Filho, C. A., Cotinot, C., Fellous, M.
|
|
<strong>The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms' tumor.</strong>
|
|
Hum. Mutat. 13: 146-153, 1999.
|
|
|
|
|
|
[PubMed: 10094551]
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[Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)13:2<146::AID-HUMU7>3.0.CO;2-I]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Bruening, W., Bardeesy, N., Silverman, B. L., Cohn, R. A., Machin, G. A., Aronson, A. J., Housman, D., Pelletier, J.
|
|
<strong>Germline intronic and exonic mutations in the Wilms' tumour gene (WT1) affecting urogenital development.</strong>
|
|
Nature Genet. 1: 144-148, 1992.
|
|
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|
|
[PubMed: 1302008]
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|
[Full Text: https://doi.org/10.1038/ng0592-144]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Burwell, E. A., McCarty, G. P., Simpson, L. A., Thompson, K. A., Loeb, D. M.
|
|
<strong>Isoforms of Wilms' tumor suppressor gene (WT1) have distinct effects on mammary epithelial cells.</strong>
|
|
Oncogene 26: 3423-3430, 2007.
|
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|
|
[PubMed: 17160023]
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[Full Text: https://doi.org/10.1038/sj.onc.1210127]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
|
Call, K. M., Glaser, T., Ito, C. Y., Buckler, A. J., Pelletier, J., Haber, D. A., Rose, E. A., Kral, A., Yeger, H., Lewis, W. H., Jones, C., Housman, D. E.
|
|
<strong>Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.</strong>
|
|
Cell 60: 509-520, 1990.
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|
[PubMed: 2154335]
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[Full Text: https://doi.org/10.1016/0092-8674(90)90601-a]
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</p>
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</li>
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Schumacher, V., Schneider, S., Figge, A., Wildhardt, G., Harms, D., Schmidt, D., Weirich, A., Ludwig, R., Royer-Pokora, B.
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<strong>Correlation of germ-line mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant history.</strong>
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[Full Text: https://doi.org/10.1073/pnas.94.8.3972]
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Smart, N., Bollini, S., Dube, K. N., Vieira, J. M., Zhou, B., Davidson, S., Yellon, D., Riegler, J., Price, A. N., Lythgoe, M. F., Pu, W. T., Riley, P. R.
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<strong>De novo cardiomyocytes from within the activated adult heart after injury.</strong>
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Nature 474: 640-644, 2011.
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Suri, M., Kelehan, P., O'Neill, D., Vadeyar, S., Grant, J., Ahmed, S. F., Tolmie, J., McCann, E., Lam, W., Smith, S., FitzPatrick, D., Hastie, N. D., Reardon, W.
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<strong>WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations.</strong>
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Am. J. Med. Genet. 143A: 2312-2320, 2007.
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Wagner, K. D., Wagner, N., Vidal, V. P. I., Schley, G., Wilhelm, D., Schedl, A., Englert, C., Scholz, H.
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<strong>The Wilms' tumor gene Wt1 is required for normal development of the retina.</strong>
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Wagner, K.-D., Wagner, N., Schley, G., Theres, H., Scholz, H.
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<strong>The Wilms' tumor suppressor Wt1 encodes a transcriptional activator of the class IV POU-domain factor Pou4f2 (Brn-3b).</strong>
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Gene 305: 217-223, 2003.
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Wilhelm, D., Englert, C.
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<strong>The Wilms tumor suppressor WT1 regulates early gonadal development by activation of Sf1.</strong>
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Genes Dev. 16: 1839-1851, 2002.
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Zhou, B., Ma, Q., Rajagopal, S., Wu, S. M., Domian, I., Rivera-Feliciano, J., Jiang, D., von Gise, A., Ikeda, S., Chien, K. R., Pu, W. T.
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<strong>Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart.</strong>
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Ada Hamosh - updated : 02/28/2019<br>Alan F. Scott - updated : 1/13/2016<br>Ada Hamosh - updated : 1/23/2013<br>Patricia A. Hartz - updated : 4/26/2012<br>George E. Tiller - updated : 12/2/2011<br>Ada Hamosh - updated : 8/24/2011<br>George E. Tiller - updated : 11/12/2010<br>Patricia A. Hartz - updated : 2/1/2010<br>Marla J. F. O'Neill - updated : 4/1/2009<br>Ada Hamosh - updated : 8/29/2008<br>Patricia A. Hartz - updated : 5/1/2008<br>Cassandra L. Kniffin - updated : 2/26/2008<br>George E. Tiller - updated : 12/4/2006<br>Patricia A. Hartz - updated : 9/15/2006<br>George E. Tiller - updated : 9/9/2005<br>Victor A. McKusick - updated : 11/24/2004<br>Natalie E. Krasikov - updated : 10/1/2004<br>Patricia A. Hartz - updated : 6/19/2003<br>John A. Phillips, III - updated : 2/4/2003<br>George E. Tiller - updated : 10/10/2002<br>Cassandra L. Kniffin - updated : 9/10/2002
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Cassandra L. Kniffin : 7/9/2002
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